Académique Documents
Professionnel Documents
Culture Documents
Chair: Andrs Cervantes; Co-Chair: George Pentheroudakis; Editorial Board: Enriqueta Felip, Nicholas Pavlidis,
Rolf A Stahel; Subject Editors: Dirk Arnold, Christian Buske, Paolo G Casali, Fatima Cardoso, Nathan Cherny,
Jrn Herrstedt, Alan Horwich, Ulrich Keilholz, Marco Ladetto, Lisa Licitra, Solange Peters, Philippe Rougier,
Cristiana Sessa; Deputy Subject Editors: Nicoletta Colombo, Elzbieta Senkus-Konefka; Staff: Keith H McGregor,
Claire Bramley, Jennifer Lamarre, Svetlana Jezdic.
628
PRIMARY BREAST CANCER
SCREENING..............................................................................................................6
DIAGNOSIS AND STAGING.......................................................................................6
TREATMENT...........................................................................................................14
Surgery...................................................................................................................14
Radiotherapy: Invasive carcinoma..........................................................................16
Radiotherapy: Non-invasive carcinoma...................................................................17
Adjuvant systemic therapy......................................................................................17
Endocrine therapy (ET)...........................................................................................18
Chemotherapy.........................................................................................................19
Human epidermal growth factor receptor 2 (HER2)-directed therapy.....................19
Adjuvant systemic therapy for ductal carcinoma in situ (DCIS)..............................20
Neoadjuvant systemic therapy................................................................................20
PERSONALISED MEDICINE....................................................................................20
FOLLOW-UP............................................................................................................21
SUMMARY RECOMMENDATIONS FOR PRIMARY BREAST CANCER................ 23
2943
ADVANCED BREAST CANCER (ABC)
GENERAL GUIDELINES...........................................................................................29
IMPORTANT ABC-RELATED DEFINITIONS..............................................................30
LOCALLY ADVANCED INOPERABLE, NON-INFLAMMATORY, BREAST CANCER.....30
LOCALLY ADVANCED INOPERABLE, INFLAMMATORY, BREAST CANCER.............32
SPECIFIC ABC POPULATIONS................................................................................32
SPECIFIC SITES OF METASTASES..........................................................................33
UPDATE ON ER POSITIVE/HER-2 NEGATIVE ABC..................................................34
UPDATE ON HER-2-POSITIVE ABC.........................................................................35
UPDATE ON HER-2-NEGATIVE ABC........................................................................36
UPDATE ON SURGERY OF THE PRIMARY TUMOUR
IN STAGE IV AT DIAGNOSIS...................................................................................36
ABC1 STATEMENTS................................................................................................37
LEVELS OF EVIDENCE GRADING SYSTEM.............................................................42
4447
BRCA IN BREAST CANCER
REFERRAL FOR BRCA TESTING.............................................................................44
MUTATION DETECTION..........................................................................................44
RISK REDUCTION: NON-SURGICAL PREVENTATIVE OPTIONS..............................44
Surveillance............................................................................................................44
Chemoprevention....................................................................................................44
RISK MODIFIERS....................................................................................................45
RISK REDUCTION: PROPHYLACTIC SURGICAL OPTIONS.....................................45
Prophylactic bilateral mastectomy (PBM)...............................................................45
Prophylactic bilateral salpingo-oophorectomy (PBSO)...........................................45
TREATMENT...........................................................................................................46
Surgery...................................................................................................................46
Systemic treatment.................................................................................................46
SUMMARY RECOMMENDATIONS FOR BRCA IN BREAST CANCER................. 47
4849
GLOSSARY
SCREENING
Biannual mammography screening has been shown to have the greatest effect
on breast cancer mortality reduction among women aged 5069 years and is
recommended by the European Union; the benefit of screening women aged
4049 years is currently disputed
INTRINSIC SUBTYPE
SURROGATE DEFINITION
Luminal A-like
ER-positive
Luminal A
HER2-negative
Ki67 low*
PgR high*
Luminal B
NOTES
*Suggested values are 20% for
both PgR and Ki67, but laboratory
specific cut-off points can be used
to distinguish between low and high
values for Ki67 and PgR
INTRINSIC SUBTYPE
CLINICOPATHOLOGIC
NOTES
SURROGATE DEFINITION
Luminal B-like (HER2-positive)
ER-positive
HER2-positive
any Ki67
any PgR
HER2 overexpression
Basal-like
HER2-positive (non-luminal)
HER2-positive
ER and PgR absent
Triple-negative (ductal)
ER and PgR absent
HER2-negative
made according to the TNM system and include: Number, location and maximum
diameter of the tumours removed; histological type and grade of the tumour;
evaluation of the resection margins, including the location and minimum distance
of the margin, vascular and lymphovascular invasion and biomarker analysis
(evaluation of ER/PgR, HER2 receptor and proliferation markers expression);
number of positive lymph nodes and extent of metastases in the lymph nodes
(isolated tumour cells, micrometastases [0.22 mm], macrometastases)
The most important prognostic factors in early breast cancer are ER/PgR and
estimation of the probability of recurrence and death from breast cancer (e.g.
Nottingham Prognostic Index [NPI], Adjuvant! Online [www.adjuvantonline.com]
or PREDICT score) and can be used to assist with treatment decisions
T1mi
T1a
T1b
T1c
T2
T3
T4
Tumour of any size with direct extension to the chest wall and/or to the skin
(ulceration or skin nodules)e
T4a
Extension to the chest wall, not including only pectoralis muscle adherence/invasion
T4b
T4c
T4d
Inflammatory carcinomaf
REGIONAL LYMPH NODES (N)
Clinical (cN)g,h,i,j,k
NX
Regional lymph nodes cannot be assessed (e.g. previously removed)
N0
No regional lymph node metastases
Metastases to movable ipsilateral level I, II axillary lymph node(s)
N1
Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or
N2
matted; or in clinically detectedk ipsilateral internal mammary nodes in the absence
of clinically evident axillary lymph node metastases
Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another
N2a
(matted) or to other structures
Metastases only in clinically detectedk ipsilateral internal mammary nodes and in
N2b
the absence of clinically evident level I, II axillary lymph node metastases
Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with
or without level I, II axillary lymph node involvement; or in clinically detectedk
N3
ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary
lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s)
with or without axillary or internal mammary lymph node involvement
N3a
Metastases in ipsilateral infraclavicular lymph node(s)
N3b
N3c
Pathological (pN)
h,i,j,k
10
pNX
pN0
pN0(i)
pN0(i+)
pN0(mol)
pN0(mol+)
pN1
Micrometastases (>0.2 mm and/or >200 cells, but none greater than 2.0 mm)
pN1a
pN1b
pN1c
pN2
pN2a
Metastases in 49 axillary lymph nodes (at least one tumour deposit >2.0 mm)
pN2b
pN3
pN3a
Metastases in 10 axillary lymph nodes (at least one tumour deposit >2.0 mm);
or metastases to the infraclavicular (level III axillary lymph) nodes
pN3b
pN3c
11
cM0(i+)
M1
12
Tis
N0
M0*
IA
T1
N0
M0
T0
N1mi
M0
T1
N1mi
M0
T0
N1
M0
T1
N1
M0
T2
N0
M0
T2
N1
M0
T3
N0
M0
T0
N2
M0
T1
N2
M0
T2
N2
M0
T3
N1
M0
T3
N2
M0
T4
N0
M0
T4
N1
M0
T4
N2
M0
IIIC
Any T
N3
M0
IV
Any T
Any N
M1
IB
IIA
IIB
IIIA
IIIB
*M0 includes M0(i+). The designation pM0 is not valid; any M0 should be clinical. If a patient presents with M1 prior to neoadjuvant
systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy. Stage designation
may be changed if post-surgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within
4 months of diagnosis in the absence of disease progression and that the patient has not received neoadjuvant therapy. Post-neoadjuvant
assessment is designated with a yc or yp prefix. Note: No stage group is assigned if there is a complete pathological response (pCR) to
neoadjuvant therapy, e.g. ypT0ypN0cM0
T1 includes T1mi
T0 and T1 tumours with nodal micrometastases only are excluded from Stage IIA and are classified as Stage IB
Edge SB, Byrd DR, Compton CC (eds). AJCC Cancer Staging Handbook, 7th ed. New York, NY.: Springer, 2010. Used with the permission
of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging
Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springer.com
13
TREATMENT
patients with large breasts, with a less favourable tumour/breast size ratio or
with a cosmetically difficult location of the tumour in the breast
Mastectomy
but some women will be advised against immediate reconstruction for oncologic
reasons, particularly when post-mastectomy radiotherapy (PMRT) is anticipated
Sentinel lymph node biopsy (SLNB) is associated with less morbidity (shoulder
stiffness, arm swelling) and reduced hospital stay and is the standard of care (SoC)
unless axillary node involvement is suspected
14
micrometastases (0.22 mm) and patients with clinical T1T2 cN0 invasive
breast cancer and 1 to 2 metastatic sentinel lymph nodes, treated with BCS
and tangential adjuvant radiotherapy
Ductal carcinoma in situ (DCIS) may be treated with total mastectomy or BCS,
provided that clear resection margins can be achieved (margins <2 mm are
considered inadequate)
Breast MRI is the most accurate modality for assessing the extent of residual
disease following neoadjuvant treatment
15
Whole breast radiotherapy (WBRT) reduces the risk of local recurrence by twothirds and is associated with a survival benefit
Boost irradiation gives a further 50% risk reduction and is indicated for patients
with unfavourable risk factors for local control (age <50 years, grade 3 tumour,
vascular invasion, non-radical tumour excision)
APBI is an option for women aged 50 years with unicentric, unifocal, node-
PMRT is recommended for women with positive deep margin, 4 positive axillary
nodes and for those with T3T4 tumours, independent of nodal status
Regional radiotherapy
The role of regional radiotherapy has not been determined. Trials demonstrating
After ALND, the resected part of the axilla should not be irradiated, except in
cases of residual disease after surgery
Shorter fractionation schemes (e.g. 1516 fractions of 2.52.66 Gy) have similar
effectiveness and side effects and have largely replaced traditional fractionation
regimens
16
WBRT after BCS for DCIS decreases the risk of local recurrence, with survival
equal to that following mastectomy
A boost can be considered for women at higher risk for local failure
(e.g. young patients)
used where available to determine the individual recurrence risk and predict
the benefit from chemotherapy in case of uncertainty regarding indications
for adjuvant chemotherapy
When considering adjuvant therapy for older patients, biological age, general
health status and comorbidities should be considered rather than formal age
17
Luminal B-like
(HER2-negative)
Luminal B-like
(HER2-positive)
HER2-positive
(non-luminal)
CTh + anti-HER2
Triple-negative
(ductal)
CTh
COMMENTS
Consider CTh if
a) high tumour burden (4 or more positive LN,
T3 or higher)
b) grade 3
Premenopausal women
18
Tamoxifen alone (20 mg daily for 510 years) is SoC. Patients becoming
postmenopausal during the first 5 years may benefit from a switch to letrozole)
The value of the addition of ovarian suppression (by gonadotropin-releasing
hormone [GnRH] agonists or ovarian ablation) is not well defined, particularly
in chemotherapy-treated patients who frequently develop ovarian failure as a
consequence of cytotoxic treatment
For patients with contraindications to tamoxifen, a GnRH analogue, alone or in
combination with an aromatase inhibitor (AI), can be used
The role of GnRH agonists in preventing chemotherapy-related ovarian failure
is not well-established
AIs (both non-steroidal and steroidal) and tamoxifen are valid options
AIs can be used upfront for 5 years, sequentially, after 23 years of tamoxifen
or following 5 years of tamoxifen (extended adjuvant therapy)
The optimal duration of adjuvant ET is currently unknown; extended adjuvant
therapy (10 years) should be discussed with all patients except those with very
low risk
Postmenopausal women
Patients on tamoxifen should be advised to avoid the use of strong and moderate
cytochrome P450 2D6 (CYP2D6) inhibitors or, if such drugs cannot be avoided,
a switch to an alternative treatment should be considered
bone loss
These patients should be advised regarding the need for adequate calcium and
vitamin D3 intake and receive periodical bone mineral density assessments by
dual energy X-ray absorption (DEXA) scan
In patients with treatment-related bone loss, bisphosphonates decrease the risk
of skeletal complications
Chemotherapy
and reduce breast cancer mortality by about one-third. Sequential rather than
concomitant use of anthracyclines and taxanes is superior
Chemotherapy is usually administered for 1224 weeks (48 cycles). Four cycles
of doxorubicin/cyclophosphamide (AC) are considered equal to 6 cycles of
cyclophosphamide/methotrexate/fluorouracil (CMF), whereas 6 cycles of 3-drug
anthracycline-based regimens are superior
19
Tamoxifen reduces the risk of invasive and non-invasive recurrences after BCS of
ER-positive DCIS and decreases the incidence of second primary (contralateral)
breast cancer, but does not affect survival
The use of tamoxifen in these cases is optional
In locally advanced and large tumours, neoadjuvant systemic therapy may
allow for reducing tumour size and achieving operability or decreasing the
extent of surgery
In operable cases, the timing of treatment (pre- versus post-operative) has
no effect on long term outcomes
Chemotherapy regimens are the same as those used in the adjuvant setting;
a sequential regimen of anthracyclines and taxanes is recommended
negative tumours and is usually given for 46 months before surgery and
continued post-operatively; for postmenopausal women, AIs are more effective
than tamoxifen
20
PREDICTIVE
ER
++
+++
IHC
Hormonal
treatment
PgR
+++
IHC
If negative,
chemotherapy
in some cases
HER2
++
+++
Anti-HER2
treatment
Ki67
++
+
IHC no consensus
Intrinsic
Gene expression profile (not
++
++
subtypes
for IHC surrogates)
Chemotherapy
if elevated
Different
response to
neoadjuvant
chemotherapy
according to
subtype
1st generation
signatures
(MammaPrint,
Oncotype Dx)
+++
Chemotherapy
if high risk or
high score
2nd generation
signatures
None yet
ER, oestrogen receptor; PgR, progesterone receptor; HER-2, human epidermal growth factor receptor 2; IHC, immunohistochemistry;
RT-PCR, reverse transcription polymerase chain reaction
FOLLOW-UP
In the first years, the risk of recurrence is higher in patients with ER-negative
tumours than in those with ER-positive tumours, but the annual risk of
recurrence drops below the level for ER-positive tumours ~58 years
after diagnosis
every 34 months in the first 2 years, every 6 months from years 35 and
annually thereafter
Mammography (ipsilateral after BCS, and contralateral) is recommended every
12 years
Breast MRI may be indicated for young patients, especially in the case of dense
breast tissue and genetic or familial predisposition
In asymptomatic patients, there are no data to indicate that other laboratory
or imaging tests are associated with a survival benefit
Weight gain and obesity are likely to negatively affect prognosis; nutritional
counselling should be recommended for obese patients
The use of hormone replacement therapy increases the risk of recurrence and
should be discouraged
Follow-up clinics should focus not only on late side effects but also on issues that
deal with the long-term implications of living with breast cancer and assessing
the various quality of life (QoL) issues
22
SCREENING
Biannual mammography screening is recommended for women aged 5069 years
Annual screening with MRI of the breast in combination with mammography is
recommended for women with familial breast cancer with or without proven BRCA
mutations
DIAGNOSIS AND STAGING
Diagnosis and treatment should be performed at specialised breast units by an
MDT who specialise in breast cancer
Diagnostic assessments include:
Medical history
Physical examination
PS
Radiological examination
Pathological examination according to the WHO classification (4th edition) and
the AJCC)/UICC TNM staging classification system (7th edition)
Laboratory assessments, including full blood count, liver and renal function
tests, alkaline phosphatase and calcium
Additional investigations, such as chest CT, abdominal ultrasound or CT and
bone scintigraphy, should be considered for patients with clinically-positive
axillary nodes, large tumours or signs, symptoms or laboratory values
suggesting the presence of metastases
FDG-PET/CT may be useful for detection of metastatic disease when
conventional methods are inconclusive
For the purpose of prognostication and treatment decision-making, tumours are
grouped into surrogate intrinsic subtypes defined by routine histology and IHC data
according to the St Gallen Consensus Conference guidance (2013)
Post-operative pathological assessment of the surgical specimen should be made
according to the TNM system
Scoring systems such as the NPI, Adjuvant! Online or PREDICT scores can be used
to assist treatment decisions
Gene expression profiles (MammaPrint, Oncotype DX Recurrence Score)
may provide additional prognostic and/or predictive information to complement
23
25
AIs can be used upfront for 5 years, sequentially, after 23 years of tamoxifen or
following 5 years of tamoxifen (extended adjuvant therapy)
The optimal duration of adjuvant ET is currently unknown; extended adjuvant
therapy (10 years) should be discussed with all patients except those with very
low risk
Patients undergoing ovarian suppression and AI users are at increased risk of
bone loss
These patients should be advised regarding the need for adequate calcium and
vitamin D3 intake and receive periodical bone mineral density assessments by
DEXA scan
Chemotherapy
The most frequently used regimens contain anthracyclines and/or taxanes
Chemotherapy is usually administered for 1224 weeks (48 cycles). The use of
dose-dense schedules (with G-CSF support) should be considered particularly in
highly proliferative tumours
HER2-directed therapy
1 year of trastuzumab should be considered for the majority patients with HER2positive tumours (eligibility based on the baseline cardiac function)
Due to its cardiotoxicity, trastuzumab should not be routinely administered
concomitantly with anthracyclines
Adjuvant systemic therapy for DCIS
Tamoxifen may be considered since it reduces the risk of invasive and non-invasive
recurrences after BCS of ER-positive DCIS, and decreases the incidence of second
primary (contralateral) breast cancer, but does not affect survival
Neoadjuvant systemic therapy
In locally advanced and large tumours, neoadjuvant systemic therapy may allow for
reducing tumour size and achieving operability or decreasing the extent of surgery
Should be delivered without unnecessary breaks (e.g. dividing it between the preand post-operative period)
Chemotherapy regimens are the same as those used in the adjuvant setting;
a sequential regimen of anthracyclines and taxanes is recommended
Neoadjuvant ET may be considered for patients with ER-positive and HER2negative tumours
27
Personalised medicine
Surrogate intrinsic tumour phenotypes, based on biomarker expression
(ER, PgR, HER2 and Ki67), are the basis for treatment individualisation
uPA-PAI1 and molecular signatures such MammaPrint or Oncotype DX can
be used, in conjunction with other clinicopathological factors, to aid treatment
decision-making in early breast cancer
FOLLOW-UP
Follow-up visits including history and physical examination are recommended
every 34 months in the first 2 years, every 6 months from years 35 and annually
thereafter
Mammography (ipsilateral after BCS, and contralateral) is recommended every
12 years
Breast MRI may be indicated for young patients, especially in the case of dense
breast tissue and genetic or familial predisposition
Routine lipid profile assessment is indicated to follow-up patients on ET
In symptomatic patients or in the case of abnormal findings on examination,
appropriate tests should be carried out immediately
Patients should have unlimited access to specialised rehabilitation facilities and
services to decrease the physical, psychological and social sequelae of breast
cancer treatment
Follow-up clinics should focus not only on late side effects but also on issues that
deal with the long-term implications of living with breast cancer and assessing the
various QoL issues
28
GENERAL GUIDELINES
GUIDELINE STATEMENT
LoE
CONSENSUS
IB
Expert
opinion
The age of the patient should not be the sole reason to withhold effective
therapy (in elderly patients) nor to overtreat (in young patients). Age alone
should not determine the type and intensity of treatment
IB
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement
29
LoE
CONSENSUS
Expert
opinion
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; ET, endocrine therapy; PD,
progressive disease; MBC, metastatic breast cancer.
30
LoE
CONSENSUS
IB
II B
Expert
opinion
IA
IA
IA
IA
IA
IA
II B
CT, computed tomography; LABC, locally advanced breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel
members in agreement with the statement; ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; PET, positron emission
tomography; PR, progesterone receptor
31
LoE
CONSENSUS
IB
IB
Expert
opinion
IB
LABC, locally-advanced breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the
statement; pCR, pathological complete remission
LoE
CONSENSUS
IC
Expert
opinion
LHRH, luteinising hormone-releasing hormone; MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of
panel members in agreement with the statement
32
LoE
CONSENSUS
II B
Expert
opinion
IB
Expert
opinion
33
IB
In patients with disease not amenable to radical local treatment, the choice
of palliative systemic therapy should be made according to principles
previously defined for MBC. These patients may still be considered for
palliative local therapy
Expert
opinion
MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement;
CTh, chemotherapy; RT, radiotherapy; ET, endocrine therapy; HER-2, human epidermal growth factor receptor 2; ER, oestrogen receptor
LoE
CONSENSUS
IA
IB
IB
100% Yes
(30 voters)
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; ER, oestrogen receptor;
ET, endocrine therapy; HD, high-dose; HER-2, human epidermal growth factor receptor 2; PFS, progression-free survival
34
LoE
CONSENSUS
In the 1st line setting, for HER-2+ MBC previously treated (in the adjuvant
setting) or untreated with trastuzumab, combinations of CTh + trastuzumab
are superior to combinations of CTh + lapatinib in terms of PFS and OS
IA
IA
There are currently no data supporting the use of dual blockade with
trastuzumab + pertuzumab associated with CTh beyond 1st line, after
treatment with trastuzumab + pertuzumab + CTh in 1st line (i.e. continuing
dual blockade beyond progression) and therefore this 3 drug regimen
should not be given beyond 1st line outside clinical trials
II C
IA
All patients with HER-2+ MBC who relapse after adjuvant anti-HER-2
therapy should be considered for further anti-HER-2 therapy, except in the
presence of contraindications.
The choice of the anti-HER-2 agent will depend on country-specific
availability, the specific anti-HER-2 therapy previously administered, and
the relapse free interval.
The optimal sequence of all available anti-HER-2 therapies is currently
unknown
IB
IC
MBC, metastatic breast cancer; LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement;
CTh, chemotherapy, HER-2, human epidermal growth factor receptor 2; RT, radiotherapy; OS, overall survival; PFS, progression-free survival;
T-DM1, Trastuzumab Emtansine
35
LoE
CONSENSUS
IA
IB
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement; CTh, chemotherapy;
MBC, metastatic breast cancer
LoE
The true value of the removal of the primary tumour in patients with de
novo stage IV breast cancer is currently unknown. However, it can be
considered in selected patients. Of note, some studies suggest that surgery
II B
is only valuable if performed with the same attention to detail (e.g. attaining
clear margins and addressing disease in the axilla) as in patients with early
stage disease
LoE, Available level of evidence; Consensus, Percentage of panel members in agreement with the statement
36
CONSENSUS
100% (29) Yes
0% (0) Abstain
(29 voters)
ABC1 STATEMENTS
GUIDELINE STATEMENT
LoE
CONSENSUS
Expert
opinion
Expert
opinion
Expert
opinion
Expert
opinion
Expert
opinion
The medical community is aware of the problems raised by the cost of ABC
Expert
treatment. Balanced decisions should be made in all instances; patients
opinion
well being, length of life and preferences should always guide decisions
Assessment guidelines
Minimal staging workup for MBC includes a history and physical
examination, haematology and biochemistry tests, and imaging of chest,
abdomen and bone
2C
37
The clinical value of tumour markers is not well established for diagnosis
or follow-up after adjuvant therapy, but their use is reasonable (if elevated)
as an aid to evaluate response to treatment, particularly in patients with
non-measurable metastatic disease. A change in tumour markers alone
should not be used to initiate a change in treatment
2C
Expert
opinion
1 C*
2C
If the results of tumour biology in the metastatic lesion differ from the
primary tumour, it is currently unknown which result should be used for
treatment-decision making. Since a clinical trial addressing this issue
is difficult to undertake, we recommend considering the use of targeted
therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at
least one biopsy, regardless of timing
Expert
opinion
Treatment choice should take into account at least these factors: HR and
HER-2 status, previous therapies and toxicities, disease-free interval,
tumour burden (defined as number and site of metastases), biological
age, performance status, co-morbidities (including organ dysfunctions),
menopausal status (for ET), need for a rapid disease/symptom control,
socio-economic and psychological factors, available therapies in the
patients country and patient preference
Expert
opinion
A small but very important subset of patients with MBC, for example those
with oligo-metastatic disease, can achieve complete remission and a long
survival. A multimodal approach should be considered for these selected
patients.
A prospective clinical trial addressing this specific situation is needed
Expert
opinion
38
IA
IA
IB
IA
IC
Concomitant CTh + ET has not shown a survival benefit and should not be
administered outside of a clinical trial
IB
IA
For patients with ER+/HER-2+ MBC for whom ET was chosen over CTh,
anti-HER-2 therapy + ET should be considered with the initiation of
endocrine therapy (provided that further anti-HER-2 therapy is available)
since anti-HER-2 therapy (either trastuzumab or lapatinib) in combination
with ET has shown substantial PFS benefit (i.e. time without CTh)
compared to ET alone. The addition of anti-HER-2 therapy in this setting
has not led to a survival benefit
IA
IB
HER-2-POSITIVE ABC
39
IB
IB
IA
IA
IA
Duration of each regimen and the number of regimens should be tailored to Expert
each individual patient
opinion
IB
IA
IA
40
IA
IB
IB
IB
IA
IA
IA
Expert
opinion
41
Expert
opinion
Expert
opinion
ABC, advanced breast cancer; MBC, metastatic breast cancer; TNBC, triple-negative breast cancer; ET, endocrine therapy; CTh, chemotherapy;
PD, progressive disease; HD, high-dose; PFS, progression-free survival; OS, overall survival; MRI, magnetic resonance imaging;
ER, oestrogen receptor; HER-2, human epidermal growth factor receptor 2; HR, hormone receptor; RT, radiotherapy
*= LoE changed since ABC1 from 2 C to 1 C based on new published data (Thompson_2010, Amir_2012, Foukakis_2012).
BENEFIT VS.
RISK AND
BURDENS
Benefits clearly
1A/ Strong recommendation,
outweigh risk and
high quality evidence
burdens, or vice versa
Strong
recommendation,
can apply to most
patients in most
circumstances
without reservation
Benefits clearly
1B/ Strong recommendation,
outweigh risk and
moderate quality evidence
burdens, or vice versa
Strong
recommendation,
can apply to most
patients in most
circumstances
without reservation
Observational studies or
case series
Strong
recommendation,
but may change
when higher quality
evidence becomes
available
1C/ Strong
Benefits clearly
recommendation, low quality outweigh risk and
evidence
burdens, or vice versa
42
METHODOLOGICAL
QUALITY OF
IMPLICATIONS
SUPPORTING
EVIDENCE
Weak
recommendation,
best action may
differ depending on
circumstances or
patients or societal
values
Weak
recommendation,
best action may
differ depending on
circumstances or
patients or societal
values
Benefits closely
Observational studies or
balanced with risks and
case series
burden
Very weak
recommendation,
other alternatives
may be equally
reasonable
43
Widely accepted clinical criteria for referral include: 3 breast and/or ovarian
cancer cases with at least one patient aged <50 years, two breast cancer cases
in patients aged <40 years, women of Ashkenazi Jewish descent aged <60 years
with breast cancer, male breast cancer and ovarian cancer or early onset female
breast cancer, early onset bilateral breast cancer, and breast and ovarian cancer
in the same patient
MUTATION DETECTION
Direct DNA sequencing is the gold standard for mutation detection, although
several techniques are available
Chemoprevention
44
RISK MODIFIERS
Parity appears to confer protection from breast cancer in women carrying BRCA
mutations, as in the general population
PBM is the most effective strategy for risk reduction in women carrying BRCA
mutations (risk reduction 90%)
Survival benefits have not been demonstrated
In addition to total mastectomy, other surgical techniques are available, but no
TREATMENT
Surgery
It is not known whether PBSO is associated with a significantly decreased risk
of breast cancer in women carrying BRCA1 mutations who have previously had
breast cancer
Systemic treatment
46
49
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