Annals of Oncology 18 (Supplement 11): xi37–xi55, 2007
session C: early and
advanced breast cancer
C1 BREAST CANCER TRANSITION FROM AN EPITHELIAL TO A
MESENCHYMAL PHENOTYPE: THE ROLE OF PERIOSTIN
Fabio Puglisi, Enrico Pegolo, Cinzia Puppin, Claudia Andreetta, Stefania Russo,
Gaetano Pascoletti, Alessandro Minisini, Mauro Mansutti, Barbara Alessi, Giovanni
Cardellino, Andrea Piga, Gianpiero Fasola, Carla Di loreto
Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine
Background: Mesenchyme-specific genes are highly expressed by various types of
human cancers. Recent lines of evidence suggest that periostin, a myoepithelial/basal
gene, may play a role in the biology of breast cancer. Periostin is involved in metastatic
process by taking part in mechanisms of adhesion and migration of epithelial cells.
Furthermore, periostin seems to have a role in tumor angiogenesis.
Aim: We aimed at investigating the immunohistochemical expression of periostin in
breast cancer and its correlation with established biological and prognostic factors.
Methods: We performed immunohistochemical analysis of periostin in a consecutive
series of 206 tumor samples from 200 patients with early breast carcinoma. The
intensity of immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak,
moderate and strong staining, respectively. Therefore, for statistical analysis, the
periostin expression level for each case was putatively defined as positive if the
predominant intensity was ‡1. We also analyzed immunohistochemical expression
of estrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A,
VEGFR-1 and VEGFR-2.
Results: Periostin was found to be highly expressed by carcinoma cells, whereas it was
absent in normal breast epithelium. The pattern of expression was mainly cytoplasmic,
although in some cases (12%) a nuclear reactivity was observed. A cytoplasmic
expression was found in 108 out of 189 (57%) evaluable cases. Interestingly,
a significant correlation was found between periostin expression and VEGF-A and
VEGFR-1 (Spearman’s rank test rho =0.36, p <0.0001 and rho=0.25, p=0.0005,
respectively). Notably, when periostin expression was examined on the nuclear
compartment, a significant correlation was observed also with VEGFR-2 (rho =0.43,
p < 0.0001).
Conclusion: These results strengthen the hypothesis of a relationship between periostin
and vascular endothelial growth factor system. The role of periostin in angiogenesis
and in other relevant molecular pathways in breast carcinoma deserves to be further
investigated.
C2 CROSS-COMPARISON OF AN ELECTRONIC SYMPTOM
ASSESSMENT RECORDER (LESAR) AND CONVENTIONAL QUALITY
OF LIFE INSTRUMENT USED IN PATIENTS WITH EARLY BREAST
CANCER
Paolo Marchetti and Federica Mazzuca
Medical Oncology, Sant‘Andrea Hospital & IDI-IRCCS, Rome; University of
L’Aquila
Background: Quality of life (QoL) is considered one of the most relevant endpoints
in the palliative setting. Even if QoL data have been repeatedly considered of
paramount importance in breast cancer treatment, very few breast cancer trials
assess QoL. Reduced or non-compliance on behalf of patients who are worse off or
those that worsen during treatment renders these instruments unpractical
considering the amount of information lost, especially in the most clinically relevant
cases. Thus, longitudinal studies aren’t relevant due to distortion of patient
selection. Considering the difficulty in achieving patient’s full compliance when
filling out paper questionnaires and the fact that physicians are less able to assess
QoL than patients themselves, the relevance of an electronic device to record these
data is evident.
Methods: From February 2005 to June 2006, twenty-six consecutive postmenopausal
patients (median age yrs 62, Range 52-77) affected by early breast cancer and treated
with anastrozole were included into a cross-comparison study between two QoL
evaluation methods: the EORTC QLQ-C30 and QLQ-BR23 questionnaires and the
electronic symptom assessment recorder (LESAR - conceived and created by Prof.
Paolo Marchetti). QoL of each patient was assessed once a week for 3 consecutive
weeks.
Results: Correlation and kappa analysis were used to compare the answers returned on
the EORTC questionnaires to those recorded with LESAR. The mean correlation
coefficient for the first measurement was 0.90 and the kappa coefficient was 0.75; for
the subsequent measurements the correlation coefficient was 0.93 and the kappa
coefficient 0.89. A correlation was also demonstrated over time.
Conclusions: Both the QoL evaluation methods (EORTC questionnaires and LESAR)
gave similar results in postmenopausal patients with early breast cancer treated with
anastrozole, but LESAR was better accepted by these women and recorded data are
more readily accessible and in an electronic format.
ª 2007 European Society for Medical Oncology
doi:10.1093/annonc/mdm425
C3 TOTAL ESTROGEN BLOCKADE DURING ADJUVANT
CHEMOTHERAPY IN PRE-MENOPAUSAL BREAST CANCER
Recchia F, Candeloro G, Necozione S, Rea S.
Oncologia, Ospedale Civile, Avezzano, Epidemiologia Clinica, Universita‘ degli
Studi, L’Aquila, Fondazione Carlo Ferri per Lo Studio dei Tumori, Monterotondo,
Roma, Italy
Background: Objective of the present study was the evaluation of the clinical
outcome of 130 consecutive, high risks, pre-menopausal, early breast cancer
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
patients, treated with an LH-RH analogue as ovarian protection, during adjuvant
chemotherapy.
Patients and methods: Following surgical treatment, patients received an LH-RH
analogue for 2 years and an adjuvant chemotherapy, which was tailored to the
individual biologic features. Characteristics: median age, 43 years (range 27-50),
78 estrogen receptor positive (ER+) and 52 ER negative (ER-), 83 stage II disease,
and 47 stage III. All patients had their serum estradiol suppressed to values <40 pg/ml.
Adjuvant chemotherapy included the following drugs in various combination:
methotrexate, cyclophosphamide, 5-fluorouracil, taxanes, anthracyclines, platinum
analogues and high-dose chemotherapy with autologous peripheral blood
progenitor cell transplantation in 11 patients with more than 10 positive axillary
nodes. 104 patients were irradiated. An aromatase inhibitor was given to ER-positive
patients, after chemotherapy, during the administration of the LH-RH analogue up
to 2 years.
Results: After a median follow-up of 79 months, amenorrhea was observed in no
patient below 40 years and in 49% of patients over 40 years. Four pregnancies were
observed: 3 at term and 1 voluntary abortion. Projected recurrence-free survival rates
at 5 and 10 years were 83% and 76%, while projected overall survival rates at 5 and
10 years were 94% and 85%, respectively.
Conclusions: These data show that in pre-menopausal patients with high risk early
breast cancer, the addition of a LH-RH analogue to adjuvant therapy and total estrogen
blockade in ER+ patients, is well tolerated, protects long-term ovarian function and
seems to improve the expected clinical outcome.
C4 IS THERE ANY SURVIVAL DIFFERENCE BETWEEN PATIENTS
session C
ACHIEVING MICROSCOPIC RESIDUAL (pTm) OR NO INVASIVE
RESIDUAL (pT0) DISEASE IN THE BREAST FOLLOWING
NEOADJUVANT CHEMOTHERAPY? UPDATED ANALYSIS OF A
MULTICENTER STUDY
MT Ionta1, ME Cazzaniga3, S Barni 3, F Atzori1, M Cremonesi3, A Trogu1, B Frau1,
M Murgia1, L Minerba2 and B Massidda1
Oncologia Medica II, Policlinico Universitario, Cagliari1, Dipartimento di Salute
Pubblica e Biostatistica, Policlinico Universitario, Cagliari2 and Oncologia
Medica, Az Osp Treviglio-Caravaggio, Treviglio3, ITALY
Background: Pathological complete response (pCR) in the breast and/or in axilla after
primary chemotherapy is strongly correlated to a better outcome and is now usually
considered to be a surrogate for survival.However, the term pCR has not been applied
in a standardized manner, making interpretation of the results difficult. Differently
from any other classification, Sataloff defines as pCR the total (pT0) or near total
(minimal microscopic residual as pTm) disappearance of invasive tumour in breast,
assuming that there is no difference in terms of DFS and OS between the two groups
(J Am Coll Surg 1995). Nevertheless, till now, no data are available in confirming this
hypothesis. Aim of the present study was to investigate whether pT0 pts have the same
prognosis of pTm, in terms of DFS and OS.
Materials and Methods: We analysed 45 out of 308 pts with initial clinical T2-3
(18 pts,40%) and T4 (27 pts,60%) BC, who achieved pCR, according to Sataloff’s
classification (pT0+ pTm), following different kinds of neoadjuvant
chemotherapy,between 1989 and 2006. Median age was 47 years (29-68), ER-negative
64% (29 pts), PR-negative 78% (35 pts). All pts received anthracycline-based
neoadjuvant chemotherapy, even standard (47%, q21) or intensified (53%, q14).
Median number of administered cycles was 5 (2-6).
Results: Twenty-seven pts achieved clinical CR (60 %), 18 PR (40%), 25 pT0 (55,5%)
and 20 pTm (44,5%),30 pN0 (67%) and 15 pN+ (33%). After a median follow up of
91 months (1-205), no difference has been observed between pT0 and pTm pts in terms
of DFS (80% vs 80%, p=0.99) or OS (84% vs 85%, p=0.90).
Conclusions: Even if small number of pts and limited number of events in each group
limit firm conclusion, our results seem to demonstrate that there is no difference
between pT0 and pTm pts, regardeless of pN status, in terms of both DFS and OS,
confirming Sataloff’s hypothesis.
session C Annals of Oncology

C5 MEDICAL ADJUVANT TREATMENT OF ELDERLY BREAST response, lends support to a paramount role of NK cells in the mechanism of action of
CANCER PATIENTS: A RETROSPECTIVE OUTCOME STUDY this drug.

Cataldo S, Bonetti F, Indelli M, Urbini B, Carandina I, Pedriali M*, and Lelli G

Clinical Oncology Unit and * Pathology Unit, Azienda Ospedaliero-Universitaria,
Ferrara, Italy C7 COST EFFECTIVENESS OF PEGFILGRASTIM vs FILGRASTIM
FOR FEBRILE NEUTROPENIA(FN) PREVENTION IN BREAST CANCER
Background: There are not explicit guidelines to standardize the treatment of the PATIENTS
different subgroups of elderly (> 65 years old) breast cancer patients.
Danova M1, Rosti G2, Dubois RW3, Chiroli S4
Materials and methods: This retrospective study included elderly patients undergoing
1Medical Oncology, IRCCS Foundation S.Matteo Pavia, Italy, 2Department of
adjuvant therapy at our institution between Jan.1999 and Dec.2005.
Oncology and Hematology, Ravenna 3Cerner LifeSciences, Beverly Hills, CA,
Results: 308 patients were evaluated, 196 from the young old (YO= 65-74 years old) USA 4Amgen, SpA Milan Italy
group, 112 from the old-old + oldest-old (OO= ‡75 years) group. The OO
group patients were characterized by bigger size tumors, less aggressive histologies,
Background: FN is one of the major adverse events which can occur during
larger estrogen receptors expression (ER), less use of chemotherapy (CT) and more use
chemotherapy (CT) and is often responsible for severe adverse events. There has been
of endocrine therapy (OT). Disease free survival (DFS) correlates to the absence of
a great interest in the economics of G-CSFs over the past decade, and several economic
nodal involvement (median not reached vs. 76 months, p=0.0000), ER positivity

(median 104 vs. 54 months, p=0.0259), HER-2 hyperexpression (median not
reached vs. 89 months, p=0.0256), and the use of adjuvant radiotherapy (median
314 vs. 79 months, p=0.0014), that also correlates to overall survival (OS, median
314 vs. not reached, p= 0.0028). Comparing CT alone with OT and with CT+OT,
a significative DFS (median 54 vs. 161 vs. 314 months, p=0,0007 for CT vs. OT,
p=0,0083 for CT vs. CT+OT) and OS (median 54 vs. 384 vs. 314 months, p=0,0214
and 0,0017) gain rise up, while CT+OT vs. OT does not provide any significative
benefit (DFS : p=0,7598; OS: p=0,3517). Stratifying for age groups (YO vs OO),
median DFS was 314 vs. 79 months, p=0,1182; median OS was not reached vs. 89
months, p=0,0176.
Conclusions: A possible explanation of our results is that the apparent advantage of
adjuvant OT on CT in elderly patients is more influenced from the biological
characteristics of disease than from therapeutic choices. Further studies are necessary,
specially in the OO subgroup.
C6 NK FUNCTION AND CLINICAL TRASTUZUMAB ACTIVITY IN
METASTATIC BREAST CANCER PATIENTS
Beano A, dSignorino E, Polimeni MA, Mistrangelo M, Spadi R, Vandone AM,
Donadio dM, Matera, P. Lista, I. Facilissimo, R. Napolitano, L, Ciuffreda
UOA Oncologia Medica, Ospedale San Giovanni Battista, Torino. dLaboratorio
di Immunologia dei Tumori, Dipartimento di Medicina Interna, Università degli
studi di Torino
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
analyses have been published on this topic. The aim of this pharmacoeconomic study
was to evaluate the cost-effectiveness of pegfilgrastim vs filgrastim given as primary
prophylaxis (6- OR 11 days) in Italian BC patients (pts) receiving adjuvant
chemotherapy associated with ‡20% FN risk.
Methods: Pharmacoeconomic evaluation was based on an analytic decisional model by
means of a specific software TreeAge Pro 2006 (TreeAge Software, Inc), which takes
into account the possible consequences of FN, i.e. death and reduction/delay of CT
dose, according to literature available data. Further parameters for the model were:
costs of pegfilgrastim and filgrastim, hospitalization, percentage of RDI<85%, RR
<85% with pegfilgrastim vs filgrastim, long term mortality due to RDI<85%, impact of
age on RDI<85%.
Results: FN case-fatality was assumed to be 3.4% in the base case. At 6 days the RR of
FN, filgrastim vs pegfilgrastim was 2.5, and the absolute risk for filgrastim was 17.5%; at
11 days they were respectively 1.79 and 12.5%. Forty % of pts who experienced
a neutropenia event received <85% RDI vs. 9% of pts who do not. The percentage of
pts with RDI<85% at 6 days was 11.1 vs 14.2, and at 11 days 11.1 and 12.7 for
pegfilgrastim and filgrastim respectively, and these results support the long term
survival in the former group. At 6 days the cost-efficacy was =C 3,316 vs 3,524
respectively for pegfilgrastim and filgrastim and, at 11 days, =C 3,316 vs 5,045. Results
were quite insensitive for the age (45 vs 65 yrs), RDI related variables, cost of CT,
number of cycles (4 or 6) and discount rate (3-10%).
Conclusions: At 6 and 11 days pegfilgrastim is competitive with filgrastim use. Primary
prophylaxis with pegfilgrastim for Italian BC pts undergoing CT associated with ‡20%
risk of FN is cost-effective compared with filgrastim.

Background: Trastuzumab is a monoclonal antibody selectively directed against Her2

and approved for the treatment of Her2 overexpressing breast cancer patients. Its
proposed mechanisms of action include also a role in mediating antibody-dependent
cellular cytotoxicity (ADCC), through triggering of the FccRIII on natural killer (NK)
cells. This study addressed the correlation between overall NK function and clinical
trastuzumab activity.
Subjects and methods: Between March and September 2006 22 patients in treatment
with trastuzumab alone (8 mg/kg load and then 6 mg/kg every 3 weeks until disease
progression) as maintaining therapy after chemotherapy were analysed for clinical and
immunological responses. According to RECIST criteria, 14 patients obtained
a response to trastuzumab, while 8 patients had disease progression. Patient’s
peripheral blood mononuclear cells were tested for cytotoxic activity against a standard
NK target (the MHC class I-negative K562 cell line) and against trastuzumab-coated
MCF-7 (Her2-negative) and SKBR-3 (Her2- positive) human cell lines in a 4-h
51
Cr-release cytotoxicity assay in the presence of grading concentrations of effector
cells.
Results: NK activity was significantly (p<0.05) higher in responder compared to non
responder patients at all the four effector:target (50:1 to 6:1) ratios tested. NK activity
of non responder patients was significantly lower than that of 25 sex and age matched
controls (p<0.02) and this was not merely due to chemotherapy- or tumor-associated
immunosuppression, since the values of responder patients did not significantly differ
from those of controls. ADCC activity against Her2-positive SKBR3 cells was also
significantly higher in responder compared to non responder patients (p<0.05) and
markedly so when compared to controls (p<0.001).
Conclusions: The fact that, as shown here, normal levels of FccR-independent and
higher than normal levels of FccR-dependent cytotoxicity are required for trastuzumab
C8 INCREASED RISK OF CENTRAL NERVOUS SYSTEM
METASTASES (CNSm) IN PATIENTS (pts) WITH BREAST CANCER
(BC) TREATED WITH TRASTUZUMAB (T): RESULTS OF A
POOLED ANALYSIS
M. C. Garassino, Serena Di Cosimo, M Dimaiuta, D. Generali, C. Bareggi, G. Gullo,
M. Cinquini, N. La Verde, G. Farina & V. Torri
The incidence of CNSm ranges from 10 to 16% among women carrying a diagnosis
of metastatic BC, whereas in early stages is <0.1%. Patients with HER2-positive BC
have been reported to show higher CNSm rates; whether T may increase such risk
remains controversial. In order to evaluate the possible correlation between the
development of CNSm and the T-based treatment in BC, we performed a pooled
analysis of all published randomised clinical trials, reporting CNS events, with the
administration of the HER2 monoclonal antibody in adjuvant or metastatic setting.
A Medline search was conducted and four papers were considered for analysis (N9831-
B31-HERA-Slamon-2001). Crude odds ratios for CNSm and other metastasis
occurrence were used for estimating the relative risk of events associated to
therapy. Overall risks (ORs) were extracted from each study and used for
comparison between groups. Conditional logistic analysis was adopted, using
studies as strata. The incidence of CNSm progression was higher in
trastuzumab-based therapy (70% of risk increase) arm in all studies (OR=0.59)
with particular regard to the adjuvant setting. However, trastuzumab appears to be
efficacious (61% of risk reduction) in controlling disease progression to other sites
(OR 2.60).

Table 1.

STUDY SETTING YRS F.UP TRASTUZUMAB (T) CONTROL (CTR) CNS CTR VS. T OTHER SITES CTR VS. T
CNS OTH PTS CNS OTH PTS OR 95% CI OR 95% CI
SLAMON 2001 ADVANCED 2.9 23 137 234 16 192 230 0.686 0.352 1.335 3.577 2.317 5.524
B31 ADJUVANT 2.4 21 62 864 11 160 872 0.513 0.246 1.070 2.907 2.132 3.964
N9831 ADJUVANT 1.5 12 38 808 4 86 807 0.330 0.106 1.029 2.417 1.628 3.588
HERA ADJUVANT 1.0 21 106 1694 15 220 1693 0.712 0.366 1.386 2.238 1.756 2.851
OVERALL 77 343 3600 46 658 3602 0.589 0.406 0.853 2.597 2.213 3.048

xi38 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology
Although we are aware of the limits related to the study such as the effect of
competing risks and the short follow-up of the adjuvant trials, this is the firs
metanalysis showing that a particular subtype of BC treated with T-based therapy
might progress to CNS. Intrinsic molecular mechanisms are warranted to be elucidated
and they will be our further purpose of investigation.
C9 EARLY BREAST CANCER IN ELDERLY PATIENTS: A
RETROSPECTIVE STUDY
A. Gambardella, S. Serra, V. Petrella, C. Mocerino, A. Santoriello*, A. Silvestri
Internal Medicine Division. Department Of Gerontology, Geriatrics And
Metabolic Disease* Geriatric Surgery Division. Second University Of Naples
Naples, Italy
Introduction: In recent years, more and more elderly patients undergo screening
for early breast cancer detection. However, often these patients are not admitted
to invasive examination or to radical surgical treatment.
Methods: To evaluate this complex problem we have lead a retrospective study on
diagnostic and therapeutic approach of elderly patients (pts) with suspicious breast
lesions.
Results: In the last five years we have observed 303 women, range 70 -85 years, with
suspicious breast lesions, all submitted to echography and mammography. Of these 264
patients (median age 73.2) have accepted a fine needle biopsy and 226 pts (age 74.3)
presented cytology positive for neoplastic cells.
After comprehensive geriatric assessment (CGA) and anaesthesiologic examination
194 pts (age 71.4) were admitted to surgical treatment. The pts with severe comorbidity
and cognitive impairment were excluded and for them radiotherapy and/or hormonal
therapy were proposed.
A conservative surgery was reserved to 52% of pts and a nodal dissection to 78%
of them.
We also evaluated the tumor characteristics in relation with age and we report
the data in following table:
pT age T1 (55%) 70.5 T2 (40%) 71.3 T3 (5%) 72.9
pN age Positive (65%) 72.8 Negative (35%) 70.8
ER/PgR age Positive (83%) 71.5 Negative (17%) 70.5
Grading age G1(31%) 73.1 G2 (52%) 72.5 G3 (17%) 70.5
c-erbB2 age 3+ (27%) 70.2 2+ (20%) 70.6 1+ (22%) 72.6 Negative
(31%) 73.2
In 78 high risk patients adjuvant chemotherapy was proposed and 65 of them accepted
it. The chemotherapy was completed in 42 patients.
Conclusion: Our retrospective study demonstrated that a careful collaboration is
necessary to optimizing the management for the elderly patients with early breast
cancer leading to a surgical risk stratification and to choice of the best possible
treatment.
C10 IN VITRO AND IN VIVO CHEMOSENSITIVITY PROFILE OF
BRCA1-DEFECTIVE BREAST CANCER CELLS
Pietragalla A, Cucinotto I, Neri P, Di Martino T, Ventura M, Bulotta A, Calimeri T,
Propato M, Barbieri V, Eramo O, Salvino A, Rotundo M. S, Caraglia M, Mazza M,
Tassone P. and Tagliaferri P
Medical Oncology Unit, University of ‘‘Magna Græcia’’, Campus ‘‘Salvatore
Venuta’’, Catanzaro, Italy
BRCA1-related breast tumors represent a distinct clinical entity. The HCC1937,
BRCA1-defective cell line and its derivative cell clone (HCC1937/WT), where normal
BRCA1 has been reconstituted by cDNA-transfection, are a interesting model to
analyze the relationships between BRCA1-related carcinogenic pathways and the
sensitivity/resistance to chemotherapeutics agents. Previously,we demostrated an
increased antitumor activity of cisplatin (CDDP) in BRCA1-defective cells and
a reduced sensitivity to paclitaxel when compared to sporadic breast cancer cells
(MDA-MB 231, MCF-7) and to the BRCA1-reconstitute clone in vitro.Here, we
investigated the in vivo activity of CDDP and the differential sensitivity mechanism
by DNA microarray. In vivo effects of CDDP were studied using HCC1937 and
BRCA1/WT cells for animal xenografts. Mice bearing tumors subcutaneusly were
treated with cisplatin 5 mg/kg or vehicle, i.p. weekly, for 4 weeks. Tumors were
measured every 3 days and survival analysis was performed by Kaplan Mayer curve.Cell
cycle analysis from retrieved tumor tissues was performed using a cycle-test. Gene
expression profile was performed by Affimetrix Technology.We first evaluated the
in vitro chemosensitivity of HCC1937 and HCC1937/WT to CDDP;a dose-dependent
reduction of cell growth was mainly observed in HCC1937 cells when compared
with BRCA1-reconstitute cells.We next studied the in vivo actvity of CDDP in our
xenograft model.A significant (p<0.005) reduction of the tumor volume was observed
in CDDP treated mice when compared to controls.The antitumor activity of CDDP
was significantly higher in the HCC1937 bearing mice than in HCC1937/WT mice.
In vivo data on cell cycle showed a cell-cycle arrest with an increase in the G0-G1 phase
in HCC1937 cells obtained from treated mice when compared with HCC1937/WT
Volume 18 | Supplement 11 | October 2007
session C
cells. Survival analysis and gene expression profile are still ongoing. Taken together our
data support the hypothesis of a specific tumor drug sensitivity related to BRCA1
status. CDDP shows high activity in BRCA1-defective breast cancer cells and should
be evaluated further as a ‘‘novel’’ agent for treatment of patient with hereditary breast
cancers. Clinical trials are ongoing in this specific area.
C11 PRELIMINARY RESULTS OF SERIAL MONITORING OF SERUM
HER-2 EXTRACELLULAR DOMAIN IN PATIENTS RECEIVING
CHEMOTHERAPY FOR REFRACTORY METASTATIC BREAST
CANCER
A. Zambelli, N. Gibelli, P. Baiardi, V. Fregoni, L. Ponchio, GA. Da Prada, P. Preti,
L. Pavesi
Medical Oncology Division 1 Fondazione Salvatori Maugeri, IRCCS, Pavia-Italy
Introduction: The HER2 extracellular domain (H-ECD) level is increased in the sera of
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
patients affected by refractory metastatic breast cancer overexpressing HER2/neu.
Circulating levels of H-ECD have been reported to predict for response to
chemotherapy and outcome. However, the role of H-ECD as tumor marker, is poorly
defined.
Patients and methods: From Jan 1999 to Jan 2003 sera of 103 consecutive refractory
metastatic breast cancer, overexpressing HER2, were tested using ELISA assays (Bayer/
Oncogene Science Diagnostic). Serial evaluations of H-ECD (cut-off 15 ng/ml) were
obtained before palliative chemotherapy, at the end of treatment and in case of
progression.
Correlation with serum level of Ca15.3 (cut-off 35 U/ml) and with response to
chemotherapy were investigated.
Results: Among the 103 metastatic breast cancer patients, 13 obtained a response (CR/
PR) after chemotherapy 60 had stable disease and 30 patients progressed. We observed
a significant correlation between serum level of H-ECD and Ca15.3 (p<0.001 r=0.418).
Moreover the same correlation was observed as regard to the response to chemotherapy
with significant evidence of increased levels of H-ECD in case of PD (p=0.022 r=0.174),
H-ECD normalization in case of CR/PR (p=0.01 r=0.448), stabilization in SD (p=0.009
r=0.112).
Conclusions: Increased levels of H-ECD seem to be a useful marker for the prediction
of chemotherapy response and for the prognosis in refractory metastatic breast cancer
receiving palliative chemotherapy. Further observations are needed to confirm these
preliminary data.
C12 BRAIN METASTASES IN PATIENTS TREATED WITH
TRASTUZUMAB FOR METASTATIC BREAST CANCER (ABC):
POLONORD GROUP EXPERIENCE
Eliana Berardi1, Virginio Flipazzi2, Monica Giordano3, Giovanna Luchena3,
Elisabetta Menatti1, Ornella Fusco1, Fabio Malugani1, Mario Fiumanò1, Alessandro
Bertolini1
1
Oncology Unit Ospedale Civile Sondrio, 2Ospedale Sacco, Milano, 3Ospedale
S. Anna, Como
Background: The HER-2 protein, overexpressed in the 25% of primary breast
carcinoma, is an independent prognostic indicator of a subset of cancers that are at
high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor
status, and lymph node status. These patients have a shorter disease-free survival than
others. Clinical studies have shown that administration of Trastuzumab, a mAb
directed against HER-2 protein, significantly inhibits the growth of breast tumour cells
in patients with higher levels of HER-2 protein overexpression assessed by Hercep Test.
Methods: We registered an high incidence of brain metastases (BM) in patients
receiving Trastuzumab. For this reason we reviewed all cases that developed since
2001 BM during Trastuzumab plus Chemotherapy treatment for advanced breast
carcinoma (ABC). All patients had visceral metastases, Performance Status 0-2 and
3+ HER-2 overexpression.
Results: Among 43 consecutive patients who had received Trastuzumab, 14 (32.5%)
developed BM during treatment. Patients relapsed at CNS at a median of 25,8 months
after diagnosis of ABC and 7,3 (2-13) months from beginning Trastuzumab. All the
BM presented neurological symptoms at the diagnosis. All stopped Trastuzumab
treatment and shifted to other chemotherapy or/and WBRT/radiosurgery. Three of
them are still alive.
Discussion: ABC to the CNS is common among patients receiving Trastuzumab,
including patients responding to therapy outside the CNS. This may be due to
predilection for the CNS by HER-2+ tumor cells and/or poor penetration of the CNS
by Trastuzumab and Taxanes. For this reason it’s important to have in clinical practice
for Her2 overexpressed breast carcinoma new drugs, e.g. Lapatinib, able to pass BEE.
C13 HER2/NEU EXPRESSION IN RELATION TO CLINICO-
PATHOLOGICAL FEATURES OF BREAST CANCER PATIENTS
Adele Traina, Biagio Agostara, Lorenzo Marasà, Stella Adamo, Rosalba Amodio,
Cecilia Dolcemascolo, Maurizio Zarcone, Giuseppe Carruba
doi:10.1093/annonc/mdm425 | xi39
session C
Experimental Oncology, Clinical Oncology, and Pathology Units, Department of
Oncology, ARNAS-Civico, Palermo, Italy; Department of ‘‘Igiene e
Microbiologia’’ of Palermo University
Many studies suggest that the assessment of HER2/Neu expression might be helpful in
decision making to treat breast cancer patients. Nevertheless, clinical studies have
yielded so far conflicting results. We have retrospectively evaluated HER2/Neu
expression in relation to clinical-pathological features of the disease in a series of 1,480
breast cancer cases, all collected by Breast Cancer Registry in Palermo, between January
1999 and December 2004. The expression of the HER2/NEU oncogene was assessed by
immunohistochemistry and scored on a scale of 0 to +3 as per the FDA
recommendations. The HER2/Neu expression levels were related to tumor size, nodal
status, estrogen (ER) and progesterone receptors (PR), and age at diagnosis. A highly
significant (P<0.001) correlation of high HER2/Neu expression and a negative ER/PR
status was observed. In addition, patients having G3 tumors and/or axillary nodal
involvement showed elevated HER2/Neu expression (P<0.001), while no significant
association could be found with the other variables. Furthermore, 596 patients having
a follow-up ‡5 years showed an overall survival (OS) of 85% after 60 months.
HER2/neu 3+ patients had a significantly worse OS with respect to patients having a
0-2+ HER2/Neu status (87% vs 78%, respectively). In these last HER2/Neu 0-2+
patients, the node-positive patients had a significantly shorter OS (P=0.0009) with
respect to node-negative ones, while in HER2/Neu 3+ patients this difference becomes
not significant (P=0.565). As regards N0 patients, HER2/Neu 3+ patients show a trend,
though not significant (P=0.081), to have a shorter OS as compared to HER2/Neu 0-2+
patients (82% vs 92%, respectively). In addition, HER2/Neu 3+ patients having
a negative ER/PR status show a significantly lower OS (66%) with respect to HER2/Neu
0-2+ patients having a positive ER/PR status (88%) after 5 years. This combined
evidence indicates that a refined recognition of the association of HER2/Neu with other
parameters may be helpful for breast cancer patients prognosis and treatment and may
also provide a basis to develop ‘‘individualized’’ therapeutic strategies.
C14 CAPECITABINE (CAP) AND CELECOXIB (CEL) FOR
PRETREATED METASTATIC BREAST CANCER (MBC): SAFETY AND
ACTIVITY OF AN ALL ORAL COMBINATION
G. Metro, A. Fabi, P. Papaldo, G. Ferretti, P. Carlini, I. Sperduti, A. Felici,
F. Cognetti and M. Milella
Division of Medical Oncology-Istituto Regina Elena - IFO, Roma
Background: Cap is an oral, tumor-activated fluoropyrimidine with established
activity in anthracycline- and taxane-pretreated MBC. Cel is a selective COX-2
inhibitor with recognized anti-tumor properties in various animal models of breast
cancer. Interestingly, Cel has been successfully combined with fluoropyrimidine-based
regimens, resulting in a lower-than-expected gastro-intestinal (GI) toxicity and hand-
foot syndrome (HFS).
Methods: Patients received Cap 2000 mg/m2 daily for 14 days, q3 wks and Cel 200 mg
b.i.d., continuously.
Results: Fourty women were enrolled. Median age was 57.5 years (range 33-82), and
median performance status (WHO) was 1 (range 0-2 ). The majority of patients (75%)
had visceral localization as dominant metastatic site. Median number of previous
chemotherapy lines for metastatic disease was 3 (1-4). All patients had been exposed to
antracycline-including regimens either in adjuvant or metastatic setting while 87.5% of
patients had received prior taxanes. The median number of cycles delivered was 6
(range 1-18). All patients were evaluable for safety and activity. Seven patients obtained
a partial response (17.5%) and stable disease was observed in 17 patients (42.5%)
providing an overall tumor control rate of 60%. At a median follow up of 13 months
(1-32 months), median duration of response was 13 months (range 11-17), median
time to progression (TTP) was 5 months (CI 95%: 3-7) and median overall survival was
18 months (CI 95%:11-25). Cap-Cel combination was generally well-tolerated: grade
2-3 treatment-related adverse events were hand-foot syndrome (23%), neutropenia
(15.5%), diarrhea (10,5%), nausea (7,5%), asthenia (7,5), liver toxicity (7,5%) and
gastric pain (5%). No grade 4 toxicities and no treatment-related deaths were observed.
Conclusions: Cap-Cel combination yielded a response rate comparable to that of single
agent Cap. However, the addition of Cel to Cap resulted in increased TTP. The good
tolerabity profile of this association suggests that Cel might also attenuate Cap-related
toxicities such as GI events and HFS.
C15 IDENTIFICATION OF FAMILIES SELECTED FOR BREAST
CANCER PREDISPOSITION RISK AND SHOWING LOW RATE OF
BRCA1/BRCA2 MUTATIONS (<10%)
Sidoni T, De Marchis L2, Midulla C2, Capalbo C1, Giusti R, Paris I5, Assalone P2,
Rocchi A2, Ronzino G4, Di Seri M2, Tomao S2, Meggiorini M. L6, Lanza R2,
Scambia G3, Ficorella C, Marchetti P5, Cortesi E2, Frati L2, Gulino A1, Giannini G1
and Ricevuto E
Medical Oncology, Department of Experimental Medicine, University of L’Aquila
Between march 2002 and december 2006, 119 unrelated families at risk for breast (BC)
and/or ovarian cancer predisposing syndrome were selected according to the following
criteria of a priori risk >10%: breast and/or ovarian cancer family history (FB/OC),
xi40 | session C: early and advanced breast cancer
Annals of Oncology
site-specific familial breast cancer (FBC), early-onset breast or ovarian cancer <35 years
and <45 years, respectively (EO-BC/OC), male BC (MBC), site-specific familial ovarian
cancer (FOC). After genetic counselling and written informed consent, BRCA1/BRCA2
analysis of structural alterations (point mutations and genomic rearrangements) was
performed in cancer probands.
Altogether, 29% BRCA1/2 predisposing mutations were identified: BRCA1+ 18%
(19 point mutations and 2 genomic rearrangements); BRCA2+ 11% (all point
mutations). In FB/OC, 65% BRCA1+: 100% in the 9 FB/OC with >2 OCs; 43% (6
BRCA1+) in 14 FB/OC with one OC. In FBC 20% BRCA1/2+ (19/96): 6% (6/96)
BRCA1 mutations (4 point mutations, 4/96, 4%; 2 genomic rearrangements, 2/96, 2%);
14% (13/96) BRCA2 point mutations.
In EO-BC probands, 28% BRCA1/2+ were detected: 7/32 (22%) point mutations
and 2/32 (6%) genomic rearrangement, all in the 23 EO-BCs with FB/OC (38%, 9/24).
In MBC, 20% BRCA2+ in probands with FBC. BRCA1/BRCA2 mutations were
detected in 15% case index BC >35 years (8/55).
No BRCA1/BRCA2 mutation was identified in 11 BC probands in the absence of
B/OC positive family history (8 EO-BCs and 3 MBC). In the subgroups of FBCs 2-3,
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16% BRCA1/2 mutations were detected (10/63): 32% in the EO-female FBCs 2-3 (6/
19); 8% in the female FBCs 2-3 (3/38).
Present data confirm the expected >10% risk of BRCA1/2 related-predisposition in
families selected according to recommended criteria and indicate two main subgroups
of at-risk families: EO or MBC with >2 BCs and FBOC with 44% BRCA1/2 mutations
(31/70); female FBC 2-3, EO-BC and MBC without BC family history accounting for
41% of at-risk families with <10% BRCA1/2 mutations (3/49, 6%).
C16 EXPRESSION OF THE LEPTIN SYSTEM AND HYPOXIA-
INDUCIBLE FACTOR 1a; IN HER2-POSITIVE AND HER2-NEGATIVE
BREAST CANCER
Elena Fiorio1,2, Andrea Remo3, Alessandra Auriemma1,2, Marianna Terrasi1,4,
Annamaria Molino2, Anna Mercanti1,2, Maria Franco Bonetti3, Gian Luigi Cetto2,
Eva Surmacz1
1
Sbarro Institute for Cancer Research and Molecular Medicine, Temple
University, Philadelphia, USA, 2Department of Medical Oncology, University of
Verona, Italy, 3Department of Anatomia Patologica, University of Verona, Italy,
4
Section of Medical Oncology, Department of Surgical Oncology, University of
Palermo, Italy
The obesity hormone leptin (Ob) has been implicated in tumorigenesis, especially in
the development of breast cancer (BC). The mitogenic, angiogenic, and antiapoptotic
activities of Ob are mediated through the leptin receptor (ObR). Data obtained in
HEK293T cells engineered to coexpress ObR and the oncoreceptor HER2 suggested
that Ob can transactivate HER2 via ObR. To address this putative interaction, we
studied whether simultaneous expression of Ob, ObR and HER2 can occur in human
breast cancer. Because in breast cancer cells Ob and ObR can be induced by hypoxia
and HER2 has been found associated with hypoxia-inducible factor 1 alpha (HIF-1a)
we also explored associations among Ob, ObR, HER2 and HIF-1a.
The abundance of Ob, ObR and HIF-1a was evaluated by immunohistochemistry in
59 BCs (31 HER2-positive, 28 HER2-negative). The expression of Ob and ObR was
classified as positive (at least +) or negative (below +), and of HIF-1a as low (0-2%) or
high (>2%). The relationships among Ob, ObR, HIF-1a and the clinicopathological
features, i.e., grading (G1, G2, G3), tumor size (diameter in mm), node involvement
(positive or negative), vascular invasion (positive or negative), ER and PgR expression
(positive or negative) were analyzed using the v2 test.
Ob and ObR were coexpressed in 78% of tumors and were correlated (p<0.001)
in all BCs and in HER2-positive (p=<0.001) and HER2-negative (P=0.045) subgroups.
In all BCs, the expression of Ob and/or ObR was associated with tumor size (Ob:
p=0.04; ObR: p=0.05) and node positivity (ObR: p=0.04; Ob/ObR: p=0.02).
Furthermore, the expression of Ob occurred more frequently in large (>10 mm),
node-positive tumors (trends p=0.06 and p=0.08, respectively). The simultaneous
expression of Ob/ObR and HER2 was found in 39% of BCs, but the Ob/ObR
system was also frequent in HER2-negative BCs. High expression of HIF-1a correlated
with Ob/ObR (p=0.03). ObR and Ob/ObR did not correlate with HER2, grading,
VI, and ER/PgR.
In summary, Ob and ObR are often coexpressed and a subset of Ob/ObR-positive
tumors exhibits concomitant expression of HER2. Thus, interactions between Ob/ObR
and HER2 might occur in breast cancer, where activation of Ob/ObR could impede
anti-HER2 treatments. The presence of Ob/ObR correlated with high levels of HIF-1a,
suggesting that hypoxia might upregulate this system. However, Ob/ObR and HER2
were not significantly associated, implying that independent mechanisms regulate these
biomarkers.
C17 USE OF NON PEGYLATED LIPOSOMIAL DOXORUBICIN
(MYOCET) ASSSOCIATED WITH CYCLOPHOSPHAMIDE OR
DOCETAXEL AS FIRST LINE TREATMENT IN METASTATIC BREAST
CANCER
Lorenzo Livi1, Icro Meattini1, Alessio Bruni1, Alessia Petrucci1, Andrea Rampini1,
Annamaria Mileo1, Lisa Paoletti1, Angela Sardaro2, Simona Borghesi1 and
Giampaolo Biti1
1
Radiotherapy Unit University of Florence, 2 Radiotherapy Unit University of Bari
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
Background: The aim of this study was evaluate the activity and safety of non-
pegylated liposomal doxorubicin (Myocet) and Docetaxel or non-pegylated liposomal
doxorubicin and Cyclophosphamide combination as first line treatment in patient with
metastatic breast cancer (MBC).
Patient and methods: fourteen patients with median age of 54 years were treated with
Myocet 60 mg/mq and Cyclophosphamide 600 mg/mq every three weeks. Twenty
patients with median age of 48.5 years were treated with Myocet 30 mg/mq and
Docetaxel 75 mg/mq every three weeks. Both of two groups after four cycles underwent
restaging to evaluate the clinical response.
Results: All the patients were assessable for response. No patient has complete response
in both groups. Patients treated with Myocet and Cyclophosphamide achieved in
21.5% (3 out of 14) partial response (>50% decrease of measureable disease), in 42.9%
(6 out of 14) stable disease and in 35.6% (5 out of 14) progression of disease. Median of
progression free survival was 8 months. Grade 2 neutropenia occurred in 42.9% of
patients and cardiac failure Grade 1 in 7%, no palmar-plantar erythrodysesthesia was
observed.
Patients treated with Myocet and Docetaxel achieved in 35% (7 out of 20) partial
response (>50% decrease of measureable disease), in 40% (8 out of 20) stable disease
and in 25% (5 out of 20) progression of disease. Median of progression free survival
was 13.8 months.
Grade 2 neutropenia occurred in 30% of patients and cardiac failure Grade 1 in 5%,
palmar-plantar erythrodysesthesia was observed in two patients (10%).
Conclusions: combination of Myocet and Docetaxel improve progression free
survival respect Myocet and Cyclophosphamide as first line treatment in MBC with
acceptable toxicity.
C18 FUNCTIONAL ANALYSIS OF THE -2548G/A LEPTIN GENE
POLYMORPHISM IN BREAST CANCER CELLS
Marianna Terrasi1,2, Elena Fiorio3, Antonio Russo2, and Eva Surmacz1
1 Introduction: HER-2 is rising up as factor predicting the response to several drugs
Sbarro Institute for Cancer Research and Molecular Medicine, Temple
University, Philadelphia, USA, 2Section of Medical Oncology, Department of
Surgical Oncology, Palermo, Italy, 3Department of Oncology, University of
Verona, Italy
Leptin, a hormone produced mainly by the adipose tissue, regulates energy balance
acting in the brain. In addition, leptin can stimulate mitogenic and angiogenic
processes in peripheral organs. Recent data suggested that leptin can be involved in
breast cancer progression, as it can induce proliferation, survival and anchorage-
independent growth of breast cancer cells and is abundant in breast cancer tissues. The
mechanisms of leptin overexpression in breast cancer are not clear. The G to A
substitution at -2548 in the leptin gene (Lep-2548G/A allele) in adipocytes correlated
with a two-fold increase of leptin secretion and elevated circulating leptin levels.
Furthermore, the occurrence of Lep-2548G/A in leukocytes correlated with increased
susceptibility for different neoplasms, including breast cancer. However, molecular
bases underlying this association have never been investigated. Here we asked whether
occurrence of Lep-2548G/A in breast cancer cells could modulate transcriptional
activation of the leptin gene.
Lep-2548G/A was identified in MDA-MB-231 breast cancer cells, while it was absent in
MCF-7 cells. DNA analysis revealed that Lep-2548G/A mapped near binding site for
a transcriptional factor SP-1 and contained a motif for binding a transcriptional
repressor nucleolin. Thus, we focused on the impact of Lep-2548G/A on the
functional interactions of SP-1 and nucleolin with the leptin gene promoter.
Chromatin immunoprecipitation assays demonstrated that the existence of Lep-
2548G/A improved efficient recruitment of SP-1 to DNA, especially under insulin
treatment, while SP-1 loading with or without insulin on DNA containing Lep-
2548G/G was minimal. In contrast, nucleolin binding to Lep-2548G/A was
downregulated in response to insulin, while it was not regulated on Lep-2548G/G.
These results were confirmed by DNA affinity immunoprecipitation with specific
Lep-2548G/A and control probes. Enhanced loading of SP-1 near Lep-2548G/A was
paralleled by higher basal and insulin-induced expression of leptin mRNA in
MDA-MB-231 cells. In conclusion, the occurrence of Lep-2548G/A can enhance basal
and insulin-induced leptin expression in breast cancer via SP-1- and nucleolin-
dependent mechanisms.
C19 CHROMOGRANIN A AS PROGNOSTIC TOOL IN METASTATIC
BREAST CANCER
Polimeni MA, Beano A, Mistrangelo M, Spadi R, Ardine M, Donadio M,
I Chiappino, N Birocco, R Volpatto, V Contu, Ciuffreda L. SC Oncologia Medica,
ASO S. Giovanni Battista, Torino
Background: Human chromogranin A (CgA) is a member of the Granin family,
mapping on chromosome 14. Its role in the physiopathology of neuroendocrine cells is
yet unknown, as the biologic and clinical meaning of neuroendocrine phenotype in
non-neuroendocrine carcinomas. The aim of present study is evaluating CgA levels as
prognostic tool in metastatic breast cancer (MBC).
Patients and methods: From January to September 2006 we evaluate CgA serum
levels with IRMA method once every four weeks in 165 MBC patients. We
considered altered CgA levels upper to 100 ng/ml. All patients achieve specific
antitumoral treatment (chemo- or hormonotherapy). Median age was 47 years
Volume 18 | Supplement 11 | October 2007
session C
(28-73). Patients with endocrine responsive disease were 65,5%; 57,6% of patients had
visceral metastatic disease. We considered three subsequent determinations in 163
patients evaluable.
Results: Overall mean CgA levels [mean (95% confidence interval, C.I.)] at first,
second and third sample was respectively125 ng/ml (2-832), 163 ng/ml (2-1111), 137
ng/ml (1-955). The correlation between CgA levels and disease response showed that,
regardless of treatment type, patients with disease progression had mean CgA levels
higher than patients with stable or responsive disease (p=0,59). Moreover, supposing
interaction between CgA secretion and specific treatment, we considered patients
subgroups: in hormonotherapy treated patients mean CgA value progressively increase,
whereas it remains steady in chemotherapy treated patients (p=0,17). Regarding the
disease sites, CgA levels were significantly higher in patients with non visceral
metastatic disease than in patients with visceral disease (p=0,008). Since visceral
metastatic disease patients rarely undergone to hormonotherapy alone, we could
suppose an hormonotherapy impact on neuroendocrine phenotype. Median survival
assessed by Kaplan-Meyer survival curves was significantly lower for patients with
baseline CgA level supranormal than for patients with normal baseline (22,7 vs 25,8
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mounths, p 0,007).
Conclusion: This data suggest that the neuroendocrine phenotype is a dynamic
phenomenon, similarly to prostatic cancer.
C20 EVALUATION OF THE PREDICTIVE EFFECT OF HER-2
POSITIVITY ON THE EFFECTIVENESS OF BREAST CANCER
ADJUVANT TREATMENT
Guarino S, Menegatti E, Bonetti F, Indelli M, Urbini B, Modena Y, Carandina I,
Querzoli P*, and Lelli G
Clinical Oncology Unit and * Pathology Unit, Azienda Ospedaliero-Universitaria,
Ferrara, Italy
employed in the treatment of early and advanced breast cancer beside its negative
prognostic value.
Patients and methods: This retrospective study was carried out in order to evaluate the
predictive role of HER-2/neu amplification/ hyperexpression on effectiveness of breast
cancer adjuvant treatment.
Results: We evaluated 840 patients, of which 256 with HER2 positive (HER2+, 30,5%)
and 584 with HER-2 negative (HER2-, 69,5%) cancers. Median follow-up was 33
months. HER2+ tumors were more frequently associated with a greater size (p=0,003),
nodal envolvement (p=0,004), poor differentiation (p=0,0001), high proliferative
index (p=0,0001) and lack of expression of hormonal receptors (p=0,0001) comparing
to those with HER2-. We did not see any significative differences in disease free survival
(DFS) between HER2+ (median 215 months) and HER2- (median 123 months,
p= 0,4900). Tamoxifen therapy did not result in significative differences between the
two groups (median DFS not reached, p=0,4593). Anthracycline-based chemotherapy
did not provide significative differences between HER2+ and HER2- (median DFS
resp. 185 vs. 87 months, p=0,6476).
Conclusions: In our study HER-2/neu amplification/ hyperexpression is associated
with other negative prognostic factors with statistic significance even if survival analysis
did not feature HER-2+ as a negative prognostic factor. These results are partly
explained by the short median follow-up (< 3 years).
C21 GYNECOLOGIC SIDE EFFECTS OF TAMOXIFEN (TAM) IN THE
ADJUVANT TREATMENT OF BREAST CANCER: A RETROSPECTIVE
OUTCOME STUDY
Indelli M, Travasoni F, Santini A, La Torre L, Querzoli P*, Martinello R**, Simone G**
and Lelli G
Clinical Oncology Unit, * Pathology Unit, **Ginecology Unit, Azienda
Ospedaliero-Universitaria, Ferrara, Italy
Background: Nowadays side effects of TAM on female genital apparatus is an actual
issue because of its still wide use in breast cancer adjuvant therapy and its mostly
discussed efficacy in avoiding cancer in high risk women.
Materials and methods: We carried out a retrospective study of 591 patients
undergoing adjuvant endocrine therapy with TAM at our institution. We evaluated the
main endocrine therapy side effects, subjective and not: flushing, leukorrhoea, spotting,
metrorrhagia. We also considered endometrial disease occurrences such as invasive
diagnostic techniques (cytology, biopsy), carcinomas, hysterectomies.
Results: Flushing was the most common TAM side effect, followed by leukorrhoea and
vaginal bleeding. Flushing and leukorrhoea are more common in post-menopausal
women (p=0,001). 28% of patients underwent one invasive diagnostic evaluation at
least (median 1.7, range 1-7). In 43% of cases no disease was histologically retrieved,
whereas among benign diseases (54%) atypic hyperplasia rate was 2%. Among the 27
hysterectomies 5 endometrial, two ovarian, two cervix, and one metastatic breast
cancers were diagnosed.
Conclusions: We confirmed a low rate of endometrial cancer. The high invasive
diagnostic techniques rate needs a careful evaluation in the absence of defined
endometrial thickness ultrasounds cut-off in asymptomatic women.
doi:10.1093/annonc/mdm425 | xi41
session C
C22 A FEASIBILITY-PHASE II STUDY EVALUATING
CARDIOTOXICITY OF WEEKLY TRASTUZUMAB(T) PLUS
EPIRUBICIN(E) AND PACLITAXEL(P) FOR HER-2 POSITIVE LOCALLY
ADVANCED(LA) AND/OR METASTATIC(M) BREAST CANCER(BC)
Cecilia Nisticò, MD1, Emilio Bria, MD1, Federica Cuppone, MD1, Armando
Carpino, MD2, Isabella Sperduti, PhD3, Giuseppe Toglia, MD2, Vanja Vaccaro,
MD1, Simona Barberi, MD1, MS3, Diana Giannarelli, PhD3, Francesco Cognetti,
MD1, Edmondo Terzoli, MD1
1Department of Medical Oncology, Regina Elena National Cancer Institute,
Rome, Italy; 2Cardiology, Regina Elena National Cancer Institute, Rome, Italy;
3Biostatistics, Regina Elena National Cancer Institute, Rome, Italy
Background: Trastuzumab for HER-2 positive advanced and adjuvant BC has changed
the natural history of the disease. Nevertheless, an increased incidence of unexpected
cardiotoxicity has been observed when T has been added to anthracyclines and taxanes.
The weekly adiministration of EP plus G-CSF in unselected MBC pts did provide a low
rate of cardiac toxicity in a previous phase II study (Nisticò, Anticancer Drugs 2007). In
order to assess the cardiotoxicity of T plus weekly ET in HER-2 pts, a feasibility-phase
II study was designed.
Methods: Untreated HER-2 positive (FISH/CISH amplification or +++ Dako Test)
LABC or MBC pts were planned to receive weekly T (4-2 mg/kg/week) on day 1, and E
(25 mg/m2/week) plus P (80 mg/m2/week) on day 2, plus G-CSF support, for 16/24
weeks in LA/M setting respectively, in absence of significant toxicity or progression.
Exclusion criteria: significant cardiac disease or L-FEV<50%. The rate of pts with
L-FEV reduction >10% after 12 weeks of treatment was the chosen primary endpoint.
According to an optimal 2-stage Simon model, with a power of 90% at a 5%
significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as
acceptable, an initial step with 15 pts was required; after 11 pts with no toxicity,
a second step with further 21 pts (total: 36) was planned. Secondary end-points were
non-cardiac toxicity and activity rates.
Results: Fiftheen pts were enrolled between May 2004 and March 2007. Pts features:
median age=47 (range 37-69); LABC/MBC=4/11; positive hormonal receptor 8/7;
menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median
baseline- and post-week-12-L-FEV was 69% (range 64-77) and 65% (range 61-76),
respectively. Three pts had a >10% L-FEV reduction (20%), with an overall median
L-FEV reduction of 5.2%, with a median number of courses of 13 (range 8-24). No
EKG alteration or specific symptoms were present. At a median follow-up of 17
months, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9-87) were
achieved, with a 9-months median duration of response. Except for severe alopecia, no
other grade 3-4 toxicity were documented.
Conclusions: From both a symptomatic and non-symptomatic (L-FEV reduction)
cardiac toxicity perspective, the weekly administration of T plus EP seems safe. Due to the
low L-FEV reduction rate, the second step of the present study is currently ongoing.
C23 MAMMOGRAPHIC SCREENING IN VERONA: IMPACT ON
CLINCAL, PATHOLOGICAL AND SURGICAL VARIABLES OF A
HOSPITAL CASE SERIES OF 4645 PATIENTS
A. Mercanti1, E. Fiorio1, A. Auriemma1, A. Caldara 1, S. Cingarlini 1, R. Micciolo2,
A. Santo1, G. L. Cetto1, A. Molino1
1
Department Oncology, University of Verona, Italy;
Background: The mammographic screening was introduced in Verona in July 1999;
the target is female population between 50 and 69 years old of age and the
mammography has performed every two years.
Patients and methods: Data are collected from the University and Civic Hospitals of
Verona, and the impact over the time of the mass screening’s introduction is evaluated
on clinical, pathological and surgical variables. The chi-squared test and multinomial
logistic regression are used to perform a time related difference.
Results: We compare clinical, pathological and surgical variables in pre- screening
versus post screening period.
The proportion of cases diagnosed with in situ disease increase from 10.7% to 16.9%
(p<0.001).
Invasive breast cancers show an increase in pT1 stage (62.9% vs 69.7%; p<0.001),
particularly those of dimension <10 mm (31.1% vs 40%, p<0,001).
We do not found a statistical significance for the impact on age at diagnosis.
There is a considerable increase in asymptomatic breast cancers both in invasive
tumours (32.6% in pre-screening period versus 47.6 in post screening period, p<0.001)
and, mostly, in in situ carcinomas (58.4% vs 80.7%, p<0.001).
There is a marked shift from demolitive to conservative surgery for both invasive
(31.5% vs 45.7%; p<0,001) and in situ carcinoma (49% vs 81.9%; p<0,001); collaterally
complete axillary dissection for both invasive (90.6% to % 70.5%; p<0,001) and,
mostly, in situ carcinoma (65.1% vs 21%; p<0,001) decreases.
Conclusions: Mammographic screening has both a direct efficacy for screen-detected
breast cancers and an indirect efficacy making the women awareness about the
importance of early breast cancer detection.
Our hospital datas prove both these effects and their impact on breast cancer
variables in operated patients.
We observe an increase of asymptomatic diagnosis, in situ carcinomas and smaller
invasive tumours; the immediate consequence is a less invasive surgery and a better prognosis.
xi42 | session C: early and advanced breast cancer
Annals of Oncology
C24 BREAST CANCER IN ELDERLY: TUMOR CHARACTERISTICS,
TREATMENT AND OUTCOME IN 182 PATIENTS
Federica Merlin1, Tiziana Prochilo1, Antonella Savio2, Francesco Metelli3, Basem
Kildani1, Giordano Domenico Beretta1
1
Ospedale Sant‘Orsola Fatebenefratelli, Medical Oncology, Brescia, ITALY,
2
Ospedale Sant’Orsola Fatebenefratelli, Pathology, Brescia, ITALY, 3Ospedale
Sant’Orsola Fatebenefratelli, Sugery, Brescia, ITALY
Background: Approximately 35-40% of all new breast cancer occurred in women aged
70 years or more. Direct data on pathology and biology characteristics and optimal
treatment in older patients are limited. The aim of this retrospective study was to
analyzed biologic, clinic characteristics, treatment and survival in 182 breast cancer
patients (pts), recruited in a single institution.
Patients and methods: Between January 1994 and September 2006, 182 consecutive
patients had a histologically confirmed diagnosis of breast cancer. Median age was 77
(range 70-94), about 40% of pts were aged 80 or more.
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Results: In 70% of pts, initial local treatment consisted of mastectomy, 27% underwent
quadrantectomy or tumorectomy. Lymph-node metastases were detected in 71 of 131
(72%) patients. Tumors were stage T1-T2 in 73 %, mostly cases (101/182) were Grade
2-3 and 78% of the tumors were hormone-sensitive. At a median follow-up of 38
months after diagnosis (range 5-137), only 21 (11%) patients dead of disease (11,5%)
and 16 pts dead for other causes. Breast cancer specific survival’s analysis demonstrated
statistical significance for the following factors: stage T, positive axillary nodes, steroid
status and high expression of c-erb2 (p>0,005). Stage T4 tumors (40 pts), had
associated unfavorable factors (ER/PgR negative, G3 and high proliferative index).
At univariate analysis, Hercep-test score 3+ indicated worse overall and disease-specific
survival; this data was significantly associated with non hormone-sensitive tumors,
positive nodal status, stage T4 and G3.
Conclusions: Also our results show that in elderly women breast cancer has more
frequently biological favorable characteristics, but in pts with more aggressive tumors
(T4 or Hercept-test 3+) disease specific survival is worse. In our study, about 30% of
women, because of clinical condition and comorbidity, didn’t received standard
treatment. We are really convinced that the goal in treating breast cancer in older
patients is considered, in decision making, not only age or age-related conditions but
also the characteristics of tumor and all new treatments available.
C25 INVASIVE BREAST CANCER AND AGE-RELATED
PROGNOSTIC FACTORS
R. di Rocco, A. Romiti, C. Amanti, D. Di Stefano, C. Renzi*, P. Pasquini*, I. Sarcina,
V. Durante, C. D‘Antonio, P. Marchetti
Sant’Andrea Hospital, IDI-IRCCS* Rome, Italy
Background: About 6% of breast cancers occur in women below 40 yrs of age. In this
group, several studies reported both a more aggressive tumour behaviour and/or
a different distribution of some clinico-pathological features. Aim of the study: to
evaluate specific pathological parameters, such as tumor size and grade, node status,
ER, PgR, HER2-neu, P53 and Ki67, with respect to patient’s age.
Patients and methods: We reviewed the charts of 712 patients diagnosed with
invasive breast carcinoma, at our institution, over a period of 10 yrs: 68 (9.5%) were <
40 yrs old at diagnosis (mean: 35.6 yrs ± 3.8 SD). A control group of 138 women,
‡40 yrs of age (mean 57yrs ± 12.7 SD), with comparable disease stage, was selected.
Relapse rate and disease free survival (DFS) were calculated in the two groups.
Immunohistochemical analysis was used for ER, PgR, HER2-neu, P53 and Ki67
determination. Statistical analysis included: the Fisher’s exact test for univariate
analysis, Cox regression model for multivariate analysis and Kaplan-Meier method to
calculate DFS. p value <0.05 was considered significant.
Results: Hormone receptors were more frequently expressed in older women
(p<0.05 for ER and PgR) while HER2-neu overexpression (3+) (p<0.05), Ki67 value
(p<0.01) and tumour grade (p<0.01) were higher in tumours of younger women.
P53 expression showed no significant difference between the two groups. At a median
follow-up time of 25 months, 11 (16.2%) and 5 (3.6%) relapses were observed in the
younger and older patients, respectively (p<0.05). 5-yr DFS was 76% and 95.2% in
younger and older women, respectively (p=0.09). Younger age and node status were
independent relapse risk factors in univariate and multivariate analyses (HR= 6.03, IC
95%: 1.01-36.08, p<0.05 and HR 11.60, IC 95%:1.27-105.49, p<0.05 respectively).
Conclusions: Our findings demonstrate a peculiar distribution of some pathologic
parameters, probably associated with a more unfavourable outcome, in younger breast
cancer patients.
C26 SAFETY AND ACTIVITY OF TRASTUZUMAB (TRA)
CONTAINING THERAPIES AS TREATMENT OF METASTATIC BREAST
CANCER (MBC): A FIVE-YEAR EXPERIENCE
Rosalba Rossello1, Barbara Adamo1, Tindara Franchina1, Claudia Garipoli1,
Monica Iorfida1, Vincenzo Festa1, Erika Montalto1, Maria Rosaria Valerio2, Antonio
Russo2, Vincenzo Adamo1
1
Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie Integrate,
A.O.U. Policlinico ‘‘G. Martino’’, Messina. 2Dipartimento di Oncologia, Sezione
di Oncologia Medica, Università di Palermo
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
Background: HER2 over-expression has been reported in 20%-30% of BC. TRA is
widely used as treatment of choice for HER2-positive MBC.
Purpose: To evaluate safety and activity of TRA containing therapies in HER2 positive
MBC patients (pts).
Patients and methods: 70 pts (median age 57 (31-81 yrs), ECOG PS/pts 0/56, 1/12, 2/2;
ER+ 57%, PR+ 40%, 49/70 pts with visceral disease and 41/70 with metastases in two or
more sites), treated with TRA from May 2001 to June 2006, were included in our
retrospective analysis. TRA was administered alone in 12 pts and in combination in 58
pts: 48% with vinorelbine, 29% with docetaxel and 23% with paclitaxel. Previous
treatments for metastastic disease were hormonotherapy in 11 pts (16%) and 1 or more
lines of chemotherapy in 25 pts (36%).
Results: First line treatment: RR 41%, SD 47%, with TTP 8 months (1-44); Second line:
RR 23%; SD 62% with TTP 9 months (3-23); beyond second line: RR 22%; SD 78%
with TTP 9 months (4-19). OS was 19,2 months (3-62). Median cumulative TRA dose
was 5286 mg (464-17940 mg). TRA was well tolerated. The median LVEF was at
baseline 62% and 59% at the end. Relevant adverse events were: only one asymptomatic
LVEF decrease to 40% (baseline 60%) requiring treatment discontinuation, 6 reversible
asymptomatic LVEF decrease (10% to 15%), 2 reversible tachycardia, 1 G3
hyperbilirubin, and 2 transient increase transaminases.
Conclusion: Trastuzumab containing therapies in MBC are safe with a remarkable
activity even in heavily pretreated women. Patients should benefit from continued
Trastuzumab therapy, as shown by the maintenance of TTP even beyond second line
treatment.
C27 TRASTUZUMAB DISCONTINUATION DUE TO
CARDIOTOXICITY IN WOMEN WITH HER2-POSITIVE OPERABLE AND
ADVANCED BREAST CANCER: A SINGLE INSTITUTION EXPERIENCE
Stefania Redana, Giorgio Valabrega, Renato Palmiero, Cinzia Ortega, Luisa Omini,
Massimo Aglietta, Filippo Montemurro
Istituto per la Ricerca e la Cura del Cancro, Candiolo, Torino, Italy
Background: Trastuzumab-related depression of myocardial contractility is of concern
and makes cardiac function monitoring mandatory during treatment. We sought to
compare treatment discontinuation because of trastuzumab-related cardiotoxicity in
women treated with trastuzumab-based therapy for advanced or operable breast cancer
(adjuvant setting).
Patients and methods: The medical charts of 113 patients with advanced disease and of
30 with operable disease were retrospectively analysed. All 143 patients underwent
regular monitoring of left-ventricular ejection fraction by ultrasonography and, if
required, by multiple gated acquisition scan. In patients with operable breast cancer
trastuzumab was started after the completion of chemotherapy and, if administered, of
radiation therapy and continued for 1 year. For these patients, we adopted the criteria
of the Agenzia Italiana del Farmaco (AIFA) protocol which called for definitive
trastuzumab stoppage in the case of congestive heart failure (CHF), LVEF drop
‡45%, or LVEF drop <50% with an absolute reduction compared to the baseline
value £10% during treatment.
Results: 10 patients, 5 with advanced (4%) and 5 with operable disease (20%), stopped
treatment because of cardiac toxicity (7%, 95% C.I. 4-12%). Of patients with advanced
disease, 2 developed congestive heart failure and 3 had an asymptomatic decline in
LVEF >20% or below the threshold of normality. Of patients receiving trastuzumab in
the adjuvant setting one developed symptomatic CHF, and 4 experienced an
asymptomatic reduction in LVEF. The Cox Proportional Hazard analysis showed that
the risk of trastuzumab stoppage was higher in patients treated in the adjuvant setting
(HR 3.674, p=0.02).
Conclusion: Trastuzumab is discontinued more frequently in the adjuvant than in the
metastatic setting on account of cardiotoxicity. This is due in part to stricter cardiac-
safety criteria adopted for patients with early disease. However, shorter time between
anthracycline-based chemotherapy and trastuzumab in the adjuvant setting is likely to
concur. Strategies aimed at increasing compliance to adjuvant trastuzumab by
reducing the risk of cardiotoxicity-related treatment stoppage are needed.
C28 NEOADJUVANT CHEMOTHERAPY WITH EPIRUBICIN-
VINORELBINE AND G-CSF IN LOCOREGIONALLY ADVANCED
BREAST CANCER: OUR EXPERIENCE
Savarino A, Fabiano E, Maniaci V, Puliafito I, Sauta M. G, Bene A
ASL 1 Agrigento; Human Pathology Department-Medical Oncology and
Innovative Therapies Unit, University of Messina
Neoadjuvant chemotherapy (NACT) has shown to be a valid help in the treatment
of locoregionally advanced breast cancer (LABC) because it reduces the use of
radical breast surgery. Epirubicin (EPI) and Vinorelbine (NVB) have demonstrated
to be the most active drugs. The aim of our study is to evaluate complete response
(CR), partial response (PR), stable disease (SD) and toxicity after 4 cycles of EPI/NVB.
From January to November 2006, twenty-four women with mean age of 48 years
old (32-69) were enrolled in this study. Clinical stage at diagnosis was T2:9 pts, T3: 7
pts, T4:8 pts. Lymphonodal status was N0:2 pts, N1: 10 pts, N2: 9 pts, N3: 3 pts.
Patients received EPI 100 mg/m2 i.v. day 1 plus NVB 25mg/m2/die from days 1 to
5 every 3 weeks for 4 cycles, with 300 lg of G-CSF as prophylaxis from day 8 to 13.
Volume 18 | Supplement 11 | October 2007
session C
Measurement of the left ventricular ejection fraction (LVEF) was carried out before
the first and after the fourth cycle. All patients completed cycles without dose
reduction. After the fourth cycle patients underwent modified radical mastectomy
(8 pts) or conservative surgery (16 pts). Radiotherapy was performed on patients
who underwent conservative surgery or in T4 tumours. Stage after surgery was: Stage
0 in 3pts, I in 7 pts, IIA in 5pts, IIB in 5 pts; IIIA in 4 pts. Her-2/neu pos in 9 pts and neg
in 15 pts. ER/PR status was ER-/PR-in 10 pts; ER+/PR+ in 9, ER+/PR- in 5. We
obtained: 6 CR; 14 PR; 4 SD. G1 thrombocytopenia occurred in 6 pts and G1 anemia
in 10 pts. Main non-haematologic toxicities were: G1 nausea (10 pts), G2 fatigue
(10 pts) and alopecia (all pts). No congestive heart failure was observed. The
combination of EPI and NVB is safe and effective in LABC pts. G-CSF offers
important benefits in terms of CT dose maintenance and haematological toxicity
prevention.
C29 DISTRIBUTION OF THE BRCA2-8765delAG MUTATION IN
BREAST CANCER IN MEDITERRANEAN AREA
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Grazia Palomba1, Antonio Cossu2, Mario Budroni2, Eitan Friedman3, Antonio
Farris4, Antonio Contu2, Marina Pisano1, Paola Baldinu1, Maria C. Sini1, Maria P.
Satta1, Milena Casula1, Francesco Tanda4, Giuseppe Palmieri1
1
Istituto di Chimica Biomolecolare-CNR, Sassari; 2Azienda USL 1, Sassari;
3
Chaim Sheba Medical Center, Tel-Hashomer, Israel; 4 Università degli Studi di
Sassari
Background: The BRCA2-8765delAG mutation was firstly described in breast cancer
families from French-Canadian and Jewish-Yemenite populations; it was then reported
as a founder mutation in Sardinian families. We evaluated both the prevalence of the
BRCA2-8765delAG variant in Sardinia and the putative existence of a common
ancestral origin through a genotype analysis of breast cancer family members carrying
such a mutation.
Methods: Eight polymorphic microsatellite markers (D13S1250, centromeric, to
D13S267, telomeric) spanning the BRCA2 gene locus were used for the genotype
analysis. Screening for the 8765delAG mutation was performed by PCR-based
amplification of BRCA2-exon 20, followed by automated sequencing.
Results: Among families with high recurrence of breast cancer (> 3 cases in first-degree
relatives), those from North Sardinia shared the same haplotype whereas the families
from French Canadian and Jewish-Yemenite populations presented distinct genetic
assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among
unselected and consecutively-collected breast cancer patients originating from the
entire Sardinia revealed that such a mutation is present in the northern part of the
island only [9/648 (1.4%) among cases from North Sardinia versus 0/279 among cases
from South Sardinia].
Conclusions: The BRCA2-8765delAG has an independent origin in geographically and
ethnically distinct populations, acting as a founder mutation in North but not in South
Sardinia. Since BRCA2-8765delAG occurs within a triplet repeat sequence of
AGAGAG, our study further confirmed the existence of a mutational hot-spot at this
genomic position (additional genetic factors within each single population might be
involved in generating such a mutation).
C30 ROLE OF VACUUM-ASSISTED BIOPSY (MAMMOTOME) IN
EARLY DETECTION OF BREAST CANCER
Pagni P. 1, Spinelli GP. 2, Miele E.1, Tomao F.1, Caprio G.1, Russillo M.1, Rossi L.2,
Ielapi T.2, Codacci Pisanelli G.1, Tomao S.2
1
Department of Experimental Medicine, ‘‘Sapienza’’ University, Rome, Italy;
2
Department of Experimental Medicine, University of Rome‘‘Sapienza’’-Polo
Pontino-Italy
Background: The role of vacuum-assisted biopsy tecnique (Mammotome) in detection
of early breast cancer (eBC) is still under evaluation. This minimal invasive device has
similar diagnostic accuracy of conventional core biopsy with few traumatisms and
aesthetical consequences. However mammotome can understimate some pathologies
such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). The
aim of our study is to evaluate advantages of eco-guided mammotome biopsy in early
detection and eventual complete excision of BC.
Patients and methods: Form January 2003 to January 2006, 229 female patients (pts)
with breast lesions were studied. The average age was 48 years (range 19–75).
Performance status (ECOG) was 0/1. The previous ultrasound examination showed
regular lesions in 173 pts (75,6%), irregular nodules in 39 pts (16,9 %), poly-lobate
nodules in 13 pts (5,6%) and dishomogeneous echostructure in 4 pts (1,7%). In 181
patients a rx mammography was also performed. All patients underwent biopsy under
echographic guidance using Mammotome with 11-Gauge needle.
Results: Hystology of biopsies carried out with Mammotome confirmed the
benign nature (fibroadenoma) of all 173 pts with echographically regular nodules.
There were 12 positive malignant pathology (10 ductal, 2 lobular infiltrating
carcinoma), 17 benign sclerosis adenosing lesions, 4 ADH and 4 fibroadenomas
diagnosed in pts with irregular nodules. The remaining biopsies showed NOS
benign lesions. The procedure was well tolerated and no side effects were reported.
The only complication of Mammotome biopsy is represented by haematoma in
a low percentage of pts.
doi:10.1093/annonc/mdm425 | xi43
session C
Conclusion: Mammotome biopsy of echographically evidenced lesions of the breast, in
our experience, is preferable if suspicion of malignancy is high. Comparing with FNAC
it gives more informations in terms of invasivity, grading, histotype and hormonal
receptors. It is a well tolerated procedure with little discomfort for the patient. Today
this device could be considered as an innovative technique for the diagnosis of BC
against it incisional and excisional biopsy and FNAC too.
C31 THE USEFULNESS OF 99MTC-TETROFOSMIN PLANAR
SCINTIMAMMOGRAPHY AND SPECT IN THE EVALUATION OF
NEOADJUVANT HORMONE OR CHEMOTHERAPY RESPONSE IN
LOCALLY ADVANCED PRIMARY BREAST CANCER (LAPBC)
Giuseppe Madeddu,1 Antonio Farris,2 Francesca Chessa,1 Daniela Sanna,1 Maria
Pittalis,2 Carlo Putzu,2 Susanna Nuvoli1 and Angela Spanu1
Depts. of 1Nuclear Medicine and 2Oncology. University of Sassari. Sassari. Italy
Aim: To evaluate and compare the usefulness of 99mTc-tetrofosmin planar
scintimammography (SM) and SPECT in monitoring neoadjuvant hormone or
chemotherapy response in LAPBC patients.
Methods: 24 LAPBC patients were studied before and after completing hormone (8
cases) or chemo (16 cases) neoadjuvant therapy prior to surgery. In all cases, following
740 MBq 99mTc-tetrofosmin i.v. injection, both conventional planar SM and SPECT
were acquired using a dual-head gamma camera with HR parallel hole collimators.
In 10 cases planar SM with a new developed small field of view high spatial resolution
(1.6 mm) DBC (LumaGEM 3200S/12k) mounted on a modified mammography unit
allowing similar projections of mammography and breast compression during
acquisition was also acquired. Planar and SPECT findings were evaluated visually,
mutually compared and correlated with definitive histopathological findings.
Results: Four patients had complete pathologic positive response, while residual tumor
was ascertained at histology in 28 patients. No uptake areas were detected at both
conventional planar SM and SPECT, excluding residual tumor after therapy in 3/3
(100%) cases. DBC planar SM was performed in 1 of these 4 cases resulting true
negative. Conventional planar SM detected residual tumor in 17/21 (80.9%) cases,
resulting false negative in 2 with a pT1c tumor and in 2 patients with subcentimetric
multiple and scattered tumor foci. SPECT was true positive in 19/21 (90.5%) cases, but
missed both subcentimetric tumors which were also false negative at conventional
planar SM. However, these latter 2 carcinomas were identified only at DBC planar SM
which was true positive also in the other 7 patients with macroscopic residual tumor in
whom the procedure was performed.
Conclusion: Both conventional planar SM and SPECT proved useful diagnostic tools
in monitoring neoadjuvant hormone or chemotherapy response in LAPBC. SPECT
appears more sensitive than conventional planar SM in detecting residual tumor;
however, our preliminary data seem to suggest that sensitivity can further increase by
high resolution DBC planar SM, especially in subcentimetric tumor foci.
C32 EVALUATION OF HER-2 STATUS ON CIRCULATING TUMOR
CELLS (CTCS) IN PATIENTS WITH BREAST CANCER
M Pestrin, S Bessi, M Truglia, F Galardi, S Cappadona, C Biagioni, W Claudino,
D Pozzessere, L Biganzoli, A Giannini and A Di Leo
Translational Research Unit, Dept. of Oncology, Hospital of Prato, Istituto
Toscano Tumori
Introduction: Recent studies suggest that HER-2 status of HER-2 negative primary
tumors could change during disease progression. The HER-2 status might be reassessed
at the time of starting treatment. Evaluation of HER-2 on CTCs isolated from blood
samples could represent a real-time analysis of the protein status.
Patients and methods: Study aims were to evaluate the correlation between:
1.CTCs number and disease features
2.HER-2 status on CTCs and primary tumor
Blood samples were obtained from 47 patients with breast cancer at different phases
(2 neoadjuvant, 7 adjuvant and 38 metastatic). CTCs were immunomagnetically
separated and fluorescently stained using the CellSearch Kit
. CTCs stained positive
for DAPI and CK8,18 and/or 19. The HER-2 status was assessed using the Tumor
Phenotyping Reagent
. Definition of HER-2 positivity was: primary as per standard
criteria; CTC ‡ 50% positive cells.
Results: CTCs could be detected in 1, 5, 31 patients in neo-adjuvant, adjuvant and
metastatic settings, respectively. The median CTCs number was 7/7,5 ml (range: 0-14),
3/7,5 ml (range: 0-5), 6/7,5 ml(range: 0-60.000), respectively. Correlation between
HER-2 status on CTCs and primary tumor was performed in 24 cases and we found
non-concordant results in 33% of cases: 39% of HER-2 negative primary tumors had
HER-2 positive CTCs and 17% of HER-2 positive primary tumors had HER-2 negative
CTCs.
Conclusions: We found CTCs in all disease phases. Moreover, our study suggests that
a subset of HER-2 negative patients develops HER-2 positive CTCs. Clinical evaluation
of anti-HER-2 compounds in the subset of patients carrying HER-2 negative primary
tumor and HER-2 positive CTCs is warranted.
xi44 | session C: early and advanced breast cancer
Annals of Oncology
C32 BIS CLINICAL BENEFIT OF FULVESTRANT IN HEAVILY
PRETREATED PATIENTS WITH METASTATIC BREAST CANCER
Giuseppa Scandurra, Guido Carillio, Rosa Anna Aiello, Maurizio Chiarenza,
Antonella Mazzola, Marco Alı̀, Gloria Barone, Filippo Greco, and Michele Caruso
Department of Medical Oncology, Humanitas Centro Catanese di Oncologia,
Catania, Italy
Fulvestrant is a steroidal estrogen receptor (ER) antagonist with no agonistic activity,
providing possible advantages over tamoxifen and other selective estrogen receptor
modulators (SERMs) in the treatment of hormone-sensitive breast cancer. The once-a-
month administration of fulvestrant 250 mg in 5 mL intramuscular injection produces
down regulation of ER levels through the bind to receptors and rapid loss of ER protein
in the tumour.
Since November 2005 to January 2007 we tested objective response, clinical benefit,
and safety of fulvestrant administered as maintenance or disease progression therapy in
heavily pretreated patients with metastatic breast cancer. Among 66 enrolled patients,
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56 of them were evaluable for the above end-points. Fifty-five female and one male
patient entered the study, ECOG PS 0-3, median age 59 years (range 32–87), estrogen
and progesterone receptor positive in 100% and 16%, respectively, HER-2/neu
overexpressed in 23%, bone metastasis as only site of disease in 14% of cases. All the
patients had already received on average two endocrine therapy lines (range 1–4) and
three chemotherapy schedules (range 1–6) including anthracyclines and taxanes.
With a median treatment duration of 5 months (range 2–18), we observed 3 partial
responses (5%) and 30 disease stabilizations (54%) for at least 6 months. The clinical
benefit rate was 59%. Partial responses occurred in patients with soft tissue or visceral
disease. A PS improvement was often recorded in the elderly patients (more than 70
years), compared with poor benefit in the younger women (less than 50 years),
probably because of more frequent HER-2/neu overexpression in the latter group.
Fulvestrant was well tolerated and none of patients reported noteworthy side effects.
Interestingly, we couldn’t always find a direct correlation between clinical benefit and
reduction of tumour markers, that probably reflects the slow and progressive drug
steady state reachable after 3 to 6 months of treatment.
Fulvestrant represents an effective and optimally tolerated therapy in heavily
pretreated patients with endocrine responsive metastatic breast cancer.
C34 PRELIMINARY RESULTS OF A DOSE-FINDING STUDY OF
PTK787/ZK222584 (PTK/ZK) IN COMBINATION WITH WEEKLY
VINORELBINE (V) AND TRASTUZUMAB (T) AS TREATMENT OF
PATIENTS (PTS) WITH METASTATIC BREAST CANCER (MBC)
OVEREXPRESSING HER-2/NEU, PREVIOUSLY TREATED WITH AT
LEAST ONE LINE OF CHEMOTHERAPY (CT)
G. Gasparini1, M. R. D’Andrea1, F. Cacciamani1, F. Salerno1, G. Filippelli2,
M. Lucia2, V. A. Lonoce1, and R. Sarmiento1
1
U.O. Oncologia Medica A.C.O. San Filippo Neri, Roma; 2Oncologia Medica
Ospedale ‘‘S. Francesco di Paola’’, Paola (CS)
Overexpression of HER2 in human cancer is associated with increased expression of
vascular endothelial growth factor (VEGF). The anti-HER2 monoclonal antibody
trastuzumab (T) inhibits tumor growth and VEGF expression. The combination of
vinorelbine (V), and T, is an active and safe 2nd-line treatment for MBC patients (pts),
overexpressing HER-2/neu. PTK/ZK is a potent, selective and orally active inhibitor of
VEGF-R tyrosine kinases. Based on the observation that HER2-induced VEGF
expression results in increased angiogenesis and that blockade of HER2 receptor and
VEGFR may result in superior antitumor efficacy, we have designed a Phase I dose-
finding study testing the combination of V, T, and PTK/ZK in HER-2/neu + MBC pts.
1ary objective of the study: MTD of the combination. 2ary objectives: safety,
pharmacokinetics (PK) and activity. The study design is based on 4 dose levels (DL): V
starting from 20 to 30 mg/mq (d 1-8-15, q 28), PTK/ZK from 500 mg/daily to 1250
mg/daily. 7 pts have been enrolled so far (median age: 54): median n. of metastatic
sites: 2; ER/PgR status negative (5/7), ER+/PgR- (2/7), HER-2/neu positive (3+ by
HercepTest in 6/7, FISH test amplified in 1 pt). First 3 pts were treated according to
the study design; no DLT was found; 3 more pts were then enrolled at the 2nd DL and no
DLT was also found. One pt has been enrolled at the 3rdDL. Combination therapy has
generally been well tolerated, being the most common toxicities observed: nausea G1
(2/7), muscoloskeletal diffusal pain G1 (2/7), pruritus G1 (1/7), non febrile neutropenia
G3 (2/7). 5 pts are evaluable for response: 1 RC and 4 SD have been observed. PK
analysis is also being conducted, by collecting blood samples on days 15 and 18 of the
cycle 0 (V and T alone), and on days 14, 15 and 18 of the 1st cycle (V, T, and PTK/ZK).
The PK analysis of both V and PTK/ZK is centralized and is ongoing.
C35 MODULATION OF g/d T-LYMPHOCYTES BY ZOLEDRONIC
ACID (ZA): RESULTS IN 23 DISEASE FREE PATIENTS WITH EARLY
BREAST CANCER HISTORY
Daniele Santini1, Federico Martino2, Maria Elisabetta Fratto1, Bruno Vincenzi1,
Sara Galluzzo1, Chiara Agrati2, Paola Piacentini2, Vittorio Altomare3, Federica
Turchi2, Fabrizio Poccia2 and Giuseppe Tonini1
1
Medical Oncology, University Campus Bio-Medico, Rome 2 National Institute
for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome 3 Breast Surgical
Unit, University Campus Bio-Medico, Rome
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
Introduction: Amino-bisphosphonates are potent activators of human c/d T cells both
in vitro and in vivo. ZA is able to activate c/d T cell effector functions also in patients
with advanced solid tumors. We conducted an osservational perspective study aimed to
evaluate immunomodulating properties of a single-dose of zoledronic acid on c/d T
cells in a selected patient subset.
Material and methods: 23 breast cancer patients without any evidence of macroscopic
disease and with diagnosis of osteopenia (Total T score </= -2) during inhibitor
aromatase treatment received a single-dose of zoledronic acid 4 mg. For each patient
blood withdrawals for total and c/d T lymphocytes evaluation (by cytofluorimetric
analysis) were obtained before ZA infusion and 7, 28, 56, 90 and 180 days after.
Results: No significant modifications in the absolute number of total lymphocytes, of
the different subsets and no of Vd1 and Vd2 T lymphocytes at the different timepoints
have been identified. Kinetics of the different c/d T cells subsets were determined:
a significant decrease of Naı̈ve Vd2 T lymphocytes after 180 days (p<0,01) and
a significant progressive decrease of Central Memory subset after 28 (p<0,05), 90
(p<0,01) and 180 days (p<0,01) was observed. ZA induced also a significant reduction
of Effector Memory Vd2 T lymphocytes after 56 (p<0,01) and 90 days(p<0,05).
Moreover, we observed that population could be divided in 2 subsets characterized by
a different c/d T lymphocyte kinetics: ‘‘responder patients’’ with a significant decrease
of c/d T lymphocytes total number and of Effector Memory and ‘‘no-responder
patients’’ without any significant modulation of c/d T lymphocytes.
Conclusions: A single dose of ZA has been shown, for the first time in literature, to
exert long-lasting activation of effector subsets of c/d T lymphocytes in healthy
patients. Data on functional analysis to verify a hypothetical constitutional anergy of c/
d T cells in no-responder patients will be presented during the meeting.
C36 NEO-ADJUVANT CHEMOTHERAPY (NACT) FOR BREAST
CANCER (BC): IS CONSERVING SURGERY STILL THE TARGET?
Ruscelli S, Masini C, Cortesi L, De Matteis E, Di Emidio K, Proietto M, Iacchetta F,
Braghiroli B, Pesce E, Federico M
Cattedra di Oncologia Medica II, Dipartimento di Oncologia ed Ematologia,
Università degli Studi di Modena e Reggio Emilia
Background: NACT was initially proposed in locally advanced inoperable disease and
also in operable BC to achieve downstaging of the tumour, avoiding mastectomy.
Moreover NACT offers the chance to use the tumour as an in vivo measure of response.
Patients and methods: We analysed 256 cases of invasive BC treated at Modena Cancer
Center between 1988 and 2005 with NACT, focusing on the rate of tumour reduction
and rate of breast-preserving surgery. Moreover we also compared the outcome of
patients treated with NACT with 4665 treated with surgery up-front.
Results: At time of diagnosis tumour size was < 2 cm (T1) in 14 patients (5.5%),
between 2 and 5 cm (T2) in 111 (43.4%), more than 5 cm (T3) in 34 (13.3%) and
locally advanced (T4) in 97 (37.9%); axillary nodes were clinically positive in 171
patients (67.8% ) including 113 (42.9%) N1, 33 (12%) N2, and 25 (9.1%) N3. 227
tumours were infiltrating ductal carcinomas (89%), 137 were G3 (54.4%), 59 (23%)
were RE- and 77 (30%) PR -. The more frequent regimens were ADM-including in
139 cases (54%), ADM and Taxanes in 75 (29%) and CMF in 23 (9%). A downstaging
was achieved in 63 patients with clinical T2 (57%), in 32 T3 (94%) and in 47 T4 (48%).
Surprisingly, only 68 patients (27.3%) underwent conserving surgery. Five-year
recurrence free survival rate was 56%, being 66% and 51% for patients treated with
conserving surgery and mastectomy, respectively (p=0.08). Comparing patients treated
with NACT with those treated up-front with surgery, we found that the 5-year
recurrence free survival was 65% vs 92% (p<0.001) for patients in stage I, 66% vs 81%
(p=0.02) in stage II and 46%vs 62% (p<0.001) in stage III.
Conclusions: Our data show the inefficacy of the NACT to achieve downstaging of the
tumour. Moreover, the outcome of responders suggests that the downstaging achieved
with NACT did not overcome the adverse prognostic effect of disease extension before
NACT.
C37 PROGNOSTIC AND PREDICTIVE FACTORS RELATED TO
BREAST CANCER CLINICAL HISTORY: AN OUTCOME STUDY
Donati D, Giuliani J, Guarino S, Urbini B, Margutti G, Indelli M, Durante E*,
Querzoli P*, Beccati D*, Guerzoni F**, Bonetti F, Carandina I, and Lelli G
Clinical Oncology Unit, *Breast Cancer Program, **Pathology Unit and **Health
Statistics, Azienda Ospedaliero-Universitaria, Ferrara, Italy
Introduction: Prognostic factors correlate to the final therapeutic outcome
independently from the therapy; predictive factors are those that correlate with cancer
therapy efficacy. Outcome studies evaluate the most reliable parameters that may
define the long term result of different strategies.
Materials and methods: Computer clinical record-chart of breast cancer patients
visited for the first time at our institution between 1/1/1999 and 31/12/2005 were
enriched with bio-pathologic data. Data were copied on paper forms at first and then
inserted into a computer database. Each patient form contemplates 181 items. They are
arranged to automatically calculate overall, disease free and progression free survival
for each patient.
Results: Database includes data concerning 1227 patients. Among these, 195 were
metastatic at diagnosis (104 deceased, 69 alive with metastases and 22 lost during
Volume 18 | Supplement 11 | October 2007
session C
follow-up) and 1032 were without metastases at diagnosis (52 deceased, 791 alive e 186
lost during follow-up).
Conclusions: Such structured database allows to obtain several informations in
order to design retrospective studies, obviously knowing their limits, such as the need
of high numbers of patients to evidence subtle differences. Nevertheless retrospective
studies are able to observe the real cohort status so defining the impact of different
factors in order to plan prospective studies later. They also may influence sanitary
policy choices and available resource distribution.
C38 CLINICAL USE OF THE SERUM MARKER HER-2/NEU IN
PATIENTS WITH BREAST CANCER
Dalu D, Cattaneo MT, Piazza E, Piva S, Gambaro A, Tosca N, Gabris A,
Filipazzi V, Esani G, Ferrario, Somma L, Sarnataro C, Zambelli S, Damiani E
Oncology Department, Sacco Hospital, Milan
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
Background: Her-2/neu is the extracellular domain of the membrane receptor Her-2,
overexpressed in cancer cells. Its levels appear to be increased in aggressive breast
cancer and in patients who do not respond to therapy.*
Methods: We selected 51 patients, from 37 to 79 years of age. The first group was made
up of 31 patients with early-stage breast cancer and the second group of 20 patients
with advanced Her-2 positive (2+ and 3+) breast cancer that were starting a course of
chemotherapy (CMF, FEC or Trastuzumab). We considered the levels of Her-2/neu
before and after surgery and before and after chemotherapy. We evaluated the levels of
serum Her-2/neu using the automated ADVIA Centaur Immunoassay System (cut-off
=12,7 ng/ml) and the expression of the tissue antigen HER-2 using the
immunohistochemical method HercepTest DAKO Corp.
Results: In the first group of patients who underwent surgery we observed a reduction
in the number of patients who had levels of Her-2/neu above the cut-off point after
surgery (67 % before surgery and 33 % after surgery) and a reduction of the average
level of Her-2/neu (15,6 ng/ml before surgery and 11,8 ng/ml after surgery). Also in the
second group of patients we recorded a reduction of the average levels of Her-2/neu:
from 63 ng/ml, before chemo-therapy (range 8,7 – 283,5), to 31 ng/ml after the
treatment (range 7,7 – 39), the number of pts with levels above the cut-off falled
from 81% to 27%.
These variations poor correlate with the clinical response to chemotherapy.
Conclusions: We observed a reduction in the levels of Her-2/neu in both groups of
patients but the correlation with clinical response was poor.This would enable us to
arrange a closer follow-up or identify the patients who are not responding to treatment.
* Diana Luftner ‘‘Serum HER-2/neu in the management of breast cancer patients.’’
Clinical Biochemistry 36 (2003).
C39 TRIPLE-NEGATIVE BREAST CANCER: OUR EXPERIENCE
Alessandro Bertolini, Elisabetta Menatti, Ornella Fusco, Eliana Berardi,
Fabio Malugani, Mario Fiumanò
Oncology Unit Ospedale Civile Sondrio
Background: Triple-negative breast cancers are defined by a lack of expression of
estrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all
types of breast cancer and for a higher percentage of breast cancer arising in African
and African-American women who are premenopausal. Triple negative tumors are
associated with a shorter survival. Patients with BRCA1 mutations develop
predominantly triple negative tumors.
Method: We reviewed in our database as prognostic factors women with breast cancer
history in the last four year. We decided to look for triple negative population and to
observe outcome after treatment.
Results: We observed 170 breast cancer, 19/170 (11.2%) of these were triple negative.
They have: ductal histological type in 18 pts and lobular in 1 pt. Grade: G3 18 pts and
G2 1 pt. Their stage at diagnosis was: I 9 pts, IIA 2 pts, IIB 6 pts, IIIA 1 pt and IIIC 1 pt;
the adjuvant treatment was CMF+RT in 8 cases, AC+T in 6 cases, FEC in 3 cases,
Taxotere in 1. 5/19 (26.3%) progressed during follow up with median PFS 20 months.
On the contrary the group not triple negative progressed for 10.6% (16/151). Some of
them were HER2 positive.
Conclusion: According to literature triple negative population in near to 15% of all
patients and they have a poor prognosis. In our study we have less patients because the
entire group is selected by need of treatment. The outcome of the group is different
from the general population. We think that lymphnode stage, grading, and tumor size
are still the most useful prognostic markers, but also other factors must be now
considered.
C40 THE MEANING OF TIME FOR BREAST CANCER PATIENTS
Cinzia Bonforte, Giuseppe Pastura, Giuseppa Scandurra, Vincenzo Adamo
Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie Integrate,
A.O.U. Policlinico ‘‘G. Martino’’, Messina
Purpose: To re-consider changes occurring into the meaning of time in cancer
experience.
doi:10.1093/annonc/mdm425 | xi45
session C
Methods: Qualitative study by narrated interviews with a sample of 6 women,
conducted in DH and interpreted using Bergson’s theory. Finding: Three times
emerged: time-changing, feelings of dis-integration, length of time prospected to the
end of life.
Result: Women felt a break into their experience of time which has changed, in
particular feelings about length, which gave continuity and connected present with the
past and future, are changed. Patient’s need to tell their history from the beginning
showed the importance to integrate cancer memory into life-memory of patients.
Conclusion: Using Bergson’s theory, we may assume that the idea of a chronological
time scanned is relative. In cancer experience, dimension of time is changed in deep.
There is a disagreement between objective time, beaten by rhythm toward illness,
and a subjective one, a time of mind, following the personal history of patients and
their possible end. Time subjective is not discontinued, it is the result of complete
history of individual representation, that is, first of all, history of body experience.
In fact we ‘‘haven’t’’ a body. We ‘‘are’’ it. It’s important to underline, assuming
memory as unit of this time, that it doesn’t exist in body-memory, the presence of
cancer. So time subjective is disturbed by need to integrate this experience.
Research implication: Although some articles of breast cancer investigating on time
now exist, future research into the experience of breast cancer is necessary.
Clinical implication: Health professional need to be aware to give patients, possibility
to re-consider the meaning to cancer into their life-time.
C41 SAFETY OF ZOLEDRONIC ACID IN BONE METASTATIC
BREAST CANCER PATIENTS: A RETROSPECTIVE ANALYSIS
Giuseppa Ferraro, Nicola Caristi, Marcello Maugeri Saccà, Concetta Arcanà,
Barbara Adamo, Roberta Briguglio, Mariangela ZanghÌ, Vincenzo Adamo
Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie
Integrateate, A.O.U. Policlinico ‘‘G. Martino’’, Messina
Background: Zoledronic acid is a new nitrogen-containing-bisphosphonate showing
a good activity in pain and skeletal events related to metastatic bone disease, with
a favourable safety profile.
Materials and Methods: We retrospectively evaluated the safety of a standard dose
(4 mg every 3 or 4 weeks in 15 minutes infusion) of zoledronic acid in 68 bone
metastasized breast cancer patients treated from January 2004 to January 2007. Median
number of administrations was 14 (range 4-68). 37 patients (54,4%) received
chemotherapy and 51 (75%) received hormonotherapy. Skeletal related events (SRE),
were defined as spinal cord compression, pathologic bone fractures, bone surgery, bone
radiotherapy and hypercalcaemia. Bone pain was evaluated with VAS pain scale.
Results: Among 68 evaluable patients, 31 (45,5%) experienced one SRE and 6 (8,8%)
had more than one SRE. Only 3 patients (4,4%) did not obtain a good pain control. We
observed 5 (7,3%) hypocalcaemia, 5 (7,3%) acute reactions, such as pyrexia and
myalgia, 4 (5,8%) increased serum creatinine levels (1,6 to 2,2 mg/dl), 2 (2,9%)
periodontal pain and 1 (1,4%) conjunctivitis. Despite this good safety profile, 2
patients (2,9%) developed osteonecrosis: 1 patient had osteonecrosis of the jaw (ONJ)
and 1 had double osteonecrosis of jaw and maxilla. Both patients underwent dental
extraction during zoledronic acid treatment, being in the course of a third-line
chemotherapy. Theese patients received 18 and 29 zoledronic acid administrations,
respectively. Patients developing ONJ had weight loss and worsening of PS.
Conclusions: our data confirm a good safety profile of zoledronic acid. ONJ was a rare
but important side effect, heavily affecting QoL of patients.
C42 HIGH-DOSE SEQUENTIAL CHEMOTHERAPY WITH
AUTOLOGOUS HAEMATOPOIETIC STEM CELLS SUPPORT IN VERY
HIGH-RISK EARLY BREAST CANCER PATIENTS (PTS): ANALYSIS OF
LONG TERM RELAPSE-FREE SURVIVAL AND TOXICITY
Alessandra Bernardi, Nicoletta Cacciari, Francesca Sperandi, Claudio Zamagni
and Andrea Angelo Martoni
Medical Oncology Unit S.Orsola-Malpighi Hospital, Bologna, Italy
Background: Results of randomized phase III trials of high-dose chemotherapy
with autologous haematopoietic stem cells support (HDCT) in the adjuvant treatment
of breast cancer were mainly considered negative and this therapeutic approach has
been abandoned by many. However several questions about the role of HDCT in this
setting remain unanswered and a meta-analysis is ongoing.
Methods: Twenty-five consecutive high risk early breast cancer pts with at least 45
months of follow-up treated in our institution with HDCT are included in the present
analysis. Median age was 44 (range 24-59 years) and 15 pts were premenopausal. The
median number of axillary lymph-nodes metastases was 13 (range 3-49) and the
pathological stage was IIB in one pt, IIIA in 3 pts, IIIB in one pt and IIIC in 20 pts.
The 10-year risk of relapse of pts with disease characteristics similar to those of our
study population is about 80-85%. Estrogen and/or progesterone receptors were
positive in 15 pts and negative in 10 pts. HER-2 status was known in 18 pts and 5 pts
(28%) were positive (HER-2 3+ (IHC) and/or FISH). The HDCT regimen used was
cyclophosphamide 7g/m2 plus G-CSF (followed by apheresis of peripheral
haematopoietic stem cells), methotrexate 8 g/m2 followed by thiotepa 600 mg/m2 and
melphalan 160 mg/m2 or by mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 and
stem cells reinfusion.
xi46 | session C: early and advanced breast cancer
Annals of Oncology
Results: At a median follow-up of 7,5 years (range 3,8–8,5 years) 13 pts (52%) relapsed
and 11 pts (44%) died. The most common sites of recurrence were lung, liver and
bones; 6 pts developed brain metastases and in 2 cases a bone marrow infiltration was
documented. No toxic deaths and no long term toxicities (except irreversible
amenhorrea in all the premenopausal pts) were observed. No secondary malignancies
occurred. Overall, the median relapse-free survival is 65,1 months, while the median
overall survival has not been reached yet. 3/5 (60%) HER-2 positive pts relapsed.
Conclusions: In our experience high-dose sequential chemotherapy with
autologous stem cells support is a safe treatment with no toxic deaths and no
long-term toxicities. This regimen should therefore be further investigated if
translational research will be able to identify subgroups of pts with the highest
probability to benefit from intensive chemotherapy.
C43 MALE BREAST CARCINOMA, A MONO INSTITUTIONAL
EXPERIENCE
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
Paola Bergnolo, Antonella Boglione, Simona Chiadò Cutin, Paolo Pochettino,
Orietta Dal Canton, Cristiano Oliva, Manuela InguÌ, Ferdinando Garetto,
Alessandro Comandone
U.O.A Oncologia, Ospedale Gradenigo, Torino
Male breast cancer is a rare disease not completely understood. Principles of
management of this tumour derived from trials done in women. We describe our
experience about treatment of male breast cancer.
Patients (pts) and methods: A total of 16 men with diagnosis of breast carcinoma were
treated in our Institution since 1998. The median age is 61 (46-72). 15 tumours were
infiltrating ductal carcinomas, 1 was DCIS (ductal carcinoma in situ); G2: 8 pts, G3:
7pts, 1 G unknown.
HER2 overexpression was measured by immunostaining in 6 pts and was negative in
all of them.
Staging of disease at the time of diagnosis: pTis: 1, pT1c pN0: 3, pT2pN0: 2, pT1c
pN1: 2, pT2 pN1: 4, pT2 pN2: 1 pT3 pN2: 1, pT4 pN2: 2. All of them received radical
mastectomy and axillary dissection.
Tumours were estrogen receptors positive > 10% in 13 pts, 12 pts received hormonal
therapy (all of them received tamoxifen, one patient refused hormonal therapy).
Adjuvant chemotherapy was administered in 13 men; 10 pts received anthracycline-
based regimes (4 of them also taxanes) and 3 were treated with CMF.
5 pts relapsed: 2 nodes, 1 chest wall, 2 bone metastasis, all received chemotherapy for
metastatic disease (3 died for disease). Median follow-up is 26 months (4-103), overall
survival is 46 months (4 – 119).
In our series none have a family history of breast cancer, but 4 (25%) pts showed
another neoplasm before diagnosis of breast cancer: 1 testicular seminoma, 2 prostate
carcinoma and 1 pts seminoma and prostate carcinoma. These data accord to those of
literature on the correlation between gonadal disfunction, due to disease or for
treatment, and male breast cancer.
The treatment of male breast carcinoma was suggested by the standard of care for
women, large studies are necessary to improve information about previous neoplasm,
course and cure of the disease.
C44 PHASE II TRIAL OF NON-PEGYLATED LIPOSOMAL
DOXORUBICIN (MYOCETâ) ASSOCIATED WITH WEEKLY
DOCETAXEL IN METASTATIC BREAST CANCER
V. Safina1, N. Giuntini1, L. Coltelli1, F. Martella2, R. Di Marsico1, E. Bejtja1,
P. G. Giannessi1, A. Falcone1*
1
Istituto Toscano Tumori. Department of Oncology. Azienda ASL 6, Livorno
Anthracyclines and taxanes are the most active drugs in metastatic breast cancer
(MBC) treatment. Mostly patients receive anthracycline-based therapy in adjuvant
setting and dose-cumulative cardiotoxicity represents a limit to re-treatment in
metastatic disease. Myocet
demostrates better cardiac tolerability than conventional
anthracyclines and interesting activity in combination with taxanes. We therefore
designed a phase II study to define the activity and tolerability of Myocet
60 mg/sqm
iv d1 combined with Taxotere
37,5 mg/sqm iv d1,8 q21 for six courses in MBC
patients previously treated with an anthracycline-based chemotherapy. Up to day
16 patients have been enrolled in the study (median age of 56 years and a median
number of 2 metastatic sites). All patients had received epirubicin-based adjuvant
treatment (median cumulative dose 420 mg/sqm) and had left-ventricle ejection
fraction (LVEF) above 50%. So far 75 courses have been administered (median number
of cycles for pt: 6) and the main toxicities observed were: neutropenia G3/G4 6%/8%
(with 2 episodes of febrile neutropenia); diarrhoea G3 1%; mucositis G3 1%. No other
haematological or non haematological noteworthy toxicities were reported.
No significant reduction of LVEF was registered by ultrasound monitoring
performed every two cycles. In one case LVEF fell below 50% after the fourth cycle, but
rapidly recovered. 14/16 pts are evaluable for activity (one too early and one withdrawn
from protocol because of drug infusion reaction). 8 patients (57.1%) obtained partial
response, 5 patients (35.8%) had a stable disease and 1 patient (7.1%) progressed
during treatment. The study is still ongoing considering the promising activity and the
good profile of tolerability of the combination. Supported by A.R.C.O. foundation.
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
C45 SAFETY AND EFFICACY OF INHALED IL-2 THERAPY IN PRE-
TREATED BREAST CANCER ELDERLY PATIENTS WITH
PULMONARY METASTASES
Marco Burgio, Fernanda Bellomo, Giuseppe Bronte, Annapaola Carreca, Dario
Piazza, Sergio Rizzo, Salvatore Russo and Ignazio Carreca
Medical Oncology Unit, University of Palermo, Palermo, Italy
Introduction: Inhaled interleukin(IL)-2 therapy has been reported to prevent
progression of pulmonary metastases of renal cell carcinoma, melanoma, breast and
ovarian cancer. Several patients have been treated with inhaled IL-2 therapy as single
therapy or in combination with systemic immunotherapy and/or chemotherapy with
minimal toxicity.
Patients and methods: Twelve elderly breast cancer patients (median age 66.5, range
60-77), with radiologically documented progressing pulmonary metastases after at least
two lines of prior systemic chemo- and/or hormonal therapy, were enrolled. All
patients had to be able to comply with inhalation technique, and were not candidates
for other treatment options. Before treatment all patients were evaluated for
Comprehensive Geriatric Assessment (CGA), ECOG PS and QoL (EORTC-QLQ-C30).
The protocol included twice-daily inhalation of nebulized IL-2 at a maximum dose
of 18 million IU/day, 5 days a week. Treatment was continued until progression, life
threatening toxicity, or patient refusal. Response was assessed only in the targeted
pulmonary lesions using the Response Evaluation Criteria in Solid Tumors (RECIST)
system. Toxicity was determined following WHO criteria.
Results: 3 pts achieved a partial pulmonary remission, 4 pts experienced stabilization of
pulmonary disease. One patient discontinued treatment because of cough and dyspnea.
Most of the pts did not show respiratory symptoms under inhalation therapy; few pts
showed slight fever. Only mild leucopenia and thrombopenia (WHO grade 1) were
observed. No patient experienced severe adverse events. QoL scores improved
significantly compared with pretreatment scores.
Conclusions: Our data suggest that inhaled IL-2 therapy is associated with minimal
toxicity and is effective in delaying progression of pulmonary metastases in advanced
breast cancer pts heavily pretreated. Inhalation therapy may be applied to almost all
elderly patients with co-morbidities. Under treatment all pts enjoy a good QoL. This long-
term safety treatment might contribute to turn progressive cancer into a chronic disease.
C46 EFFECT OF FULVESTRANT TREATMENT ON COMPLETE
BLOOD LIPID PROFILE IN HORMONE-SENSITIVE METASTATIC
BREAST CANCER PATIENTS
Andrea Camerini1, Domenico Amoroso1, Ornella Garrone2, Sara Donati1, Gianna
Tartarelli1, Maura Vincenti3, Chiara Valsuani1, Olimpia Siclari1, Cheti Puccetti1,
Romana Prosperi Porta4, Marianna Rondini1, Paolo Pronzato5, Alessandro
Sgambato6
1
Medical oncology, Ospedale Versilia - AUSL 12 Viareggio; 2Medical oncology,
Ospedale Santa Croce e Carle - Cuneo; 3Medical oncology, Ospedale degli
Infermi - Biella; 4Medical oncology, Ospedale S. Chiara - Pisa; 5Oncologia
medica A, IST - Genova; 6Universita Cattolica - Roma
Background: Fulvestrant (F) is a pure anti-estrogen agent available for post-
menopausal hormone-sensitive advanced breast cancer (ABC) treatment. Aim of the
study is to analyze the effect(s) of F on lipid profile, endometrial mucosa and
coagulation indices (CI).
Patients and methods: 31 pts (mean age 64.5 ± 9.8 yrs) with hormone-sensitive ABC
were enrolled. All patients (data on 28 pts) received at least one previous hormone-
treatment (HT) course, with 89.3% receiving ‡2 HT courses. Last HT was
exemestane in 17/28, letrozole in 6/28 and other in 5/28 with a median withdrawal time
of 18 days (range 3–1456). All pts but three received at least one previous CT regimen,
with 60% receiving ‡2 CT regimens. Complete fasting lipid blood profile and CI were
assessed before F administration, every 3 months and at discontinuation time.
Endometrial mucosa thickness was evaluated by trans-vaginal echography before F
administration and at end-study time. All patients referred no significant dietary
changes during treatment. Body weight and body mass index did not vary during study.
Pts receiving statins were excluded.
Results: Pts received a median of 5 F injections (range 3-19). We observed SD in 12 and
PD in 16/28 pts with a mean time to progression of 6.5 ± 3.9 months. Total cholesterol
(C) levels significantly decreased during treatment (222.9 ± 50.2 vs 204.7 ± 43.5 mg/dl;
p = 0.0047) together with LDL-C (129.4 ± 43.9 vs 117.4 ± 40.2 mg/dl; p = 0.012).
Instead, HDL-C (64.9 ± 17.7 vs 65.3 ± 18.3 mg/dl; p = ns) and triglycerides (140.2 ±
62.4 vs 137.9 ± 59.4 mg/dl; p=ns) did not vary. Reduction of C and LDL-C was
independent from the type of last HT or the treatment duration. Mean endometrial
mucosa thickness and CI value did not vary.
Conclusions: We observed a clear lipid lowering effect of F. We suggest a possible effect
of F on lipid metabolism.
C47 ACTIVITY AND SAFETY OF FRONTLINE DOCETAXEL AND
CAPECITABINE COMBINATION THERAPY IN PATIENTS WITH
METASTATIC BREAST CANCER(MBC)
S. Ceniti, V. Liguori, S. Turano, R. Biamonte, R. DeSimone, A. Filice, C. Manfredi,
C. Mastroianni, A. Rovito, C. Viscomi and S. Palazzo
Volume 18 | Supplement 11 | October 2007
session C
Medical Oncology Division,Cosenza,Italy
Background: MBC is a chronic disease and no treatment may be considered as the
standard approach.Capecitabine(C) and Docetaxel (D) have demonstrated synergy in
both preclinical and clinical studies in MBC, but not in clinical practice.
Methods: From February 2005 to September 2006, 13 consecutive pts with median age
44 (range 26-68), ER+ 50%PG+65%HER2 3+ 30%,performance status 2 or better
(ECOG), adequate bone marrow, renal, hepatic and cardiac function ; no prior
chemotherapy for metastatic disease; previous adjuvant chemotherapy (8 with
anthracyclines and 5 CMF) received six or eight cycles: D75 mg/m2 i.v. on day 1 + C
850 mg/m2 p.o. bip on days 1-14 each q3w and in HER2 3+ Trastuzumab 8 mg/kg
loading dose and 6 mg/kg each q3w, or until unacceptable toxicity. Routine medication
for D was given. Primary endpoint was ojective response according to WHO criteria.
Results: Disease sites were 3 LN, 2 chest wall, 2 bone,7 lung, 9 liver. Mean age was
44(range 26-65)A total of 95 cycles was given, with median 6 (range 2-10). 6 pts had
G2/3neutropenia,0 febrile neutropenia,5 G3 hand-foot syndrome, 9 G1/2 stomatitis
and diarrhea, 6 G1/2, 5nausea/vomiting, 7 asthenia.With median follow-up of 28 wks
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
(range 7-52).
There were 3 RC((23%),5 RP(38.6%), 2 SD(15.4%) and 3 PD(23%).All the RC
and 3 RP were observed in anthracycline naı̈ve, 2 RC and 2 RP were observed in HER
2+ Trastuzumab administered. Median response duration was 25 wks and median
TTP was 30 wks.
Conclusions: DC combination is a efficacious frontline-therapy also in clinical
practice, with high RR in pts anthracycline naı̈ve MBC, and an important treatment
option for women with anthracycline-pretreated, with the manageable toxicity profiles.
C48 CORRELATION BETWEEN PLASMA D-DIMER LEVELS AND
AXILLARY LYMPHNODE STATUS IN OPERABLE BREAST CANCER
PATIENTS
V. Fregoni1, L. Regolo2, A. Zambelli1, G Da Prada1, P. Preti, L. Ponchio1,
L. Pavesi1, A. Costa2
1
Divisione di Oncologia Medica 2IRCCS Fondazione S Maugeri, Pavia, Italy
In patients bearing solid tumours, several mechanisms may induce activation of the
coagulation process. The extent of such activation has been reported as correlating with
tumour stage and prognosis in some malignancies. D-dimer is a stable end-product of
fibrin degradation, and levels of D-dimer are elevated by enhanced fibrin formation
and fibrinolysis. Consistently, D-Dimer levels are increased in patients with various
solid tumours.
Some authors have suggested a tight correlation between early tumour metastasis,
lymphovascular invasion, and plasma D-dimer levels in operable breast cancer patients.
However, the usefulness of combining plasma D-dimer levels with sentinel lymph node
biopsy (SNB) in primary breast cancer is still unclear. The aim of our study is to verify
a possible correlation between quantitative D-dimer levels (Instrument Laboratory)
and lymph node involvement, in particular focusing on sentinel node (SN) status.
One hundred forty-two breast cancer patients were enrolled in the study. All patients
(aged 29-84) underwent preoperative D-dimer plasma evaluation before surgery.
40 out of 142 patients (28 %) underwent axillary lymph node dissection, while 102/
142 patients (72%) were eligible for SNB technique.
The median D-dimer level of the whole series was 210 ng/ml (range 45-709)
D-dimer levels resulted higher in patients with nodes involvement as compared with
nodes negative patients. However this difference did not reach the statistical
significance (p=0.37), both for patients with multiple metastatic axillary nodes
(p=0.27) and for patients with single SN involvement (p=0.60).
In conclusion, we found no statistical correlation between D-dimer plasma levels
and clinical stage in breast cancer patients. Such lack of correlation does not support
the hypothesis that D-dimer plasma might be related to lymphovascular invasion and
clinical stage.
C49 DIFFERENT TRASTUZUMAB SCHEDULE ALLOWS
SAVING MONEY
E. Pazè, D. Perroni
Ospedale Civile, Saluzzo (CN)
The availability of new very expensive drugs is challenging health systems because of
the economic burden on budgets. Some strategies have been devised in order to use
targeted therapies appropriately, but still ways to reduce costs are needed.
Trastuzumab is a new drug used in advanced and early breast cancer. It was initially
used at a dose of 2 mg/kg/week, but proportionally higher doses and longer intervals
proved to be pharmacokinetically equivalent and safe, and now it is commonly
administered at a dose of 6 mg/kg every 3 weeks. For a 60 kg woman this schedule
translates into administering 360 mg per cycle. Being the drug marketed in 150 mg
strength vials, 3 vials are needed to prepare the appropriate dose for each cycle.
We think that a strategy to minimise drug wastage is flexibility in the frequence with
which the treatment is administered. We administer Trastuzumab at a fixed dose of
300 mg per patient, and we schedule the administrations so that every patient receives
the 2 mg/kg/weekly dose intensity. For instance a 60 kg woman will therefore receive
300 mg every 17-18 days, so for one year treatment it translates into using 44 vials of
doi:10.1093/annonc/mdm425 | xi47
session C
drug (2 · 22 administrations) rather than 52 (3 · 17 administrations) with 15% of
costs saving.
A table with most common body weights and corresponding intervals can be easily
drawn (see below).
Kg 6 mg/kg/3w Vials for Vials for Intervals (days) N. cycles in Vials for Costs
1 cycle 1 year with 300 mg 1 year 1 year saving
fixed dose
55 330 mg 3 52 19 20 40 23%
60 360 mg 3 52 17–18 22 44 15%
65 390 mg 3 52 16 23 46 12%
70 420 mg 3 52 15 25 50 4%
C50 REVERSION OF ENDOMETRIUM THICKNESS AFTER THERAPY
SWITCH FROM TAMOXIFEN TO AIS IN BREAST CANCER PATIENTS
Laura Pisanu, Davide Adriano Santeufemia, Giovanni Maria Fadda, Giovanni
Sanna, Maria Giuseppa Sarobba, Carlo Putzu and Antonio Farris
Cattedra di Oncologia Medica, Università di Sassari, Sassari, Italy
Purpose: To investigate the effect on endometrium thickness of third generation
aromatase inhibitors (AIs), administered as adjuvant switched therapy in
postmenopausal women with endocrine-responsive breast cancer and abnormal
uterine bleeding (AUB) or transvaginal ultrasonography (TU) proven of asymptomatic
Tamoxifen-induced endometrial thickening.
Materials and methods: 35 postmenopausal women who was taking adjuvant
tamoxifen 20 mg/day (> or =12 months, < or = 48 months) and developed AUB and/or
asymptomatic endometrial thickness >9 mm were switched to an AI. 8 patients (23%)
were switched to Anastrozole, and 20 (57%) and 7 (20%) women were treated with
Letrozole and Exemestane respectively. All patients underwent endometrial
investigation before the start of AIs therapy and, thereafter, at 10 month intervals.
Endometrial assessment was based on TU; hysteroscopy and endometrial biopsy were
performed if necessary.
Results: Median age of women was 67 years. The mean Tamoxifen intake duration was
27± 13 months. The mean endometrial thickness at baseline TU was 13± 4 mm.
Hysteroscopy with endometrial biopsy was performed in 24 patients (68,5%):
benignant uterine abnormalities were diagnosed in 3 cases (8,6%). The average period
of endometrial surveillance after the start of AIs therapy was 10±.8 months and
a progressive decrease of endometrial thickness (mean 8±.6mm) was observed in 21
(68%) woman (p=001). Of those 13 (62%) where switched to letrozole, 5 (23%) to
exemestane and 3 (15%) to anastrozole. During AIs administration no endometrial
pathology was found in all patients.
Conclusions: When administered as switched therapy after tamoxifen withdrawal, AIs
may reverse tamoxifen-associated endometrial thickening.
C51 TOPOISOMERASE II ALPHA EXPRESSION IN INVASIVE
DUCTAL CARCINOMA OF THE BREAST WITH FIBROTIC FOCUS
Antonino Mafodda, Raffaella Giuffrida, Marzia Mare, Giusi Blanco, Stefania
Munaò, Lorenzo Memeo, Dario Giuffrida
Dipartimento di Oncologia Sperimentale, Istituto Oncologico del Mediterraneo,
Viagrande (CT)
Invasive ductal carcinoma (IDC) with fibrotic focus (FF) is a rare, recently described
subtype of IDC with aggressive characteristics and significantly poorer survival. FF is
composed of fibroblasts and various amounts of collagen fibers, and they occupy
almost the entire center of the IDC. IDCs with FF exhibit significantly greater tumor
angiogenesis and higher tumor cell proliferative activity and the presence of FF is an
independent prognostic parameter. IDCs with FF are characterized by higher
frequencies of Her2 protein expression, abnormal nuclear accumulation of p53 and
aneuploidy than those without FF. In addition, the former show significantly higher
proliferation activity than the latter. These findings indicate that the presence of FF in
IDCs is an important histological parameter for predicting the outcome of patients
with IDC of the breast.
Recent clinical trials have suggested that patients whose breast tumors overexpress
HER2 may derive particular benefit from anthracycline-containing chemotherapy
compared to that without anthracycline. It has been proposed that the HER2
amplification might mask an underlying TOP2A amplification that occurs frequently
and concurrently with HER2 amplification probably due to the close genomic position
on chromosome 17. Topoisomerase II alpha, is a direct molecular target of
anthracycline and is potentially useful as a predictive marker of response to
anthracycline therapy.
Therefore we studied Topoisomerase II alpha expression by immunohistochemistry
in five cases of IDC with FF selected from the files of our institution.
Patient’s age ranged from 43 to 71 (mean, 60 years); all cases showed an high
proliferation index (Ki-67>20%) while 4 of 5 demonstrated Her-2 overexpression, in
line with the previous findings about IDC with FF and 3 of 5 were positive for both ER
and PR.
We found that Topoisomerase II alpha was overexpressed in all the 5 cases studied,
and if this data will be confirmed by larger cohorts of patients, it would suggest that
xi48 | session C: early and advanced breast cancer
Annals of Oncology
patient with IDC with FF would benefit from an anthracycline-containing
chemotherapy.
C52 THE REHABILITATION OF FEMALE BREAST CANCER
PATIENTS
M. Panella*, A. Di Leo*, S Santini*, E. Cantisani*, M. C. Villani , S. Bonini ,
I. Bessi , S. Nepi , A. C. Marinià, and A. Bevilacqua§
*Dipartimento Oncologico- USL 4 di Prato, Ospedale di Prato, Istituto Toscano
Tumori,  Associazione Progetto Aurora Donna Onlus, àU.O. Recupero ed
educazione funzionale, §C.Ri.D.A – Centro di Riabilitazione Ambulatoriale
Introduction: Cancer represents for the patient and the family an event that involves all
aspects of life: the patient’s relationship with his/her own body, the meaning of pain,
disease, death, social and professional relationships.
Objectives: The main objective of this project is improving the quality of life in patients
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with breast cancer through the integration of a multidisciplinary staff, and the patient’s
family in a way that is completely supportive of the patient.
An innovative aspect is the clinical management of the activities of all professionals
involved in the cure and rehabilitation process, in synergy with volunteer services and/
or associations, where breast cancer patients can talk in a confidential environment
with volunteers who have lived with and been through cancer.
Methods and instruments: The plan foresees the active involvement of several
professional figures and the active participation of the patient. Main steps of the plan
are as follows: 1. Experimentation of the integrated program in the defined and
structured ‘‘continued assistance’’ 2. Diagnosis that finds its fulcrum in the
‘‘Acceptance’’ of the disease 3. Rehabilitation program foresees: specialist visit(s),
functional evaluation before and after treatment, psychological counseling, survey of
needs (indicated by the staff), individual rehabilitative treatment, informative/
formative seminaries and meeting of patients, relatives, hospital staff and volunteers.
All steps are monitored and aim at effectuating the necessary corrective actions in
order to improve the services rendered.
Conclusions: The project is ongoing. At the meeting we will present the early results of
this rehabilitation program.
C53 VINORELBINE (VNB) AND 5FLUOROURACIL (5FU)
COMBINATION IN PATIENTS WITH ANTHRACYCLINE AND
TAXANE-PRETREATED METASTATIC BREAST CANCER (MBC):
A PHASE II STUDY
Cristiano Oliva, Manuela InguÌ, Paola Bergnolo, Paolo Pochettino, Simona Chiadò
Cutin, Antonella Boglione, Manuela Biscardi, Ferdinando Garetto, Orietta Dal
Canton, Alessandro Comandone
UOA Oncologia, Ospedale Gradenigo, Torino
VNB and 5FU are effective drugs in MBC. Anthracyclines and Taxanes are often used in
adjuvant setting or as first line treatment. Patients (pts) with MBC undergo often
different lines of chemotherapy (CT).
To evaluate safety and efficacy of the combination of VNB and 5FU we started
a phase II study in pts with MBC previously treated with Anthracyclines and Taxanes.
From 12/2002 to 12/2006 43 pts (median age 59; range 38-76) were treated with
the combination of bolus Folinic Acid (FA) 100 mg/m2 intravenous (IV), bolus 5FU
400 mg/m2 IV, and 24 hours continuous infusion 5FU 600 mg/m2 on days 1-2, and
VNB 25 mg/m2 on day 1 every 14 days for 6 months. 432 cycles of CT were administered
(median 12, range 3-12). 22 pts (51,2%) completed the 6 months treatment.
Patients were all pretreated with Anthracyclines and Taxanes in adjuvant setting or
for metastatic disease. Most common sites of metastatic spread were: bone 26, liver 22,
lymph nodes 15, lung 12, local recurrence 8. 23 pts (53,5%)received this therapy as first
line CT, 16 as 2nd and 4 as 3rd. PS (ECOG) was 0-2 (median 0). We recorded
neutropenia G3 19 times (4,4% of cycles), fatigue G3 in 5 cases and G3 mucositis in 4.
4 pts interrupted CT cause intolerable toxicity (1 liver toxicity, 1 febrile neutropenia,
1 chronic constipation, 1 protracted G3 mucositis).
12 pts (27,9%) achieved a partial response, 21 (48,8%) had no changes and
10 (23,3%) experienced disease progression.
After a median follow up of 15,6 months, median time to progression was 9,2
months and median overall survival was 17,3 months.
In our phase II study VNB and 5FU demonstrated an interesting activity with an
acceptable toxicity in Anthracyclines and Taxanes pretreated pts with MBC. The regimen
warrants development with administration of oral VNB and fluoropyrimidine derivates.
C54 DOSE-DENSE ‘‘MYTAX’’ REGIMEN IN BREAST CANCER: A
DOSE-FINDING STUDY
M. Mancini1, K. Cannita1, A. Santomaggio1, M. Tudini1, F. De Galitiis2,
A. I. Rispoli1, F. Martella1, G. Porzio1, M. Pelliccione1, P. Lanfiuti Baldi1, A. Bafile3,
P. Marchetti3, C. Ficorella1, E. Ricevuto1
1
Medical Oncology, S. Salvatore Hospital, University of L’Aquila
Background: We describe the toxicity of dose-dense TLC-D99 and Docetaxel (TXT) in
breast cancer patients (pts).
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
Methods: Nine pts were enrolled in the dose-finding study and treated with a fixed
TXT dose (50 mg/m2) days 1 and 15, and TLC-D99 at three dose levels, 40-45-50
mg/m2 days 1 and 15 every 2 weeks, using an intra- and inter-patient approach. Dose-
limiting toxicity (DLT) was defined as G3-non haematological or G4 haematological.
Cardiac monitoring was planned with LVEF and Precursor Brain Natriuretic Peptide
(PBNP).
Results: Disease extension: metastatic breast cancer (MBC), 5; locally advanced BC, 2;
T2-T3 BC, 2. Previous chemotherapy: untreated, 6 pts; adjuvant chemotherapy, 3 pts.
Patients enrolled for each dose-level: I, 7; II, 8; III, 8. Newly treated patients: I does-
level, 7; II dose-level, 2. Total valuable cycles, 53: I dose-level, 14; II, 19; III, 20. Total
DLTs in 3 patients, 33%, and 3 cycles, 6%: 2 cardiac, characterized by a 19% LVEF
decrease and an arrhythmia with symptoms; one G4 hematologic resistant to G-CSF.
DLTs at single dose-level per patients and cycles, respectively: I, 14% (1/7 pts) and 7%
(1/14 cycles); II, no DLT in 8 pts and 19 cycles; III, 25% (2/8 pts) and 10% (2/20 cycles).
Cumulative G3-4 toxicities by patients and cycles, respectively: cardiac arrhythmia
11% and 2%, cardiac general (symptomatic FEV decrease), 11% and 2%; alopecia 89%
and 49%; neutropenia resistant to G-CSF, 11% and 2%. Cardiac DLTs were observed in
2 pts >65 y old. G2 toxicities by patients and cycles, respectively: asthenia 44% and
20%, stomatitis/mucositis 11% and 2%, nausea 33% and 11%. Median rDI of TLC-
D99 was 22,5 mg/m2/w and TXT 25 mg/m2/w per patient, respectively. Objective
responses in 8 assessable pts: MBC, 3 PR and 2 SD; LA-BC, one pCR; T2-T3 BC, 1 PR
and 1 SD.
Conclusion: To date, maximum tolerated dose wasn’t reached, thus the third dose-
level (TLC-D99, 50 mg/m2) can be recommended for phase II studies.
C55 FULVESTRANT AND CAPECITABINE IN ELDERLY ADVANCED
BREAST CANCER PATIENTS: THE PROPOSAL FOR AN EFFECTIVE
AND SAFE COMBINED TREATMENT SCHEDULE
Giuseppe Bronte, Fernanda Bellomo, Marco Burgio, Annapaola Carreca,
Dario Piazza, Sergio Rizzo, Salvatore Russo and Ignazio Carreca
Medical Oncology Unit, University of Palermo, Palermo, Italy
Background: Fulvestrant is the first of a new class of pure estrogen receptor
antagonists. It was studied in comparison to anastrozole and tamoxifen in the 1st and
2nd line of hormonal treatment in women with advanced breast cancer. AIM: Since
elderly patients develop rapid and often fatal toxicity during treatment with cytotoxic
drugs, we tried to design a new schedule for combined chemo-endocrine therapy in
elderly breast cancer patients. The target is to identify a treatment regimen that could
be effective and safe for pre-treated and comorbid pts with positive comorbidity score.
Methods: 20 elderly advanced breast cancer patients (mean age 70; range 65-86)
previously treated with adjuvant endocrine therapy. Comprehensive Geriatric
Assessment (CGA) was previously performed. Primary endpoint: clinical response
rates (RR) according to WHO criteria. Secondary endpoints were toxicity profile using
NCI-CTC v2.0 and quality of life (QoL) score measured through EORTC QLQ-C30
questionnaires.
Results: 20 pts were treated with capecitabine 1000 mg/m2 twice daily p.o. on days 1
to 14 every 21 days and fulvestrant 250 mg as a single 5 mL intramuscular injection,
once-monthly until disease progression. Based on CGA all patients were included into
groups I-II, according to Balducci’s classification of frailty. None of the pts needed any
delay in drugs delivery. We observed 7 (35%) objective responses (OR) (2 complete
(CR); 5 partial responses (PR)). Stable disease was acquired in 8 (40%) pts. Clinical
benefit in 15 (75%) pts. No grade-4 toxicity was found. QoL score underwent
amelioration after treatment in all pts.
Conclusions: This pilot study could identify a safe schedule for managing elderly
comorbid breast cancer pts, that couldn’t be treated otherwise. Preliminary data are
encouraging, thus induce the authors to continue and enlarge the study in order to
confirm these first outcomes.
C56 PRIMARY SYSTEMIC THERAPY FOR ADVANCED INOPERABLE
BREAST CANCER
V. Palmisano, V. Leonardi, A. Pepe, A Usset, C. Arcuri, A. Laudani, G. Savio,
G. Rondello, A. Giresi, P. Amari and B. Agostara
Dipartimento di Oncologia PO ‘‘M. Ascoli’’, ARNAS Civico Palermo
Background: Primary systemic therapy is used in the treatment of patients with
advanced inoperable breast cancer in order to downstage the primary breast tumor.
Docetaxel and Epidoxorubicin are some of the most active agents in the treatment of
breast cancer.
Patients and methods: Fourty five patients with histologically confirmed advanced
inoperable breast cancer were treated with epidoxorubicin 30 mg/mq weekly and
docetaxel 35 mg/mq weekly for 6 consecutive weeks every 8 weeks for two cycles.
Clinical tumor size and nodal status were assessed by palpation and by ultrasound
before each cycle of chemotherapy.
The main characteristics of enrolled patients were: median age 54 (range 34-62),
median initial clinical tumor size 6 cm (range 2-13), 7 patients had inflammatory breast
cancer. Axillar lymph nodes were palpable in 75 % patients; out of 56 % had hormone-
receptor-positive disease and 20 % of tumors showed over-expression of HER2/neu.
Volume 18 | Supplement 11 | October 2007
session C
Results: The clinical response rate was 79 %. All patients but 5 proceeded to surgery, all
patients but 3 were treated with modified mastectomy. All patients received 3 o 4 cycles
of adjuvant chemotherapy, in addition hormonotherapy was given to patients with
hormone-receptor positive tumors after completion of chemotherapy. Non-
hematological toxicity was generally moderate with grade 3-4 toxicity in 11 % of the
cycles; most common non-hematologic toxicities were nausea and vomiting, alopecia
mucositis and asthenia. Hematological toxicity grade 2-3 was observed in 14 % of the
patients.
Conclusion: The preliminary data seems to show a safe and highly effective
combination treatment for patients with advanced inoperable breast cancer. If these
results will be confirmed, we extending this approach to the management of patients
with earlier stages of breast cancer.
C57 FOUR YEARS OF EXPERIENCE WITH COMBINED WEEKLY
NON-PEGYLATED LIPOSOMAL DOXORUBICIN AND TAXANE IN
BREAST CANCER SECOND-LINE TREATMENT
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M. S. Rosati, M. L. Basile, P. C. Sacco, L. Cerbone, G. Pasciutti, T. Falbo,
M. Di Seri
Dpt of Clinical Oncology, University ‘‘La Sapienza’’, Rome, Italy
Introduction: We performed a phase II study to determine the activity and toxicity of
combined weekly non-pegylated liposomal doxorubicin (Myocet
)and taxane as
second line treatment in patients with advanced breast cancer.
Patients and methods: Thirty-two patients with stage IV breast cancer and ECOG
PS 0-1 were treated with liposomal doxorubicin (25 mg/m2) and (schedule A)
paclitaxel (50 mg/m2) or (schedule B) docetaxel (30 mg/m2) on days 1,8 and 15 every 4
weeks for a maximum of six cycles. Twenty patients had received prior chemotherapy
with an anthracycline regimen. Twenty-seven patients had disease at multiple sites.
Hepatic and pulmonary disease were the predominant metastatic site.
Results: Seventeen patients (median age, 56 aa) were treated with schedule A and
fifteen patients with schedule B. G1-2 hematologic toxicities (mainly neutropenia)
occurred in 27% of cycles while G3-4 occurred in 16%. Significant alopecia G3 was
common (72%) and cutaneomucous toxicities G3-4 occurred in 18% of cycles (three
patients). Except for mucositis (4% vs 32%, p< 0.05), there were no differences in
terms of toxicity between schedule A and B. LVEF was conserved throught all cycles.
Overall response (OR) was 87.5% and median time to progression (TTP) was
8.08 months (2.8-13.4); 4-years overall survival was 25.02 months (15.2-30.6).
Conclusion: Giving a combination of non-pegylated liposomal doxorubicin and
taxane at weekly intervals as II line treatment in advanced breast cancer is an active and
well tolerated approach with good toxicity profile. Our data encourage phase III trials.
C58 FULVESTRANT (FASLODEX) IN WOMEN WITH
METASTATIC BREAST CANCER AFTER PROGRESSION ON
PRIOR ANTI-ESTROGENIC THERAPY
Pasqualina Di Bitonto*, Antonio Abate*, Giacomo Vessia*, Mario De Lena**
*Struttura Semplice di Oncologia, Struttura Complessa di Medicina, P.O.
UMBERTO I, Viale Regina Margherita, ALTAMURA.** Oncologic Consultant
Background: The estrogen receptor has proven to be the single most important target
in breast cancer over the last thirty years, changing therapeutical and preventive
approach to this disease. After tamoxifen, a selective ER modulator, Aromatase
inhibitor (AI) have proven to be more efficacious in first and second line therapy and
even in adjuvant setting in post menopausal women. Fulvestrant is the first pure
estrogen receptor degradation and has proven to be just as effective as Aromatase
inhibitors in breast cancer patients who have had disease recurrence or progression and
pretreated with tamoxifen and aromatase inhibitors.
Aim: To evaluate efficacy and tolerability of Fulvestrant.
Patients and methods: From August 2006 to March 2007 we treated with Fulvestrant
ten post-menopausal patients with metastatic breast cancer in progression, pretreated
with tamoxifen and aromatase inhibitor.
Eigth patients were affected by a tumor with Estrogen (ER) and Progesteron
receptor (PgR) positive. Two patients were ER positive but PgR negative. Median age
was 63 years (range 48-78), PS: 0-1, visceral disease in six patients, skeletal disease in
four patients. CA 15-3 was high in 8 patients.
Results: Important side effects were not observed, but 70% of patients referred
a sensation of ‘‘burst of heat’’on day three or four after Fulvestrant injection. After six
months of this treatment seven patients were valuable for disease response: six had
stable disease whereas one had progression disease; in all patients (8) there was
a reduction of 50% of the marker CA15-3.
Conclusions: These data demonstrate that Fulvestrant is a well-tolerated treatment,
which allows marker control after prior anti-estrogenic therapies.
C59 CMFVP IN HEAVILY PRETREATED ADVANCED BREAST
CANCER (BC)
Claudia Mucciarini, Giampaolo Di Carlo, Fabrizio Artioli
Medical Oncology Unit, Ramazzini Hospital, Carpi, Modena, Italy
doi:10.1093/annonc/mdm425 | xi49
session C Annals of Oncology

Refractory advanced breast cancer is one of the most controversial areas for medical
oncologist.
The efficacy of second and subsequent lines of chemotherapy in this setting is
uniformly poor.
Anyway women with fairly good compliance can be expected to live for a long time
and should be offered the chance to benefit from multiple chemotherapy lines.
We used a modified schedule of CMFVP in the treatment of metastatic BC patients
with a good performance status whose disease was resistant to various
chemotherapeutic regimens, including anthracyclines and taxanes.
We treated 10 patients with cyclophosphamide 100 mg die orally every day,
metotrexate 25 mg/mq and 5-FU 400 mg/mq on day 1 weekly, vincristine 1 mg i.v. on
day 1+8 and afterwards once a month, prednisone 12,5 mg/day orally for 14 days from
day 1 and subsequently 7,5 mg daily, until progression and/or toxicity.
Mean age was 60 years (range 54-67); ECOG PS was 0-1; all patients had multiple
metastatic sites except one that had only brain lesions; sites of involvement were as
follow : brain, lymphonodes and/or bone 50% of pts, liver, pleura and/or lung 25% of
pts. Mean number of previous chemotherapies was 5 (range 3-7). The schedule had a
evalueting the role of AIs. With this intent, all RCTs where patients were randomized to
receive standard tamoxifen or Ais (whatever strategy) were meta-analyzed.
Methods: A literature-based meta-analysis was accomplished, and event-based
relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed-
(FEM) and a random-effect (REM) model according to the inverse variance and
heterogeneity test were applied as well. Absolute difference (AD) and the Number
of patients Needed to Treat (NNT) were calculated. A linear regression model
considering 5-years DFS and OS rates has been used to look for correlation, estimated
by adopting the Pearson, R2 (parametric tests) and Spearman (non-parametric test)
coefficients.
Results: In an overall sample of 10 RCTs (27653 patients), 8 RCTs reporting all data
were eligible for the correlation analysis. AIs significantly improved DFS, with a AD
ranging from 2.3 to 3.5%, which translate into 29-43 NNT; OS was significantly
prolonged in the overall an in the early switch strategy, with an AD of 0.8 and 1.61%,
which translate into 120 and 62 NNT, respectively.
Population Pts (#RCTs) RR (95% CI) p Het. AD (%) NNT

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mild toxicity, with 6 pts developing grade 2-3 neutropenia without fever, 5 pts with
a grade 2 nausea, 3 pts with a grade 2 astenia and 2 pts with a grade 1/2 neuritis.We had FEM/REM
a 25% of partial response and a 50 % of partial response/stable value of the bioumoral DFS Overall 27563 (10) 0.80 (0.76, 0.85) <0.0001 0.034 2.8 36
rate of CA 15.3 (elevated in all the pts). The response was obtained only on the 0.77 (0.69, 0.85) <0.0001
lymphonodes sites. At present, 75% of the patients is dead, the most for brain disease Up-Front 11163 (2) 0.86 (0.80, 0.94) 0.0004 0.58 2.3 43
progression. Early Switch 8776 (5) 0.76 (0.68, 0.84) <0.0001 0.14 3.5 29
In conclusion, in our experience this combination had a mild toxicity and a quite Late Switch 7624 (3) 0.67 (0.56, 0.80) 0.00001 0.28 2.5 40
low efficacy in very heavily pretreated BC patients, expecially if brain lesions are OS Overall 25109 (8) 0.89 (0.82, 0.97) 0.01 0.16 0.8 120
present. Up-Front 11163 (2) 0.95 (0.86, 1.06) 0.41 0.59 - -
Early Switch 8776 (4) 0.80 (0.69, 0.92) 0.003 0.17 1.61 62

C60 AXILLARY NODE DISSECTION AND SENTINEL LN: A
MONOINSTITUTIONAL EXPERIENCE
Fasola C, Filipazzi V, Gambi V, Piazza E, Damiani E, Isabella L, Ferrario
S, Somma L, Cattaneo MT, Tosca N, Zambelli S, Gambaro A, Sarnataro C.
e Nosenzo MA
Oncology Department, Sacco Hospital, Milan (Italy)
Background: We evaluated disease recurrence after surgery in breast cancer pts with or
without sentinel lymph-node (LNS +/-) who did, or did not, undergo axillary node
dissection.
Methods: From 2002 we recruited 103 patients:17 in pre and 86 in post menopause, on
average 63 years old (29-80), with early-stage breast cancer (T<=2,5cm),staging with
identifying the LNS, biopsying it, resection of the tumour, followed by systemic therapy
(CT-HT) and locoregional therapy (RT). The follow-up included a chest X-ray, an
abdominal ultrasound, a yearly mammogram or breast ultrasound, a clinical
examination, an evaluation of the tumour markers and a bone scintigraphy for the first
five years. Ultrasound of the axillary region was performed every three months for two
years if the LNS +.
Results: In 76 patients (74%) the LNS -, 27 patients (27%) metastasis were found.
In this second group 14 patients (52%) underwent radical surgery of the axillary
region and 13 patients (48%), of whom 4 had macrometastasis, did not undergo
surgery given the favourable prognostic factors (age, high expression of ER-PR, stage
T, HER-2 score 0) and the patient’s desires. These 27 patients underwent adjuvant
chemo-therapy with schedules containing anthraciclines followed by hormone,
according to the guidelines of S.Gallen 2003. After a median follow-up of 36 months we
observed disease progression in 4 patients (mTTP 20 months). Two with LNS -
(2,6%)one had an axillary and the other a lung recurrence. The other two were in LNS
+ and both had a loco-regional recurrence without any difference between the surgery
groups.
Conclusions: This data suggests that lymph node involvement is not as decisive as the
biological characteristics of the tumour in the choice of the therapy. Even if there is no
formal indication for radical surgery with LNS -, there is not sufficient data to prove
that, in cases LNS + for micrometastasis, immediate axillary dissection is better than
observation after an aggressive chemotherapy. We will continue with a follow-up at 5
years.
C61* SHOULD DISEASE FREE SURVIVAL (DFS) BE USED AS
SURROGATE END-POINT FOR OVERALL SURVIVAL (OS) IN
RANDOMIZED CLINICAL TRIALS (RCTS) EXPLORING ADJUVANT
AROMATASE INHIBITORS (AIS) FOR BREAST CANCER (BC)?
UPDATE OF A META-ANALYSIS LOOKING AT THE MAGNITUDE OF
THE BENEFIT
Federica Cuppone, MD1, Emilio Bria, MD1, Mariangela Ciccarese, MD2, Cecilia
Nisticò, MD1, Paolo Carlini, MD1, Isabella Sperduti, PhD3, Vito Lorusso, MD2,
Edmondo Terzoli, MD1, Francesco Cognetti, MD1, Diana Giannarelli, PhD3
1
Department of Medical Oncology, Regina Elena National Cancer Institute,
Rome, Italy; 2Medical Oncology, Vito Fazzi Hospital, Lecce, Italy; 3Biostatistics,
Regina Elena National Cancer Institute, Rome, Italy;
Background: To date, DFS is considered the traditional end-point for adjuvant RCTs
in BC. Actually, its eventual correlation with OS has not been addressed in trials
A linear strong correlation between DFS and OS was present in the overall population
(r=0.78, R2=0.60, p=0.001; Rho=0.77, p=0.001), and in the early switch strategy
(r=0.83, R2=0.68, p=0.003; Rho=0.84, p=0.002). A trend for correlation was found in
the upfront strategy as well (r=0.88, R2=0.79, p=0.11; Rho=1.00), maybe not-
significant for the low number of accrued RCTs.
Conclusions: With these data, DFS confirms to be an accurate and reliable surrogate
end-point for OS in RCTs exloring AIs as adjuvant endocrine treatment for early BC.
The predictive role of earlier DFS (3-years) estimation for ultimate/late survival
deserves a deeper analysis.
C62* TIMING OF ADJUVANT CHEMOTHERAPY AND TAMOXIFEN IN
WOMEN WITH BREAST CANCER: FINDINGS FROM TWO
CONSECUTIVE TRIALS OF GRUPPO ONCOLOGICO NORD-OVEST
-MAMMELLA INTERGRUPPO (GONO-MIG) GROUP
Lucia Del Mastro1, Beatrice Dozin2, Enrico Aitini3, Tiziana Catzeddu1, Editta
Baldini4, Antonio Contu5, Antonio Durando6, Saverio Danese7, Giovanna
Cavazzini3, Giuseppe Canavese8, Paolo Bruzzi2, Paolo Pronzato1 and Marco
Venturini1,9
1
Oncologia Medica A, Istituto Nazionale per la Ricerca sul Cancro, Genova –
Italy. 2Epidemiologia Clinica, Istituto Nazionale per la Ricerca sul Cancro,
Genova –Italy. 3Presidio Ospedaliero C. Poma, Mantova, Italy. 4Ospedale S.
Chiara, Pisa, Italy. 5Ospedale Civile, Sassari, Italy. 6DH oncologico, Ospedale S.
Anna, Torino, Italy. 7Divisione Ginecologia ed Ostetricia C, Ospedale S. Anna,
Torino, Italy. 8Senologia Chirurgica, Istituto Nazionale per la Ricerca sul Cancro,
Genova –Italy. 9Current affiliation: Oncologia Medica, Ospedale Sacro Cuore,
Negrar – Verona, Italy
Purpose: The aim of the present study was to analyze the timing of adjuvant
chemotherapy and tamoxifen (TAM) in breast cancer women. We evaluated the
outcome of both premenopausal and postmenopausal women who were enrolled in
two randomized trials (GONO-MIG1 and GONO-MIG5) on adjuvant chemotherapy
and who received either concurrent or sequential TAM.
Patient and methods: We considered for the analysis patients who received any of the
three antracycline-based regimens used in GONO-MIG1 and MIG5 studies and
concurrent or sequential TAM. The end-point was overall survival (OS). Hazard ratios
of death or recurrence for treatment comparisons were estimated by Cox proportional
hazards regression models.
Results: We analized data of 1183 patients, 575 (48.6%) received concurrent TAM and
608 (51.4%) received sequential TAM. At 10 years the OS was 83% (95%CI:79-87) and
80% (95%CI:75-86%) in the concurrent and sequential groups, respectively. Event free
survival (EFS) was 63% (95%CI:57-70%) in the concurrent and 55% (95 CI:43-67%)
in sequential groups, respectively. No significant difference in the hazard of death
(HR=1.12; 95%CI:0.78-1.6, p=0.53) and recurrence (HR=1.03; 95%CI: 0.81-1.32;
p=0.8) between the two groups was observed in multivariate analysis. A potential
interaction between timing of TAM and patient age was observed: a decreasing trend
(p=0.005) in HR of death with increasing age suggested that concurrent therapy might
be more effective than sequential therapy in young patients.
Conclusions: No outcome difference between sequential and concurrent chemo-
endocrine therapy in early breast cancer patients was observed. The potential advantage
of the administration of TAM concomitantly with chemotherapy in young patients
need further investigation in prospective trials.

xi50 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology
C63* IN PRE-TRASTUZUMAB ERA ESTROGEN RECEPTOR (ER)-
NEGATIVE, PROGESTERONE RECEPTOR (PR)-NEGATIVE, AND
HER2-POSITIVE INVASIVE BREAST CANCER (BC) HAD A POORER
PROGNOSIS COMPARED TO BC WITH TRIPLE-NEGATIVE
PHENOTYPE
E. De Matteis1, L. Cortesi1, S. Ruscelli1, S. Messinese1, G. Cervo1,C Cirilli1,
M. Federico1
1
Cattedra di Oncologia Medica II, Università di Modena e Reggio Emilia,
Background: Triple negative BC (ER-, PR- and HER2-) has been recognized as an high
risk BC that lacks the benefit of specific therapy targeting these proteins. However, also
double negative BC (ER-, PR- and HER-2+) should be regarded as high risk BC. We
compared the outcome of triple and double negative BC treated at Modena Cancer
Center (MCC) in the pre-tastuzumab era.
Patients and methods: 2191 women diagnosed with BC between 1999 and 2006,
resident in the Province of Modena and referred to the MCC were evaluated. Triple-
negative were compared to double negative and other BC, in terms of clinical
presentation and outcome.
Results: One hundred and seventy triple-negative BC (7.8 %) and 85 double negative
BC (3.9%) were found and compared with 1936 hormonal sensitive BC (88.3%).
Compared to triple negative BC those with double-negative BC had larger tumours
(p=0.008), node positive status (p=0.030) and high grade (p<0.0001). Double-negative
BC had also a poorer outcome compared with triple-negative and other BC; the 5-year
survival rate was 72%, 76% and 89%, respectively for double-negative, triple-negative
and other BC (p<0.001). Also the DFS was significantly shorter for double-negative
(72%) than for triple-negative (76%) and for other BC (88%) (p<0.001). As a result,
the event-free survival at 5 years was worst for double-negative (53%) than for triple-
negative (66%) and for other BC (77%) (p<0.001).
Conclusions: In the pre-trastuzumab era double-negative BC are to be considered at
higher risk than those with triple-negative phenotype in terms of recurrence, event free,
and overall survival. Our finding confirm the additional negative role of HER-2
overexpression, that seems fortunately overcome by the availability of specific target
therapy.
C64* COGNITIVE AND SEXUAL SIDE EFFECTS OF ADJUVANT
THERAPIES IN EARLY BREAST CANCER PATIENTS (BC PTS).
RESULTS FROM THE NORA STUDY
Cazzaniga ME1, Mustacchi G2, Pronzato P3, De Matteis A4, Di Costanzo F5, Rulli E6,
7
Latini L, 1Barni S, 8Merlano M, 9Floris C on behalf of NORA Study Group
1
Treviglio Hospital, 2University of Trieste, 3IST Genova, 4Pascale Institute,
5
Careggi Hospital, 6Mario Negri, 7Ospedale Civile di Macerata, 8Ospedale
S.Croce e Carle di Cuneo, 9Ospedale Oncologico ‘‘Armando Businco’’ - ASL
8 - Cagliari
Background: Chemo- and endocrine therapies administered in the adjuvant setting
present peculiar adverse events (AEs), mainly in the acute time. On the contrary, few
data are available about the late AEs, in particular those regarding the cognitive and
sexual area.
NORA is a cohort study aimed at investigating treatment modalities and clinical
outcome in 3515 early BC pts radically resected in 71 Oncological Italian Centers.
Patients and methods: We collected cognitive and sexual AEs by using a dedicated
CRF only throughout the prospective cohort, in which we asked doctors to report the
number and the typology of AEs per pt. We asked to fill in cognitive and sexual form
not before than 3 months from the start of the adjuvant therapy and every 3 months
thereafter . 584 pts (46.8%) had at least 1 report, 326 had 3 reports.
Results: Median age of pts with cognitive disorders was 54.9 years, the one of pts
with sexual disorders was 52.6 (44.7-80.8. At baseline, 136 pts (23.3%) reported
cognitive AEs, 133 (22.8%) sexual ones. Among 136 pts with cognitive AEs, 63 (46.3%)
had memory disorders, 57 (41.9%) difficulty in concentration, 96 (70.6%)
behavioural and 25 (18.4%) required psychological support. Sexual disorders were:
modification of the libido (51 pts, 38.5%), vaginal dryness (87, 65.4%), recurrent
urinary infection (21, 15.8%) and hair loss (24, 18%). During the approximately 1-year
follow up period, 89 (27.3%) and 96 pts (29.4%) reported to have had 1or more
cognitive or sexual disorder, respectively. Among cognitive AEs, most pts had
behavioural disorders (63/89, 70.8%), whereas among sexual AEs, vaginal dizziness was
the most frequent (60/96, 62.5%). The majority of the pts reported cognitive and
sexual AEs when treated with chemotherapy followed by hormones (47/152, 30.9%
and 56/152, 36.8%), respectively.
Conclusion: Late AEs coming from adjuvant treatments, even if often misunderstanding,
represent an important medical and social issue in the strategy of BC pts.
C65* SAFETY COMPARISON OF WEEKLY DOCETAXEL VS CMF AS
ADJUVANT CHEMOTHERAPY FOR ELDERLY BREAST CANCER
PATIENTS (THE ELDA TRIAL)
A. de Matteis, F. Nuzzo, M. C. Piccirillo, S. Gori*, A. Morabito, F. Di Rella,
A. Gravina, V. Labonia, G. Landi, C. Pacilio, E. Rossi, G. D’Aiuto, R. Thomas,
M. D’Aiuto, M. Rinaldo, G. Signoriello, C. Gallo, F. Perrone
On behalf of the NCI-Naples Breast cancer Group
Volume 18 | Supplement 11 | October 2007
session C
*Ospedale Silvestrini, Perugia
Background: The ELDA phase 3 study (cancertrials.gov ID: NCT00331097) is
comparing weekly docetaxel vs CMF as adjuvant treatment of elderly breast cancer
patients. An amendment has been approved in December 2006 to adjust methotrexate
dose according to creatinine clearance. Safety data collected before the amendment
have been compared.
Patients and methods: Early breast cancer patients, 65 to 79 years old, are eligible if
they have metastatic lymphnodes or average to high risk of recurrence according to
2001 St.Gallen criteria, PS£ 2, adequate bone marrow, renal and hepatic function.
Patients are randomly assigned to CMF (cyclophosphamide 600 mg/m2, methotrexate
40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15),
both every 4 weeks.
Results: Data of 101 patients, 53 in the CMF and 48 in the docetaxel arm, median age
70, enrolled up to October 2006, were analysed. At least one grade 3-4 toxic event of
any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel,
respectively (exact p=0.0002). Grade 3-4 hematological events were observed in 37
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
(69.8%) vs 4 (8.3%) cases (exact p<0.0001) and grade 3-4 non-hematological toxicity
in 12 (22.6%) vs 15 (31.2%) patients, with CMF and docetaxel, respectively (exact
p=0.11). In particular, a significantly higher incidence of anemia, neutropenia,
thrombocytopenia and febrile neutropenia was reported in CMF arm. Among non-
hematological toxicity, constipation, mucositis, nausea and vomiting were significantly
more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver
toxicity were significantly more frequent in docetaxel arm. No significant interaction
was found between severe toxicity and baseline variables, including creatinine clearance
and geriatric assessment.
Conclusions: In the present analysis, weekly docetaxel was less toxic than CMF.
Efficacy data must be awaited to draw conclusions on the role of adjuvant weekly
docetaxel for elderly early breast cancer patients.
C66* IS 3-YRS DISEASE-FREE-SURVIVAL (DFS) A RELIABLE
SURROGATE END-POINT FOR PREDICTING 5-YRS OVERALL-
SURVIVAL (OS) BENEFIT IN ADJUVANT TAXANE-BASED
CHEMOTHERAPY FOR BREAST CANCER (BC)? ANALYSIS OF
RANDOMIZED CLINICAL TRIALS (RCTS)
Mariangela Ciccarese, MD1, Emilio Bria, MD2, Federica Cuppone, MD2, Paolo
Carlini, MD2, Michele Milella, MD2, Isabella Sperduti, PhD3, Vito Lo Russo, MD1,
Cecilia Nisticò, MD2, Edmondo Terzoli, MD2, Francesco Cognetti, MD2, Diana
Giannarelli, PhD3
1
Medical Oncology, Vito Fazzi Hospital, Lecce, Italy; 2Department of Medical
Oncology, Regina Elena National Cancer Institute, Rome, Italy; 3Biostatistics,
Regina Elena National Cancer Institute, Rome, Italy
Background: DFS is considered the traditional end-point for adjuvant trials for BC.
The eventual correlation between earlier DFS (i.e. 3-yrs) with 5-yrs OS is still unclear in
trials addressing the role of taxanes; if correlation exists, it would be faster to trasfer
new drugs from clinical research into daily practice. In this analysis, all trials evaluating
the role of adjuvant taxanes for early BC have been gathered to determine the
correlation between 3-yrs DFS and 5-yrs OS.
Methods: RCTs with at least 60 month follow-up were considered eligible. A linear
regression model has been applied to explore the correlation by considering both each
single outcome pair (DFS and OS) for all arms (extracted by curves), their differences,
and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following
2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2)
correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was
estimated according to Pearson (r) and R2 coefficients (parametric tests) and Spearman
(Rho) coefficient (non-parametric test). A model to calculate the target sample size to
determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well.
Results: Data for DFS and OS were available for 10 RCTs (17067 patients). When
considering 5-yrs outcomes a linear correlation was found between rates (r=0.74,
R2=0.55; p<.0001; Rho=0.83; p<.0001), and HRs (r=0.90, R2=0.81; p<.0001;
Rho=0.91; p<.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81,
R2=0.66; p<.0001; Rho=0.92; p<.0001), and RRs (r=0.84, R2=0.71; p=0.002;
Rho=0.85; p=0.002). Moreover, a linear strong correlation between 3-yrs DFS and
5-yrs OS absolute differences was found (r=0.86, R2=0.74; p=0.001; Rho=0.84;
p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculate
2733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to
improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively.
Conclusions: According to this analysis, 3-yrs DFS seems reliable in predicting an
ultimate survival advantage when adressing te role of new drugs in early BC.
Furthermore, a smaller patient’ sample is required when DFS is chosen as primary end-
point; this allows to have relible results in a shorter time period.
C67* TUMOR AND NORMAL INTERSTITIAL FLUID PROTEOMIC
CHARACTERIZATION IN BREAST CANCER PATIENTS RECEIVING
NEOADJUVANT CHEMOTHERAPY
Cortesi L1, Barchetti A2, De Matteis E1, Ruscelli S1, Della Casa L2, Tazzioli G3,
Lazzaretti M. G4, Iannone A2, Federico M 1
doi:10.1093/annonc/mdm425 | xi51
session C
1
Cattedra di Oncologia Medica II, 2Dipartimento di Scienze Biomediche,
3
Dipartimento di Chirurgia Generale, Università di Modena e Reggio Emilia,
Modena,4Divisione di Chirurgia Generale,Ospedale Carpi (Modena)
Background: Tumor progression is related to the malignant potential of cancer cells
and microenvironment. To better define the role of proteins secreted by tumor cells
and the effect of neoadjuvant chemotherapy (NACT) in breast cancer (BC), we
analyzed the bi-dimensional maps of secreted proteins in Tumor Interstitial Fluid
(TIF) and in Normal Interstitial Fluids (NIF) before and after NACT.
Methods: Eleven patients with stage II and III BC treated with 4 courses of FEC90 and
4 cycles of TXT were investigated. Tumor and normal tissue samples were collected
before and post NACT. Samples were incubated at 37C for 1h and secreted proteins
were analyzed with 2D electrophoresis and silver stained. Spots of potential interest
were purified, digested with trypsin and analyzed with HPLC-ESI-MS/MS.
Results: 140 proteins have been characterized. Glucidic metabolism (PGK1, PKM2 and
FBP1), proteasome subunits (TCP1, PSA, EF1A1, PSME1) and Rho-GDI family
proteins were up-regulated in TIF while small heat shock proteins (CRYAB),
homeostasis regulators (CAI,II) and antioxidant proteins (PRDX2) resulted expressed
in NIF. In 9 cases, TIF and NIF samples were also collected at the surgery time showing
a correlation between pathological response and proteomic expression profile. In
5 patients with pathological response >50%, a sharp decrease of total TIF protein
expression was observed; in the four minor responders, the TIF pattern was almost
unchanged. The EF1A1 protein resulted overexpressed in non-responders before and
after NACT, while it was absent in major responders in which a dephosphorilation of
Rho-GDI was also present.
Conclusions: The proteomic characterization of interstitial fluid perfusing the breast
tumor microenvironment represents a sensitive tool for the detection of differentially
expressed proteins. Moreover the TIF/NIF study seems a promising novel resource for
biomarker discovery and for identifying selective targets for therapeutic interventions.
C68* EGFR, MAPK, AKT AND PTEN STATUS BY
IMMUNOHISTOCHEMISTRY (IHC): CORRELATION WITH CLINICAL
OUTCOME IN HER2-POSITIVE (HER21) METASTATIC BREAST
CANCER (MBC) PATIENTS (PTS) TREATED WITH TRASTUZUMAB (T)
6CHEMOTHERAPY (CT)
Stefania Gori1, Verena De Angelis1, Angelo Sidoni2, Mariantonietta Colozza1, Ivana
Ferri2, Daniela Fenocchio3, Vienna Ludovini1, Carlo Basurto1, Paola Anastasi1,
Lucio Crinò1
1
Medical Oncology and 3Pathological Anathomy and Histology Service, Azienda
Ospedaliera, Perugia, 2Institute of Pathological Anatomy and Histology, Perugia
University, ITALY
T alone or in combination with CT has been shown to be an active therapy in HER2+
MBC pts. However, not all pts will benefit and mechanisms of resistance to T are still
poorly understood. The aims of this study were to evaluate the IHC expression of EGFR,
MAPK and Akt (two downstream effectors of the EGFR family signaling) and PTEN and
their correlation with clinical outcome in HER2+MBC pts treated with T ± CT.
Methods: 133 consecutive HER2+ MBC pts were treated between 04/99 and 03/06 but
tumor tissue was available for this analysis only from 45 pts. HER2 evaluated by CB11
was scored according to Herceptest.Tumors were considered EGFR positive if ‡1%
positive tumor cells and MAPK positive and Akt positive if the percentage of positive
tumor cells was ‡10%. PTEN expression was assessed by IHC on a scale from 0 to 400
(percentage of positive cells x staining intensity) as described by Hirsch F et al (JCO
21:3798;2003).
Results: At median follow up of 57 months (range 5-229) from the start of T,
45 pts were evaluable for TTP and OS and 42 for response to T. Median age of pts was
53 years (23-77). We observed 27 responses (CR+PR) to T ± CT (64.28%); median TTP
was 24 months (3.3-179.8). In 11 of the 27 responsive pts (40.7%), progression was
observed in CNS ± other sites. Median OS from the start of T was 74 months. EGFR+
tumors were 10 (22.2%), MAPK+ tumors were 16 (35.5%) and Akt+ tumors were 23
(51.1%). Only 2 pts had PTEN expression score of 0-99 (PTEN-). We analyzed the
correlation of HER2, EGFR, MAPK, Akt and PTEN status with response to T, TTP and
OS. HER2 was significantly correlated with response to T (p= 0.013): in HER2 3+
tumors we observed 22 (9 CR and 13 PR) out of 27 objective responses but no
significant correlation was found between HER2 status and TTP and OS. EGFR,
MAPK, Akt and PTEN status of tumors were not significantly associated with
response to T, TTP and OS in our series.
Conclusions: We did not find any significant correlation between EGFR, MAPK, Akt,
PTEN status evaluated by IHC and clinical outcome in HER2+ MBC pts treated with
T ± CT. Only HER2 status evaluated by IHC significantly correlated with response to
T ± CT.
C69* EFFECT OF GENETIC POLYMORPHISMS (GP) ON TOXICITY
AND SURVIVAL IN EARLY BREAST CANCER (EBC) PATIENTS (PTS)
TREATED WITH ADJUVANT CHEMOTHERAPY (CT)
V. Ludovini1, S. Gori1, A. Rulli2, I. Floriani3, L. Pistola1, G. Nocentini4, V. N. Talesa5,
S. Piattoni6, P. Anastasi1, C. Basurto1, F. R. Tofanetti1, M. Tonato7, M. Colozza1,
L. Crinò1
xi52 | session C: early and advanced breast cancer
Annals of Oncology
1
Medical Oncology and 2Breast Unit Azienda Ospedaliera of Perugia, 3Oncology
Dept, Istituto di Ricerche Farmacologiche Mario Negri, Milan,4Pharmacology
Dept,5Experimental Medicine and 6Internal Medicine University of
Perugia,7Regional Cancer Center, Azienda Ospedaliera, Perugia, Italy
Drug resistance and severe toxicity are often limiting factors in effectiveness of
adjuvant CT used for treatment of EBC. Several functional single nucleotide
polymorphisms (SNPs) of genes GSTT1, GSTM1, GSTP1, TS, MTHFR, RFC1,
involved in the transport and metabolism of these drugs could affect the toxicity
and treatment efficacy. We investigated whether these SNPs were associated with
toxicity and treatment effectiveness in pts with EBC treated with CMF, FEC and
FAC regimens.
Methods: PCR-RFLP-analysis of germ-line polymorphism was performed for GSTP1,
RFC1 and MTHFR, while PCR assay for GSTT1, GSTM1 and TS genes. Toxicity was
graded using the WHO criteria.
Results: From June 2000 to September 2005, 244 consecutive pts entered the study. GP
frequencies were:MTHFR C677T genotype 27.5% C/C, 47.5% C/T, 25% T/T;5’UTR TS
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genotype 32% 2R/2R, 35.2% 2R/3R, 32.8 3R/3R;RFC1 G80A genotype 23.4% A/A,
46.3% A/G, 30.3 % G/G; GSTP1 A313G genotype 59.4% A/A, 39.3%A/G, 1.2% G/
G;GSTT1 and GSTM1 null genotypes 20.5% and 54.1%, respectively.119 pts (48.7%)
were treated with FEC, 125 pts (51.3%) with CMF. The most significant hematologic
and non-hematologic toxicities observed with CMF/FEC were neutropenia (63 pts)
and oral mucositis (46 pts). Pts with 2R/3R TS genotype showed severe neutropenia
G3/G4 compared to pts with 2R/2R TS genotype (p=0.038) while the same group
had a lower probability of developing oral mucositis (G2/G3) (p=0.012). When
considering toxicity of any grade (G1-4), pts with RFC1 G80A genotype had
significantly lower risk of developing mucositis (p=0.05) compared to G80G allele.
At median follow-up of 2.8 years, 10 pts (4.1%) died, 217 pts (88.9%) are alive and
free of tumor relapse and 27 pts (11.1%) have experienced local and/or distant
recurrences. Relationships between genotypes and recurrence were also evaluated
and only GSTT1-null genotype was significantly associated with shorter
PFS(p=0.042).
Conclusions: Our data suggest that 2R/3R TS and RFC1 G80G genotypes may have
a potential role to identify patients with greater risk of toxicity to CMF/FEC and that
GSTT1-null genotype may be an important marker in predicting clinical outcome in
EBC pts.(Research project CNR-MIUR).
C70* BRCANESS PHENOTYPE AND METHYLATION OF BRCA1
PROMOTER IN SPORADIC BREAST CANCERS
Giorgetti G, Galizia E, Bianchi F, Piccinini G, Loretelli C, Belvederesi L, Catalani R,
Gargliardini D, Ferretti C, Corradini F, Bracci R, Santinelli A, Cellerino R
Centro Regionale di Alta Specializzazione in Genetica Oncologica, Istituto di
Medicina Clinica e Biotecnologie Applicate-Oncologia Medica, Università
Politecnica delle Marche, Ancona
Background: BRCA1 protein is involved in distinct DNA-repair processes. Hereditary
breast cancers diagnosed in BRCA1 mutation carriers have ‘‘triple negative’’ phenotype
for Oestrogen Receptor (ER), Progesterone Receptor (PgR) and ERB B2. Similar
features are present in basal-like sporadic cancers. Since genetic inactivation due to
somatic mutations of BRCA1 is a rare event in sporadic breast cancers, we have
investigated if epigenetic mechanisms, such as methylation of its promoter, could play
a role in patients with ‘‘triple negative’’ phenotype.
Methods: We have retrospectively analysed two groups of sporadic breast cancer
patients: ‘‘triple negative’’ (‘‘BRCA-like’’) cases (42) and positive (‘‘BRCA-unlike’’)
ones (47).
Methylation Specific PCR and Bisulfite Genomic Sequencing on genomic DNA
(obtained from sections of paraffin-embedded tissues and modified with sodium
bisulfite) were used to analyze the methylation pattern of BRCA1 CpG island. BRCA1
immunohystochemical analysis (IHC) was performed in all patients, to associate the
reduction or lack of BRCA1 protein with epigenetic damage. The association between
methylation and type of tumours was evaluated using Chi-square test. A probability of
5% was used as level of significance.
Results: BRCA1 promoter methylation was present in 18/42 (43%) of ‘‘BRCA-like’’
cases and in 13/47 (28%) of ‘‘BRCA-unlike’’ ones. The BRCA1 IHC was performed in
all available samples (table).
Conclusion: We have observed that the methylation of BRCA1 promoter is higher in
‘‘BRCA-like’’ tumours than in ‘‘BRCA-unlike’’ ones. Although this difference is not
statistically significant (p=0.133), further studies are in progress to better
understand the possible role of BRCA1 promoter methylation in sporadic
breast cancers.
Methylation Methylated Unmethylated IHC IHC -/+ IHC ++/+++
Analysis
‘‘BRCA-like’’ 42 18 (43%) 24 40 35 (87%) 5 (13%)
‘‘BRCA- 47 13 (28%) 34 47 31 (66%) 16 (34%)
unlike’’
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
C71* BRCA1 EXPRESSION: A CORRELATIVE STUDY AMONG
NESTED PCR, REAL TIME PCR AND IHC IN SPORADIC BREAST
CANCERS
Piccinini G, Galizia E, Santinelli A, Bianchi F, Loretelli C, Belvederesi L, Gagliardini D,
Giorgetti G, Catalani R, Ferretti C, Corradini F, Bracci R, Cellerino R
Centro Regionale di Alta Specializzazione in Genetica Oncologica, Istituto di
Medicina Clinica e Biotecnologie Applicate -Oncologia Medica, Università
Politecnica delle Marche, Ancona
Background: BRCA1 protein is involved in several DNA repair pathways. BRCA1
mRNA is induced at late G1/early S phase. In sporadic breast cancers, the loss or
reduction of BRCA1 expression is rarely due to BRCA1 mutations and most frequently
to epigenetic events. BRCA1-associated breast cancers are usually ‘‘triple negative’’
(Estrogen Receptor-ER, Progesterone receptor- PgR, and ERBB2) and share many
features with the ‘‘ basal like’’ subtype. Our study aims to evaluate the possible role of
BRCA1 in sporadic breast cancers showing a ‘‘triple negative’’ phenotype.
Methods: We selected 23 and 37 sporadic breast specimens on the basis of triple-
negative or positive staining for ER, PgR and ERBB2. Total RNA was extracted from
paraffin-embedded tumours. BRCA1 mRNA was reverse transcribed and analysed
by nested-PCR. Negative samples were re-assessed by Real Time PCR. BRCA1 protein
was evaluated by Immunohystochemical (IHC) assay. The association between
tumours and the expression of both mRNA and protein was evaluated by the Fisher’s
exact test.
Results: BRCA1 mRNA and protein expression was present in 6/23 (26%) triple
negative and in 24/37 (65%) positive tumours. BRCA1 mRNA was absent in 4/23
(17%) triple negative and in 3/37 (8%) positive samples. Noteworthy, in 13/23 (56%)
triple-negative patients BRCA1 mRNA is transcribed but the protein is absent, whereas
in positive ones this occurs in 10/37 (27%) patients (p=0.01, table).
Conclusion: BRCA1 mRNA and IHC were positive in 26% of triple-negative and in
65% of positive breast cancers. Even though BRCA1 IHC is not credited by high
reliability, the lack of BRCA1 protein in 56% of triple negative tumours expressing
mRNA suggests that there might be other mechanisms by which BRCA1 expression is
controlled at post-translational levels, such as miRNA deregulation.
Triple Negative Triple Positive
mRNA+/IHC+ (6/23) 26% (24/37) 65%
mRNA+/IHC- (13/23) 56% (10/37) 27%
mRNA- (4/23) 17% (3/37) 8.1%
C72* DOWN-REGULATION OF HYPOXIA INDUCIBLE FACTOR-1a
(HIF-1a) EXPRESSION, THROUGH MTOR PATHWAY, BY
LETROZOLE (FEMARA
) IN ER1VE BREAST CANCER (BC)
PATIENTS
Daniele Generali, Alfredo Berruti, Stephen B. Fox, MariaPia Brizzi, Manuela Milani,
Simone Bonardi, Rossana Dionisio, Luigi Dogliotti, Alberto Bottini and
Adrian L. Harris
Unità di Patologia Mammaria - Istituti Ospitalieri di Cremona
Introduction: HIF-1 a, as marker of hypoxia, is involved in the selection of
more aggressive phenotype being associated with both chemo and endocrine
resistance in BC. Letrozole is a potent and selective non steroidal aromatase inhibitor
used for the treatment of estrogen positive (ER+ve) post-menopausal BC women.
Whether HIF-1 a expression could be modulated by AI is the subject of this
investigation. HIF-1 a expression was evaluated before and after primary letrozole
therapy in a series of elderly ER+ve patients enrolled in a randomized prospective trial
(Bottini et al JCO 2006).
Patients and methods: 114 women with T2-4 N0-1 and ER+ve BC were randomly
assigned to 6 months of primary Letrozole plus/minus oral ‘‘metronomic’’
cyclophosphamide. Tumor response was assessed clinically with a calliper. On TMAs
HIF-1 a and mTOR expression (an upstream regulator of HIF-1 a) were evaluated in
tumor specimens collected before and after treatment. The intensity of the staining for
TMAs marker was scored from 0 (no staining) to 2 (strong staining) in nuclear
intensity for HIF-1 a expression.
Results: At baseline HIF-1 a expression inversely correlated with grading (p<0.01) and
nodes (p<0.01) while it did not correlate with stage, p53, bcl2, Ki67, PgR or ER a
expression. HIF-1 a and mTOR baseline expression were directly correlated (p=0.01).
Letrozole treatment led to a significant reduction in HIF-1 a expression (p <0.004,
Wilcoxon Rank sum test), with no difference between the arms. Reduction in HIF-1 a
did not show any relationship with disease response. As previously observed (Generali
et al SABCS 2006) letrozole-based therapy was also able to down-regulate mTOR
pathway. Interestingly, mTOR and HIF-1 a reduction after treatment were significantly
associated (p=<0.03).
Conclusions: Letrozole reduced HIF-1 a expression and mTOR downregulation could
be a possible mechanism. Whether these changes correlate with drug efficacy or not is
a matter of future research. However, these results should be taken into account when
Volume 18 | Supplement 11 | October 2007
session C
planning to administer new therapies targeting either HIF-1 a and/or mTOR in
association with Letrozole.
C73* KINETIC DISTRIBUTION OF CARDIAC MARKER NT-PROBNP
IN CHEMONAIVE BREAST CANCER PATIENTS RECEIVING
ANTHRACYCLINES-BASED ADJUVANT CHEMOTHERAPY
A. Zambelli, A. Lanza, P. Sagrada, GB. Vadacca, A. Papalia, G. A. Da Prada,
V. Fregoni, L. Ponchio, P. Preti, M. De Salvo, F. Cobelli, L. Pavesi
UO di Oncologia Medica 1, IRCCS Salvatore Maugeri Foundation and Università
degli Studi di Pavia, Pavia Italy
Introduction: The natriuretic peptides are counterregulatory hormones involved in
volume homeostasis and cardiovascular remodeling. The predictive significance of
plasma natriuretic peptide levels in apparently asymptomatic patients receiving
cardiotoxic chemotherapy (CT) has not been established.
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The aim of the study was to describe the kinetic distribution of N-terminal pro-
brain natriuretic peptide (NTproBNP) levels over time during chemotherapy to
elucidate factors associated with changes of NTproBNP at different time points and to
correlate with cardiotoxic events defined as symptomatic CHF or absolute decrease in
LEVF by > 20% (or >10% points below 50%).
Patients and methods: A total of 480 determinations of NTproBNP and
Troponin I (TnI) were performed in 20 consecutive chemonaive breast cancer patients
receiving 6 cycles (q3wks) of anthracycline-based chemotherapy and compared with
10 patients receiving anthracycline-free chemotherapy regimens.
Serum concentrations of cardiac markers NTproBNP and TnI were obtained at each
treatment cycle before chemotherapy, at the end, after 2 and 24 hours and after 21 days.
Echocardiography, to assess LVEF, was performed at baseline, every 3 cycles during
CT and every 6 months thereafter.
Results: After 24 months of follow up, in breast cancer patients receiving
anthracyclines, we describe a slight increase of NTproBNP at the end of CT, after
2 hours with a peak at 24hours. The median NTproBNP was 101 pg/mL at baseline
and 173 pg/mL at 24h.
The NTproBNP rise at 24 hours was mainly reversible, recovering normal values
(i.e. <155 pg/mL) at 21 days. No changes in TnI levels were observed.
The sole patient that experienced cardiotoxicity, for an asymptomatic drop of LVEF
by 25%, had NTproBNP increase that persisted during the whole CT period.
Conclusion: Our results show a reversible increase of NTproBNP early after
anthracycline-based chemotherapy. This NTproBNP rise is frequent and
uninformative about the cardiotoxic risk. However the lower reduction rate after
21 days could represent a marker for early detection of cardiotoxicity. The timing
of measurement will be important to consider when using NTproBNP for risk
assessment.
C74* PROGNOSTIC FACTORS FOR SURVIVAL IN OPERABLE
BREAST CANCER (OBC): ANALYSIS OF PARMA CANCER REGISTRY
IN THE YEARS 1998-2001
M. G. Pescarenico*, F. Bozzani§, P. Sgargi§, G. Vasini, V. De Lisi§
*Dipartimento Cure Primarie, Azienda Unità Sanitaria Locale di Parma, §Registro
Tumori di Parma, U. O. di Oncologia Medica, Azienda Ospedaliero-Universitaria
di Parma, Parma, Italia
Introduction: The biological factors are measurable parameters at the diagnosis that
correlate with disease free and overall survival and, in absence of treatments, can
correlate with natural history of disease. The multivariate analysis is currently ongoing
to identify which factors are independent predictors and to develop and validate
a single survival model for oBC.
Aim: This study considers the oBC in the female population of Parma, in the period
1998-2001, with age 40-74, and correlates the overall survival with some prognostic
factors: age, tumour size, axillary lymph-nodes involvement, histological type and
biological parameters (hormonal receptor status, histological grade, Ki67 and Her2/
neu expression).
Methods: From January 1998 and December 2001 1559 women with BC were
identified from our tumour registry. Women with distant metastases (n=58) and
carcinoma in situ (n=247) were excluded from our study. Women were divided into
two groups, considering 230 cases in the group of age 40-49 and 1024 in the group of
50-74. Stage was known in 99% of cases, receptor status in 87%, grade in 72%, Ki67 in
86% and Her2/neu in 72%.
Results: 5-year overall survival was 92% in the 1254 women. Overall poor survival was
associated with lymph-nodes involvement (P=0.001), receptor status (P=0.01) and
Ki67 expression (P=0.02). No significant difference in the mean score for age, tumour
size, histology, Her2/neu, when considered singularly, while patients with more than
two factors among receptor status negative, Ki67 >10%, high nuclear grade, Her2/neu
positive (+++) showed a poor 5-year overall survival rate compared with the others
(P= 0.01). On the other hand, in the node-negative group, no prognostic factors turned
out significant, except the association with the tumour size (T).
Conclusions: Prognostic factors of oBC are important for overall survival. Patients
who had multiple unfavourable risk factor were associate with significant differences in
doi:10.1093/annonc/mdm425 | xi53
session C
median survival and the most important prognostic factors was axillary lymph nodes
involvement.
C75* DIFFERENT PROGNOSTIC ROLE OF MUTATIONS IN THE
HELICAL AND KINASE DOMAINS OF THE PIK3CA GENE IN INVASIVE
BREAST CARCINOMAS (IBC)
Antonella Ferro1, Mattia Barbareschi2, Fiamma Buttitta3, Lara Felicioni3, Sabrina
Cotrupi2, Fabio Barassi3, Maela Del Grammastro3, Paolo Dalla Palma2, Antonio
Marchetti3 Enzo Galligioni1
1
Unit of Medical Oncology and 2 Pathology, Trento. 3 Clinical Research Center,
Center of Excellence on Aging, University-Foundation, Chieti, Italy
Background: The PI3K-AKT pathway plays a fundamental role in signal
transduction following tyrosine kinase growth factor receptors activation. Mutations
in the PIK3CA gene are among the most frequent mutational events in IBC. In IBC,
the PIK3CA gene is frequently mutated at ‘‘hot spots’’ in exons (E) 9 and 20,
corresponding to the helical (E542K and E545G) and kinase (H1047R) domain
respectively. Little is known about the possible clinical significance of these
mutations. We studied the association of PIK3CA mutations with pathological
features and clinical outcome in a mono-institutional series of IBC patients.
Materials and methods: Frozen samples of 163 consecutive IBC with complete
pathological and clinical data were analyzed for mutations in E9 and E20 of the
PIK3CA gene using SSCP and direct sequence analysis.
Results: We identified 46 missense mutations, 24 (53%) in E9 and 21 (47%) in E20.
Twelve (50%) of the 24 mutations in E9 were of the E542K type and 11 (46%) were of
the E545K type. Twenty (95%) of the 21 mutations in E20 were H1047R substitutions.
Mutations in E9 were more frequent in lobular carcinomas (42% of cases) than in
ductal carcinoma (11%) (p=0.002). There was no significant correlation between
PIK3CA mutations and other clinicopathological and biological variables. At
univariate survival analysis PIK3CA E20 mutations were associated with prolonged
overall (OS) and disease free survival (DFS) while mutations in E9 were associated with
significantly worse prognosis. At multivariate analysis E9 PIK3CA mutations were the
strongest independent factor to predict poor prognosis in term of DFS (P = 0.0003)
and OS (P = 0.001).
Conclusion: Our data show that E9 PIK3CA mutations are typical of infiltrating
lobular carcinomas. Moreover, E20 PIK3CA mutations are associated with better
prognosis, while E9 mutations are independently associated with early recurrence and
death. This is of relevance concerning potentially therapeutic approaches, as it suggests
that PIK3CA E9 mutations could be the most important targets for PI3K inhibiting
drugs.(Submitted to CCRJ).
C76* CARDIOTOXICITY AFTER ANTHRACYCLINE
CHEMOTHERAPY IN BREAST CARCINOMA: EARLY AND 1-YEAR
FOLLOW-UP
Ornella Garrone, Mauro Feola, Marcella Occelli, Antonella Francini, Fabrizia Albrile,
Gian Luca Visconti, Valentina Polla Mattiot, Alberto Biggi, Marco Bobbio,
Marco Merlano
Ospedale S. Croce e Carle Cuneo
Anthracyclines are among the most used drugs in breast cancer treatment.
Unfortunately they induce a dose dependent chronic cardiotoxicity. In order to
prospectively evaluate the cardiotoxic effects of epirubicin-containing adjuvant
chemotherapy in early breast cancer patients, we performed cardiac evaluation by
means of multigated radionuclide (MUGA) scan, troponin I and neurohormonal
assessment.
Methods: Patients with early breast cancer undergoing surgical treatment followed by
chemotherapy were enrolled. The chemotherapy regimen consisted of epirubicin
90 mg/sqm, cyclophosphamide 600 mg/sqm and fluorouracil 600 mg/sqm on day 1
every three weeks for 6 cycles. The presence of coronary artery disease, valvular disease,
abnormal left ventricular ejection fraction (LVEF<50%), were considered exclusion
criteria. All patients underwent clinical assessment, MUGA scan, troponin I, brain
natriuretic peptide (BNP), at baseline, 1 month after the last chemotherapy cycle (T1),
and then after 1 year (T2).
Results: 52 patients median age 57 years (range 28-73) were included. Hypertension
y/n 21/52 patients. All patients performed T1 and T2 evaluations. Statistical analysis
was performed according to the Student Test.
A significant reduction of LVEF was observed (from 62±5.5 % to 58.5±7.7 %,
p=0.001) at T1 without any change at T2 (from 58.5±7.7 % to 58.3±6.6%, p=0.9); BNP
plasma level increased (from 36.1±42.8 pg/ml to 62.5±93.3 pg/ml, p=0.005) at T1 and
remained slightly increased at T2 (from 62.5±93.3 pg/ml to 58.8±99 pg/ml, p=0.5).
Troponin I increased at T1 (from 0.006±0.01 ng/ml to 0.05±0.04 ng/ml, p=0.0001) but
returned at the baseline level at T2 (0.005±0.08 ng/ml). In 17/52 (35%) patients LVEF
reduced >5% at T2. Moreover patients with LVEF reduction at T2 did not have
increased secretion of troponin I after chemotherapy (0.07±0.05 ng/ml vs 0.05±0.04
ng/ml, p=0.14).
Conclusions: The modification in LVEF and BNP developed early after anthracycline
chemotherapy and did not recover completely after 1 year. Before chemotherapy none
of the analysed parameters might predict the systolic dysfunction at T2.
xi54 | session C: early and advanced breast cancer
Annals of Oncology
C77* SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
LEVELS CORRELATE WITH TUMOR VEGF AND P53
OVEREXPRESSION IN ENDOCRINE POSITIVE PRIMARY BREAST
CANCER
G. Catalano, M. Orditura,*F. Iovino, ^F. Ferraraccio, §G. Antoniol PhD, F. Morgillo,
C. Belli, G. Santabarbara, T. Fabozzi, M. Fasano, M. R. Diadema, F. Ciardiello,
*F. Lo Schiavo, F. De Vita
Division of Medical Oncology - Department of Clinical & Experimental Medicine;
^
Pathology; *Division of Oncological Surgery- Second University of Naples, Italy
Background: VEGF is a potent stimulator of angiogenesis, associated with unfavorable
clinical characteristics in breast cancer. We evaluated the serum VEGF concentrations
in endocrine positive breast cancer patients and relate these results to the
immunohistochemical expression of VEGF by the tumor and to the other established
clinico-pathological prognostic markers, namely microvessel density (MVD), tumor
size, grading and lymph node status.
Downloaded from annonc.oxfordjournals.org at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
Methods: Serum levels of VEGF were determined using a commercially available
sandwich enzyme immunoassay kit (Endogen VEGF ELISA kit). Four– lm tissue
sections were used for immunohistochemical procedure. The antibodies used were
a mouse monoclonal antibody against human VEGF, p53,c-erb-B2 and CD34 class II .
Results: The mean serum VEGF levels of the breast cancer patients were significantly
elevated compared with those of the control group (294.95±113.51 vs 62.5±25.2 pg/ml;
p<0.01). Serum VEGF in ductal cancer or NOS was not significantly elevated compared
with lobular carcinoma (p=0.20). Nodal status did not appear to influence serum
VEGF levels (p=0.52).A significant correlation was seen between basal VEGF serum
concentrations, microvessel density (p=0.01), neoplastic embolization (p=0.007) and
p53 status (p= 0.004). Serum VEGF levels did not show any significant correlation with
tumor grade (p=0.81), multifocality (p=0.77), perineural invasion (p=0.87), Ki67
(p=0.15) and platelet count (p=0.85). A VEGF positive staining was detecteded in
50 out of 71 ER- positive tumors (70%).In these patients VEGF expression was
significantly associated with neoplastic embolization (p= 0.041) and circulating VEGF
levels (p=0.047). Finally 13 of 56 tumours were classified as c-ERB-b2 positive. In these
patients a significant correlation was observed with neoplastic embolization (p=0.040),
serum VEGF levels (p=0.02), tissue VEGF expression (p=0.004) and CA 15-3 levels
(p=0.023).We found no significant correlation between VEGF expression and other
parameters examined. Using stepwise multivariate analysis MVD, neoplastic
embolization, p53 status were the only covariates that were independently associated
with serum VEGF levels.
Conclusions: Our results confirm that in primary endocrine positive breast cancer
serum VEGF levels are elevated and show a positive relationship with tumor VEGF and
p53 overexpression.
C78* CORRELATION BETWEEN FDG –PET EVALUATION AND
PATHOLOGICAL RESPONSE TO NEOADJUVANT CHEMOTHERAPY
IN BREAST CANCER PATIENTS: FINDINGS FROM THE ARIANNA
01 PROJECT
Sara Quercia, Claudio Zamagni, Alessandra Musto, Alessandra Bernardi,
Donatella Santini, Marta Rosati, Manuela Lenzi, Stefano Fanti, Mario Taffurelli and
Andrea Angelo Martoni
Medical Oncology Unit, Nuclear Medicine Unit, Pathology Unit, General Surgery
Unit, S.Orsola-Malpighi Hospital and University of Bologna, Bologna – Italy
Background: Pathological complete remission is an important goal of primary
chemotherapy because it correlates with a better prognosis in terms of relapse-free and
overall survival. In most of the trials published in the literature, the response to primary
chemotherapy is evaluated with physical exam, mammography and, in some cases,
ultrasounds. The correlation between clinical and pathological complete response is
quite poor (about 50%).
The primary aim of this study is to investigate if 18F FDG PET improves the
correlation between clinical and pathological response and if it is able to identify early
predictive signs of response in pts treated with primary (neoadjuvant) anthracycline-
and taxane-based chemotherapy for breast cancer.
Patients and methods: T2-4 N0-3 M0 hystologically confirmed breast cancer pts,
candidates for primary chemotherapy were eligible; M1 olygometastatic patients were
also eligible if the therapeutic program included breast surgery after chemotherapy. Pts
were evaluated at baseline, every 2 courses and at the end of primary chemotherapy
with physical exam, mammography, ultrasounds, breast MRI and PET scan. In the first
10 pts PET scan was carried out before each cycle. Metabolic therapy response was
quantitatively measured by SUVmax within the primary lesion and by relative (%)
SUVmax decrease. Pathological response was evaluated according to Miller and Payne
classification system, that ranges from grade 1 (no response) to grade 4-5 (only small
clusters or individual cells residual, or no malignant cells at all).
Results: Up to now 24 pts have been enrolled and 6 of them are still on chemotherapy.
The present analysis is focused on the first 18 pts. Median age 50 (range 31-72), median
KPS 100%; stage II: 8 pts; stage III: 8 pts; stage IV (olygometastatic): 2 pts. After 6-8
courses of primary chemotherapy we observed 8 (44%) grade 4 pathological
remissions. Baseline PET was pathological (focal lesion with SUVmax >2, median 10,
range 2.5-20) at primary tumor level in all pts; a complete normalization (SUV max £2)
was observed in 12/18 cases (66%) at the end of primary chemotherapy. The overall
Volume 18 | Supplement 11 | October 2007
Annals of Oncology
concordance between PET and pathological evaluation was 78% (14/18), while the
concordance of PET with grade 4 pathological remission was 67%. PET overestimated
pathological response in 4/18 cases (22%). After the 2nd course of chemotherapy 7/8
pts (87.5%) with grade 4 pathological response and 2/10 pts (20%) with grade 1 to 3
pathological response had a SUVmax decrease ‡75% (p<.01 ).
Conclusion: The correlation between FDG-PET response and grade 4 pathological
remission is 67% (95% CI: 46-88%). An early (after 2 courses) decrease of SUVmax
‡ 75% on primary breast lesions is significantly more frequent in grade 4 pathologic
responders.
C79* MORPHOLOGICAL AND MOLECULAR ANALYSIS OF
CIRCULATING TUMOR CELLS (CTCS) IN BREAST CANCER
S Bessi, M Pestrin, M Truglia, F Galardi, S Cappadona, C Biagioni, W Claudino,
M De Stefanis, L Biganzoli, A Di Leo, and A Giannini
Translational Research Unit, Dept. of Oncology, Hospital of Prato, Istituto
Toscano Tumori
Background: The detection of CTCs in peripheral blood may have some clinical use for
monitoring response to therapy and disease recurrence. It is very important to use
reproducible systems to isolate and characterise CTCs.
Experimental design: 7.5 ml blood samples were collected from 47 patients with breast
cancer in different disease phases (2 neoadjuvant, 7 adjuvant, 38 metastatic). CTCs
were isolated with the CellSearch System
(Immunicon Co.) by means of
immunomagnetic separation, using ferrofluid nanoparticles binding anti-epithelial cell
adhesion molecules (EpCAM), and fluorescently stained with Epithelial Cell Kit
.
CTCs were defined as nucleated (DAPI positive), epithelial (CK 8, 18, 19 positive) and
negative for CD45. Concomitantly, we used Tumor Phenotyping Reagent
to
investigate HER-2/neu expression. Moreover, CTCs were isolated using the Profile
Kit
: slides were set up and investigated by Papanicolaou staining,
immunocytochemestry (ICC), fluorescence in-situ hybridization (FISH).
Results: CTCs could be detected in 1, 5, 31 patients in the neoadjuvant, adjuvant, and
metastatic settings and the median CTC number was 7/7.5 ml, 3/7.5 ml, 6/7.5 ml
respectively.
CTCs HER-2/neu expression was investigated in 33 samples (45% were negative,
55% positive). The morphological analysis after Papanicolaou staining showed two
cellular sub-types: the most representative one is characterized by small size, round cells
with a large nucleus (high nucleus/cytoplasmic ratio)that were both isolated and in
clusters; the other group is characterized by bigger and sometimes more elongated cells.
CTCs were also evaluated by ICC (Cytokeratins, ER, PGR, Ki67, C-erbB2) and FISH
(HER2/neu).
Conclusions: CellSearch System
, with minimal operator involvement, is a reliable,
simple, automated and standardized method to isolate and better bio-characterize
CTCs.
C80* NEOADJUVANT TOREMIFENE (TOR) IN OLDER WOMEN WITH
ESTROGEN RECEPTOR (ER)-POSITIVE BREAST CANCER (BC):
A CLINICAL AND BIOLOGICAL STUDY
Antonia Martinetti2, Luigi Celio, Roberto Bajetta1, Angela Denaro, Ettore Seregni,
Maddalena Mancin Emilio Bajetta
Medical Oncology Unit, Pharmacy Unit1, Nuclear Medicine Unit2; Fondazione
IRCCS Istituto Nazionale Tumori, Milan, Italy
Volume 18 | Supplement 11 | October 2007
session C
A small study was conducted to determine the clinical and biological effectiveness of
TOR (60 mg/day) as a short-term pre-operative therapy in elderly patients (pts) with
newly diagnosed, (ER+) operable or locally advanced (T2-T4b, N0-1) BC.
The diagnosis of BC was established by core-needle biopsy. A cut-off of 10% of
stained cells was used to define ER+. Response to the treatment was based on changes
in clinical measurements by callipers. After 3 months of TOR, all pts were referred to
the breast surgeon. Blood samples were collected at baseline and monthly thereafter.
Serum oestradiol (E2), testosterone (TST), sex hormone-binding globulin (SHBG),
and bone metabolism markers (BAP and ICTP) were assessed by IRMA or RIA
methods.
Forty-seven pts entered the study. The median age was 78 years (range, 65-90 years);
72% of pts were classified as T2 without clinical nodal involvement. By WHO criteria,
response rate was 42.5% (95% CI, 28.3 to 57.8%), with further 25 pts achieving disease
stabilisation. After 3 months of therapy, a significant decrease in both circulating E2
and TST levels was observed (median decrease 28% and 13%, respectively; paired t test
p=0.01), with a concurrent rise (median value 77%) in SHBG levels (p=0.01). No
significant changes in serum BAP and ICTP occurred.
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In conclusion, neoadjuvant TOR appears to be an effective endocrine option in this
patient population. Despite the changes in endocrine parameters, short-term TOR
induces no apparent impact on bone metabolism markers.
The Authors would like to thank the ITMO office for their data management
support.
C81* WEEKLY PACLITAXEL AND PEGYLATED LIPOSOMAL
DOXORUBICIN IN METASTATIC BREAST CARCINOMA
V. Leonardi, V. Palmisano, A. Pepe, A. Usset, G. Savio, A. Laudani, C. Calabria,
L. Tartaglia, P. Amari, G Carruba and B. Agostara
Oncologic Department, Division of Medical Oncology, PO ‘‘M. Ascoli’’, ARNAS
Civico, Palermo
Introduction: Systemic chemotherapy has saved the life of many patients with
cancer, but the maximum efficacy of cytotoxic agents is severely limited by their
adverse effects. Peg-LD has the advantage of delivering the active anthracycline
directly to the tumor site while exposing the patient to a lesser degree of doxorubicin-
associated toxicities. More recently, a regimen in which Paclitaxel is infused weekly
over 1 hour produced substantial anti-tumor activity, with little myelosuppression.
Materials and methods: We designed a phase II trial to study the efficacy and toxicity
of Peg-LD 10 mg/m2 d1,8,15 plus Paclitaxel 70 mg/m2 weekly in metastatic breast
cancer patients with high cardiologic risk. All patients were premedicated with
Pyridoxine 300 mg/daily per os and Desametasone 8 mg i.v. before each chemotherapy
administration to prevent the palmar-plantar erythrodysesthesia (PPE). To date, 31 pts
have been recruited, 27 pts (87 %) evaluable for efficacy and 31 pts (100 %) for toxicity.
Adjuvant chemotherapy had been administered in 25 pts (anthracycline-based in
16 pts); 20 pts (64.5%) have two or more sites of disease.
Efficacy: Overall, 3 CR, 14 PR have been recorded with an overall response rate of
62.8%. 6 NC and 3 PD had been registered.
Toxicity: Toxicity was generally manageable; the only grade 3,4 side effects recorded
were: PPE 6 %, mucositis 3 %, Leucopenia 12.6 %, AST/ALT 3 %. No cardiotoxicity
was seen.
Conclusions: The weekly Paclitaxel and Peg-LD appears to be a well tolerated and
effective approach in metastatic breast cancer patients with high cardiologic risk. This
phase II study will continue to accrue patients until 40 pts are enrolled.
doi:10.1093/annonc/mdm425 | xi55