Gynecologic Oncology 148 (2018) 79–85

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Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Letrozole may be a valuable maintenance treatment in high-grade serous

ovarian cancer patients
V. Heinzelmann-Schwarz a,d,⁎,1, A. Knipprath Mészaros a,1, S. Stadlmann b, F. Jacob c,d, A. Schoetzau d, K. Russell e,
M. Friedlander f, G. Singer b, M. Vetter a
a
Gynecological Cancer Center, University Hospital Basel, University of Basel, Spitalstrasse 21, 4031 Basel, Switzerland
b
Institute of Pathology, Cantonal Hospital Baden, Im Ergel 1, 5404 Baden, Switzerland
c
Glyco-Oncology Group, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 20, 4056 Basel, Switzerland
d
Ovarian Cancer Research, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4056 Basel, Switzerland
e
Caris Life Sciences, Jakobsstrasse 199, 4052 Basel, Switzerland
f
Department of Medical Oncology, Prince of Wales Hospital, Prince of Wales Clinical School, University of New South Wales, Barker St, Randwick NSW 2031, Sydney, Australia

H I G H L I G H T S

• ESR1 and ER expression are similarly high in HGSOC and in breast cancer.
• ER expression did not differ between platin-sensitive or –resistant HGSOC.
• ER expression did not differ between matched primary or recurrent HGSOC.
• Letrozole maintenance showed improved progression-free survival.

a r t i c l e i n f o a b s t r a c t

Article history: Objectives. Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and
Received 8 August 2017 has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as
Received in revised form 24 October 2017 maintenance in high-grade serous ovarian cancers (HGSOC).
Accepted 26 October 2017
Methods. We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on
Available online 20 November 2017
all cancers (n = 8901) and HGSOC (n = 527) were followed by investigation of ER expression via immunohis-
Keywords:
tochemistry (IHC) (n = 4071). The same was performed in an independent cohort for matched primary and
Ovarian cancer recurrent HGSOC (n = 80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy
HGSOC with Letrozole.
Letrozol maintenance Results. ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER
Aromatase inhibitor expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant
ER subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly
prolonged recurrence free interval (after 24 months 60% when taking Letrozole versus 38.5% in the control
group; p = 0.035; RFS: IC50 reached by one subject versus 13.2 months). This effect was also present in patients
treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12 months compared to 87.5%
when taking Letrozole in addition to Bevacizumab (p = 0.026).
Conclusions. Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where
aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of
Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.
© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

The prognosis of ovarian cancer is still poor, with a 5 year relapse

⁎ Corresponding author at: Gynecological Cancer Center, University Hospital Basel,
rate of 75% for advanced HGSOC [1–3]. Despite better treatment options
Spitalstrasse 21, 4031 Basel, Switzerland.
E-mail address: viola.heinzelmann@usb.ch (V. Heinzelmann-Schwarz). including maximal cytoreductive surgery and new-targeted therapies,
1
Contributed equally. the outcome has improved only marginally over the last decades,

https://doi.org/10.1016/j.ygyno.2017.10.036
0090-8258/© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
80 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85

particularly in HGSOC. Therefore, several drugs have been evaluated in 2. Methods

ovarian cancer in clinical trials in the primary and recurrent setting.
The most promising agents so far are anti-angiogenesis inhibitors and
PARP-inhibitors [4–9]. Bevacizumab, a VEGF-antibody, is approved for
maintenance, based on a post-hoc analysis for high-risk cancers [10].
Olaparib, a PARP-inhibitor, is approved in Europe for patients with a
germline BRCA mutation or BRCA mutated tumors in the recurrent
setting after re-introduction of platinum-based chemotherapy [11]. In
contrast, in the United States olaparib is approved for the treatment of
adult patients with deleterious or suspected deleterious germline
BRCA-mutated (gBRCAm) advanced ovarian cancer treated with three
or more prior lines of chemotherapy [12]. Since 2016, two other PARP
inhibitors, rucaparib and niraparib, are approved by the FDA [9,13].
Thus, there is an urgent need of new drugs as to improve out-
comes, particularly by maintaining the status quo of these patients,
without decreasing their quality of life. One important target with
recent new and promising results as maintenance until time to
next treatment (TTNT) is anti-hormonal therapy [14]. Several
small case series demonstrated a benefit in ER + ovarian cancer in
particular in low-grade serous ovarian cancer (LGSOC) patients,
suggesting that there are subgroups of patients with a specific
tumor biology that responds very well to endocrine therapy [14].
Recently, Gershenson presented a retrospective analysis of endo-
crine maintenance therapy for LGSOC including 180 patients [15].
For patients receiving endocrine maintenance therapy (n = 66)
after Platinum-based adjuvant chemotherapy, progression-free
survival (PFS) was significantly better than for patients under obser-
vation only (n = 112, 64.9 months versus 27.3 months, p b 0.001).
Most patients received treatment with Letrozole (54%) or Tamoxifen
(28%). The same authors demonstrated already in 2012 in 69 pa-
tients with recurrent LGSOC who received 89 different hormonal
therapy regimens a high clinical benefit rate. Patients receiving dif-
ferent regimens of endocrine maintenance therapy for relapse
showed a response rate of 9% and stable disease of 62% [16]. Hereby,
the rationale for endocrine treatment is based on the high ER/PR IHC
expression as a predictive marker, since ovarian cancer is partly
driven by the estrogen-pathway [17].
In one of the largest consortia studies (n = 2933), ER expression rate
was between 20 and 90%, depending on the subtype, being high both in
low grade and HGSOC (87% and 81%, respectively) [18]. The authors
were able to demonstrate that strong ER expression in HGSOC was not
significant for prognosis (p = 0.49). None of the previous trials and
analysis on anti-hormonal treatment was ever done prospectively in
the maintenance setting but rather as a treatment regimen in heavily
pretreated patients, hereby mostly without providing information in
regards to ER/PR expression.
2.1. Patient cohorts
Four patient cohorts are used for this analysis; (A) ESR1 gene expres-
sion was measured in the publicly available US-American TCGA and the
Australian Tothill datasets; (B) ER expression in HGSOC FIGO III/IV can-
cer patients was measured in another US-American cohort from Caris
Life Sciences; (C) primary and matched recurrent HGSOC FIGO stage
III/IV patients were examined for ER expression in 80 Swiss patients;
and finally, (D) all newly diagnosed HGSOC FIGO III/IV with positive
ER expression using IHC were prospectively included in our single-site
Letrozole maintenance treatment approach at the University Hospital
Basel, Gynecological Cancer Centre (Table 1).
The primary and matched recurrent HGSOC on tissue microarray
(TMA, Cohort C), as well as all clinico-pathological data were collected
from 1985 to 2002 as previously described [19] (Cohort C; Table 1).
Time of recurrence was defined as symptomatic relapse confirmed
by RECIST in the radiological examination. Cancers with a time to
recurrence of less or equal 6 months after completion of platinum-
based chemotherapy were defined as chemo-resistant.
2.2. TCGA data analysis
TCGA datasets were accessed through the UCSC Cancer Genomics
Browser website [20,21].
ESR1 expression was analyzed using TCGA_PANCAN HiSeq_V2
dataset (Cohort A; Table 1). In regards to HGSOC, the TCGA
(GSE68661 Affymetrix HAT Human Genome U133A Array [22]) and
Tothill (GSE9899, Affymetrix Human Genome U133 Plus 2.0 Array
[23]) ovarian cancer transcriptomic data sets were downloaded from
Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/).
2.3. Immunohistochemistry
ER expression of consecutive tissue samples (referrals from 2008 to
2016) submitted to a commercial CLIA-certified molecular profiling lab-
oratory (Caris Life Sciences, Phoenix, AZ) was used for initial assessment
(Cohort B; Table 1). The tissue diagnoses were submitted based on path-
ological assessment of physicians who requested the assays and were
further verified by a pathologist at the Caris Laboratory. IHC was per-
formed on formalin-fixed paraffin-embedded tumor samples using com-
mercially available detection kits, automated staining techniques
(Benchmark XT, Ventana, Tucson, AZ) and antibodies against ER (Clone
SP1; Ventana, Tucson, AZ). Positive ER was defined as 2+ staining in at
least 75% of tumor cells, or 3 + staining in at least 50% of tumor cells.

Table 1
Clinicopathological variables of patients with HGSOC in the various cohort.

Cohort A B C D

Nationality US US Swiss Swiss

Clinicopathological characteristics TCGA PANCAN ER IHC Caris Matched primary/recurrent Letrozole maintenance No maintenance

Date of sampling (years) 1985–2003 2013–2017 2009–2017

Median age (years) 59 71.1 66.9
IQR 20–77 57.2–75.8 59–68.8
FIGO stage (%)
I 0 0 0
II 3.7 0 0
III 96.3 60 75
IV 0 40 25
Number of patients 527 4071 80 23 27
Platinum-sensible 57 22 29
Platinum-resistant 23 1 2
Number of platin-containing cycles
6 cycles (n, %) 73; 91.3 21; 91.3 25, 80.6
b6 cycles (n, %) 7; 8.7 2; 8.7 6; 19.4
 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85
ER results from Caris commercial biomarker database were obtained
using a data extraction tool. In accordance with Western Institutional
Review Board guidelines, patient identification was not possible
throughout the study, so the study was considered exempt, and institu-
tional review board approval was waived.
In the second independent Swiss matched primary/recurrent
HGSOC cohort (Cohort C; Table 1), protein detection of ER on TMA slides
were stained using an HRP Linked- Antibody Conjugated automated
Staining System (Bond Leica Biosystems, Muttenz, Switzerland). For an-
tigen retrieval, paraffin embedded tissue slides were incubated accord-
ing to standard procedures. Slides were incubated with the anti-human
ER-alpha (Clone 6F11, Leica Biosystems Muttenz, Switzerland, dilution
1:25) for 30 min. Negative controls involved the omission of the prima-
ry antibodies. Counterstaining was performed with hematoxylin and 1%
acid alcohol. ER staining is regularly checked in international round
robin tests. To assess ER expression levels, each core sample was scored
for overall percentage (between 0 and 100) and overall intensity (0 to
3) by two independent pathologists (S.S. and G.S.) and discrepancies re-
solved by consensus. The scoring system IRS (Immunoreactive Score)
and ATS (Allred Total score) were used and in addition total percentage
of positive nuclei was recorded. Positive ER by IRS score was defined as
at least 10% positive nuclei and at least a moderate or strong staining
intensity. Positive ER by ATS score was defined as at least N1% positive
nuclei and moderate or strong staining intensity and positive ER by
percentage was defined as staining N0% (Table 2).
2.4. Single-site prospective Letrozole maintenance
Since 2013 all newly, diagnosed HGSOC FIGO III/IV patients with ER
positive cancers equal or above 1% were offered Letrozole 2.5 mg daily
maintenance treatment in an off-label fashion following debulking sur-
gery and adjuvant Platinum-based chemotherapy (Cohort D; Table 1).
All patients were informed and consented about the off-label use of
Letrozole and about the potential use of their clinical information pro-
vided to the hospital in line with the National Human Ethics Regulations
in Switzerland. Discontinuation of Letrozole treatment was possible
whenever the patient wished to stop the treatment, had significant
side effects or showed a symptomatic recurrence demanding further
chemotherapy treatment. The Letrozol group was compared to the
group of patients, who declined maintenance treatment and who had
only observation (non-letrozole group).
To be included in the Letrozole analysis group, patients had to have
taken Letrozole for at least three subsequent months. Maintenance ther-
apy did not have to start directly after the end of adjuvant treatment and
could be initiated at any time during this initial relapse free interval,
resulting in a wide range when maintenance was initiated. We assessed
Table 2
Association of ER immunoexpression in matched primary and recurrent HGSOC. Percent-
ages in tables are related to subjects with expression values in primary and relapsed tu-
mors; p-values of independent data are based on Fisher's exact tests, p-values of
dependent data are based on McNemar tests (Cohort C; Table 1). Three different scoring
systems were used: IRS (Immunoreactive Score), ATS (Allred Total score) and ER expres-
sion N0%.
Primary tumors Recurrent tumors
+ER expression (IRS)
- Platinum-sensible (%) 23.9 19.6
- Platinum-resistant (%) 36.8 21.1
- p-Value 0.39 1 cohort, however, examined ER at any time of disease presentation,
+ER expression (ATS)
- Platinum-sensible (%) 32.6 37.0
- Platinum-resistant (%) 42.1 52.6
p-Value 0.43 0.19
+ER expression (percentage N 0)
- Platinum-sensible (%) 32.6 39.1
- Platinum-resistant (%) 42.1 52.6
p-Value 0.43 0.29
81
the interval between the end of adjuvant chemotherapy and TTNT in
correlation with/without the use of Letrozole using Kaplan-Meier
analysis. Patients with residual disease after debulking surgery received
Bevacizumab maintenance treatment 7.5 mg/m2 3-weekly for
15 months as to the Swiss guidelines. Hereby patients could receive
both Bevacizumab and Letrozole in parallel. Patients in the non-
Letrozole group did not receive Letrozole maintenance after adjuvant
chemotherapy. Survival analysis was done by Kaplan-Meier-analysis.
Relapse free survival was defined as the length of time after finishing
primary adjuvant chemotherapy until relapse defined by progression
on a CT scan.
2.5. Data analysis
In order to compare independent categorical or ordinal variables
across study groups, Fisher's exact tests or Mann-Whitney U tests
were performed as appropriate. Paired categorical data were explored
using McNemar-tests. Time to event data was analyzed using Kaplan-
Meier method or Cox-regression with corresponding hazard ratios and
p-values.
ESR1 expression was dichotomized using tree based model
partitioning (“ctree” in R package “party”). In addition, we have also
dichotomized the data set based on quartiles in order to create four
groups for ESR1 expression. A p-value of ≤0.05 was considered statically
significant. Statistical analysis was performed with the statistical soft-
ware R version 3.1.1 (https://www.R-project.org/). Ethical approval
for the retrospective analysis of clinico-pathological data was granted
by the Northwestern Swiss Ethical Board.
3. Results
3.1. Elevated ESR1 expression correlates with better disease outcome in the
TCGA PANCAN datasets
We reviewed the TCGA PANCAN database and found ESR1 expres-
sion to be a predictor in all cancers with an overall disease-free survival
(n = 8901, HR 0.935, CI [0.9222 to 0.9474], p-value based on Cox
regression b 2e − 16) and relapse-free survival (n = 5664, HR 0.909,
CI [0.8905 to 0.9287], p-value based on Cox regression b 2e − 16)
(Fig. 1A and B). The outcome was comparable using quartile dichoto-
mized data (Fig. 1A and B). Next, we studied the expression of ESR1 in
different TCGA cancer types and found that ESR1 expression was strik-
ingly upregulated in breast, endometrial and ovarian cancer (Fig. 1C),
indicating, that endometrial and ovarian cancer might be targetable
with similar drugs as currently performed in ER positive breast cancer
patients. In order to study the ESR1 expression in serous ovarian cancer
patients in more detail, we examined the TCGA (n = 527) and Tothill
(n = 274) transcriptomic datasets and found that neither increased
histopathological grading nor FIGO staging impacted on ESR1 ex-
pression in those samples, pointing towards a promising treatment
using aromatase inhibitors both in LGSOC and HGSOC (Fig. 1D).
3.2. Almost half of HGSOC express ER
p-Value ER positivity was found in 49.3% of HGSOC FIGO III/IV US-American
patients as measured by IHC (n = 4071; Cohort B, Table 1). Interesting-
0.75
ly, different sampling sites (n = 14) revealed a similar ER expression
0.45 pattern and therefore had no effect on the overall result (Fig. 1E). This
either at diagnosis or at recurrence.
0.80
0.72
3.3. ER expression remains unaffected in primary and recurrent HGSOC
independent of drug resistance
0.63
0.72 To our knowledge, there is no dataset yet available examining ER
expression in primary and matched recurrent HGSOC FIGO III/IV
82 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85

A B

Relapse-free survival
Disease-free survival

ESR1 (0, 4.61) ESR1 (4.61, 6.39) ESR1 (6.39, 8.31) ESR1 (6.31, 16.1) ESR1 (0, 4.61) ESR1 (4.61, 6.39) ESR1 (6.39, 8.31) ESR1 (6.31, 16.1)

C D E

ESR1 expression

ESR1 expression

IHC ER
percentage
ESR1 expression

ESR1 expression

IHC PR
percentage

Fig. 1. ESR1 expression in TCGA dataset. Overall disease-free survival (A) and relapse-free survival (B) in the TCGA PANCAN dataset (Cohort A, Table 1) p-value (log rank test). (C) Box-
Whisker blot ESR1 expression for anatomical origin sorted by descending median ESR1 expression among all TCGA cancer types; (D) ESR1 expression for histopathological grading and
FIGO staging in the Tothill and TCGA data set for high-grade serous ovarian cancer samples (Cohort A, Table 1). (E) Barchart showing percentage of IHC results for ER and PR in HGSOC
broken down into various sampling sites (Cohort B, Table 1).

(Cohort C, Table 1). ER expression was equally high in primary and III and 25% FIGO IV Stage in the non-Letrozole group, respectively.
recurrent HGSOC using three different methods of assessment, Both groups were also comparable in regards to residual disease
namely IRS and ATS score and ER expression N 0% (Table 2). For ER, (R0 in 58%).
the expression rate was equally high in all subgroups, independent During a median observation time of 14 months, the recurrence free
of platinum-sensible or resistant disease (Table 2). interval ranged from 4 to 123 months. The use of Letrozole as mainte-
nance after adjuvant chemotherapy independent of the time when
3.4. Letrozole maintenance improves progression free survival in HGSOC this treatment was started was associated with a significantly
patients prolonged recurrence free interval (RFS, Table 3). After 24 months,
60% of patients were recurrence free in the Letrozole versus 38.5% in
In the single-site prospective maintenance group 50 ER positive the control group (p = 0.035, Fig. 2). Whilst the control group reached
HGSOC FIGO III/IV patients were treated with standard adjuvant IC50 after 13.2 months, no recurrence free survival could be calculated
Platinum-based chemotherapy. After this treatment had ceased, for the Letrozole maintenance group at this point in time as only one
23 patients received Letrozole 2.5 mg daily off-label as a mainte- subject reached the endpoint so far. The improvement of the RFS
nance therapy whilst 27 patients did not receive any such mainte- could also been seen in the high risk group of patients with residual
nance treatment (Cohort D, Table 1). The Letrozole group disease treated with Bevacizumab maintenance; 20.8% of patients had
consisted of 60% FIGO III and 40% FIGO IV Stage versus 75% FIGO no recurrence after 12 months against 87.5% when taking Letrozole in

Table 3
Median recurrence free survival in months for ER + patients in various subgroups. Median in the Letrozole group not reached for no Bevacizumab/no residual disease and +/−
Bevacizumab/residual disease as yet with only one event so far (*). Estimate 64 months.

− Letrozole (N = 27) (months) + Letrozole (N = 23) (months) p-Value

− no Bevacizumab 20.8 (N = 21, 77%) (N = 16, 69.5%)* 0.11

− no residual disease
+ Bevacizumab 8.8 (N = 6, 22%) 21.6 (N = 7, 30.5%) 0.026
+ residual disease
+/− Bevacizumab 13.20 (N = 27) (N = 23)* 0.035
+/− residual disease
 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85 83

Fig. 2. Relapse-free survival of HGSOC FIGO III/IV treated with/without Letrozole as a maintenance therapy. Letrozole treated (red line; n = 23) vs untreated group (black line; n = 27),
showing a significantly longer relapse-free survival when using Letrozole (p = 0.035). RFS is defined from the end of adjuvant chemotherapy till first symptomatic recurrence, confirmed
by RECIST. IC50 not reached in the Letrozole vs untreated group (13.2 months) (Cohort D; Table 1).

addition to Bevacizumab (p = 0.026, Fig. 3). Also in this situation, the
start of Letrozole was not linked to the start of Bevacizumab and could
have been at a later point in time. Precaution and assessment of side
effects during anti-hormonal therapy with Letrozole, especially in con-
text to the possible bone loss, was performed according to the standards
used in breast cancer patients, namely by performing regular bone
scans and supplementing Vitamin D, Calcium or Denosumab where
necessary. During the therapy with Letrozole, no major side effects
were observed. Only two patients (6.4%) did interrupt the treatment
due to minor side effects (hot flushes, fatigue, bone pain) after 5, respec-
tively 9 months.
4. Discussion
4.1. Endocrine therapy in ovarian cancer
At present, the role of endocrine therapy with aromatase inhibitors
or Tamoxifen is only established for ovarian cancers in the recurrent set-
ting [24]. Randomized controlled trials are scarce and these drugs are
therefore mainly used in relapsed and heavily pretreated patients to
prolong TTNT [25,26]. However, even in the recurrent situation, results
of these trials and retrospective analysis were rather disappointing due
to the lack of reported ER and PR expression as predictive markers.

Fig. 3. Relapse-free survival of HGSOC FIGO III/IV treated with Bevacizumab as a maintenance therapy. Letrozole treated (red line; n = 9) vs untreated group (black line; n = 6), showing a
significantly longer relapse-free survival when using Letrozole in combination with Bevacizumab in patients with residual disease (p = 0.026). RFS is time from end of adjuvant
chemotherapy until first symptomatic relapse as confirmed by RECIST.
84 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85
Newer data from a large retrospective cohort of LGSOC demonstrat-
ed a large benefit of endocrine treatments as maintenance after primary
surgery and chemotherapy [15]. In this specific subgroup, endocrine
therapy can induce long-term remission. For HGSOC, the use of mainte-
nance endocrine treatment is not clear and might be an important treat-
ment part for this subtype.
There is little data in regards to maintenance treatment after
primary surgery and chemotherapy altogether, despite the vast ex-
perience in breast cancer where endocrine maintenance therapy
for 5 to 10 years includes Tamoxifen, aromatase inhibitors, Faslodex
and Progestin Acetat as standard therapy has been known for de-
cades in ER positive cancers [27–30]. Currently, there is no clear rec-
ommendation for aromatase inhibitor-based maintenance therapy
in ovarian cancer as the literature is inconsistent in regards to prog-
nostic and predictive effects [18]. In a 2013 published meta-analysis
including N6000 patients, a survival benefit was demonstrated for
PR positive disease only [31]. Therefore, only anti-angiogenetic
drugs and PARP-inhibitors have so far been used in the 1st and 2nd
line maintenance setting [4,11]. The great disadvantage of these
drugs, however, is the high costs, toxicity and poor quality of life
aspects [32].
Data in several large and independent cohorts clearly demonstrate
that the ER receptor and ER protein is markedly present in primary
HGSOC. Moreover, ER protein expression marginally alters during dis-
ease progression and acquired chemo-resistance. In our small single-
site prospective observation in HGSOC FIGO III/IV patients, we could
demonstrate a significant PFS benefit from maintenance treatment
with Letrozole following standard of care. This positive effect could par-
ticularly be seen when the treatment was initiated within three months
after the end of adjuvant chemotherapy.
A recent phase II basket trial (Paragon) using endocrine therapy for
ER positive gynecological cancers after 1st relapse reported a high clin-
ical benefit rate of 44% and an improved quality of life compared to the
control group [33]. Our results, data from the Paragon study and data
from large breast cancer studies [34], strongly suggest that endocrine
maintenance therapy has more advantage than disadvantage for use
in ovarian cancer patients and seems clearly justified.
In contrast to available expensive maintenance medications like
anti-angiogenic and PARP-inhibitors, anti-hormonal drugs have a favor-
able safety profile, low cost, easy intake regimen with one tablet daily
and an established prognostic target.
4.2. Conclusion, limitations of the study and further steps
The presented data give a solid review about estrogen receptor as a
potential target in HGSOC. Four different cohorts gave information
about gene expression of ERS1, expression of ER in primary and relapsed
HGSOC and therapeutic implication of letrozole in a smaller cohort of
HGSOC. Early treatment in the maintenance setting might be beneficial
and effective even in HGSOC. The limitation of this study is the small
number of patients and the uncontrolled randomization. (Cohort
D) The data are hypothesis generating and further clinical trials including
biomarker evaluations are warranted.
Acknowledgements
Construction of the TMA was supported by the Swiss Cancer League
(Oncosuisse) grant number OCS 01506-02-2004 (to G.S.). This study
was partly sponsored by Swiss Cancer League (KLS-3841-02-2016 to
F.J. and V.H.S.). We would also like to thank all the pathologists, gynecol-
ogists and oncologists involved in the treatment of the included
patients.
Conflict of interest
All authors declare no conflict of interest.
References
[1] R. Siegel, K. Miller, A. Jemal, Cancer statistics, 2015, CA Cancer J. Clin. 65 (2015), 29.
https://doi.org/10.3322/caac.21254.
[2] J.D. Wright, L. Chen, A.I. Tergas, S. Patankar, W.M. Burke, J.Y. Hou, A.I. Neugut, C.V.
Ananth, D.L. Hershman, Trends in relative survival for ovarian cancer from 1975 to
2011, Obstet. Gynecol. 125 (2015) 1345–1352, https://doi.org/10.1097/AOG.
0000000000000854.
[3] W.E. Winter, G.L. Maxwell, C. Tian, J.W. Carlson, R.F. Ozols, P.G. Rose, M. Markman,
D.K. Armstrong, F. Muggia, W.P. McGuire, Gynecologic Oncology Group Study, Prog-
nostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group
Study, J. Clin. Oncol. 25 (2007) 3621–3627, https://doi.org/10.1200/JCO.2006.10.
2517.
[4] R.A. Burger, M.F. Brady, M.A. Bookman, G.F. Fleming, B.J. Monk, H. Huang, R.S.
Mannel, H.D. Homesley, J. Fowler, B.E. Greer, M. Boente, M.J. Birrer, S.X. Liang,
Gynecologic Oncology Group, Incorporation of bevacizumab in the primary treat-
ment of ovarian cancer, N. Engl. J. Med. 365 (2011) 2473–2483, https://doi.org/10.
1056/NEJMoa1104390.
[5] K.S. Tewari, M.W. Sill, H.J. Long, R.T. Penson, H. Huang, L.M. Ramondetta, L.M.
Landrum, A. Oaknin, T.J. Reid, M.M. Leitao, H.E. Michael, B.J. Monk, Improved surviv-
al with bevacizumab in advanced cervical cancer, N. Engl. J. Med. 370 (2014)
734–743, https://doi.org/10.1056/NEJMoa1309748.
[6] C. Aghajanian, S.V. Blank, B.A. Goff, P.L. Judson, M.G. Teneriello, A. Husain, M.A.
Sovak, J. Yi, L.R. Nycum, OCEANS: a randomized, double-blind, placebo-controlled
phase III trial of chemotherapy with or without bevacizumab in patients with
platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian
tube cancer, J. Clin. Oncol. 30 (2012) 2039–2045, https://doi.org/10.1200/JCO.
2012.42.0505.
[7] E. Pujade-Lauraine, F. Hilpert, B. Weber, A. Reuss, A. Poveda, G. Kristensen, R. Sorio, I.
Vergote, P. Witteveen, A. Bamias, D. Pereira, P. Wimberger, A. Oaknin, M.R. Mirza, P.
Follana, D. Bollag, I. Ray-Coquard, Bevacizumab combined with chemotherapy for
platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized
phase III trial, J. Clin. Oncol. 32 (2014) 1302–1308, https://doi.org/10.1200/JCO.
2013.51.4489.
[8] J. Ledermann, P. Harter, C. Gourley, M. Friedlander, I. Vergote, G. Rustin, C.L.
Scott, W. Meier, R. Shapira-Frommer, T. Safra, D. Matei, A. Fielding, S. Spencer,
B. Dougherty, M. Orr, D. Hodgson, J.C. Barrett, U. Matulonis, Olaparib mainte-
nance therapy in patients with platinum-sensitive relapsed serous ovarian
cancer: a preplanned retrospective analysis of outcomes by BRCA status in a
randomised phase 2 trial, Lancet Oncol. 15 (2014) 852–861, https://doi.org/
10.1016/S1470-2045(14)70228-1.
[9] M.R. Mirza, B.J. Monk, J. Herrstedt, A.M. Oza, S. Mahner, A. Redondo, M. Fabbro, J.A.
Ledermann, D. Lorusso, I. Vergote, N.E. Ben-Baruch, C. Marth, R. Mądry, R.D.
Christensen, J.S. Berek, A. Dørum, A.V. Tinker, A. du Bois, A. González-Martín, P.
Follana, B. Benigno, P. Rosenberg, L. Gilbert, B.J. Rimel, J. Buscema, J.P. Balser, S.
Agarwal, U.A. Matulonis, ENGOT-OV16/NOVA Investigators, Niraparib maintenance
therapy in platinum-sensitive, recurrent ovarian cancer, N. Engl. J. Med.
(2016)https://doi.org/10.1056/NEJMoa1611310.
[10] T.J. Perren, A.M. Swart, J. Pfisterer, J.A. Ledermann, E. Pujade-Lauraine, G. Kristensen,
M.S. Carey, P. Beale, A. Cervantes, C. Kurzeder, A. du Bois, J. Sehouli, R. Kimmig, A.
Stähle, F. Collinson, S. Essapen, C. Gourley, A. Lortholary, F. Selle, M.R. Mirza, A.
Leminen, M. Plante, D. Stark, W. Qian, M.K.B. Parmar, A.M. Oza, ICON7
Investigators, A phase 3 trial of bevacizumab in ovarian cancer, N. Engl. J. Med.
365 (2011) 2484–2496, https://doi.org/10.1056/NEJMoa1103799.
[11] J. Ledermann, P. Harter, C. Gourley, M. Friedlander, I. Vergote, G. Rustin, C. Scott, W.
Meier, R. Shapira-Frommer, T. Safra, D. Matei, E. Macpherson, C. Watkins, J.
Carmichael, U. Matulonis, Olaparib maintenance therapy in platinum-sensitive re-
lapsed ovarian cancer, N. Engl. J. Med. 366 (2012) 1382–1392, https://doi.org/10.
1056/NEJMoa1105535.
[12] B. Kaufman, R. Shapira-Frommer, R.K. Schmutzler, M.W. Audeh, M. Friedlander, J.
Balmaña, G. Mitchell, G. Fried, S.M. Stemmer, A. Hubert, O. Rosengarten, M.
Steiner, N. Loman, K. Bowen, A. Fielding, S.M. Domchek, Olaparib monotherapy in
patients with advanced cancer and a germline BRCA1/2 mutation, J. Clin. Oncol.
33 (2015) 244–250, https://doi.org/10.1200/JCO.2014.56.2728.
[13] E.M. Swisher, K.K. Lin, A.M. Oza, C.L. Scott, H. Giordano, J. Sun, G.E. Konecny, R.L.
Coleman, A.V. Tinker, D.M. O'Malley, R.S. Kristeleit, L. Ma, K.M. Bell-McGuinn, J.D.
Brenton, J.M. Cragun, A. Oaknin, I. Ray-Coquard, M.I. Harrell, E. Mann, S.H.
Kaufmann, A. Floquet, A. Leary, T.C. Harding, S. Goble, L. Maloney, J. Isaacson, A.R.
Allen, L. Rolfe, R. Yelensky, M. Raponi, I.A. McNeish, Rucaparib in relapsed,
platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international,
multicentre, open-label, phase 2 trial, Lancet Oncol. 18 (2017) 75–87, https://doi.
org/10.1016/S1470-2045(16)30559-9.
[14] S.P. Langdon, C. Gourley, H. Gabra, B. Stanley, Endocrine therapy in epithelial ovarian
cancer, Expert. Rev. Anticancer. Ther. (2016) 1–9, https://doi.org/10.1080/
14737140.2017.1272414.
[15] D.M. Gershenson, D.C. Bodurka, R.L. Coleman, K.H. Lu, A. Malpica, C.C. Sun, Hormonal
maintenance therapy for women with low-grade serous cancer of the ovary or peri-
toneum, J. Clin. Oncol. 35 (2017) 1103–1111, https://doi.org/10.1200/JCO.2016.71.
0632.
[16] D.M. Gershenson, C.C. Sun, R.B. Iyer, A.L. Malpica, J.J. Kavanagh, D.C. Bodurka, K.
Schmeler, M. Deavers, Hormonal therapy for recurrent low-grade serous carcinoma
of the ovary or peritoneum, Gynecol. Oncol. 125 (2012) 661–666, https://doi.org/
10.1016/j.ygyno.2012.02.037.
[17] L. Björnström, M. Sjöberg, Mechanisms of estrogen receptor signaling: convergence
of genomic and nongenomic actions on target genes, Mol. Endocrinol. 19 (2005)
833–842, https://doi.org/10.1210/me.2004-0486.
 V. Heinzelmann-Schwarz et al. / Gynecologic Oncology 148 (2018) 79–85
[18] W. Sieh, M. Köbel, T. a Longacre, D.D. Bowtell, A. Defazio, M.T. Goodman, E. Høgdall,
S. Deen, N. Wentzensen, K.B. Moysich, J.D. Brenton, B. a Clarke, U. Menon, C.B. Gilks,
A. Kim, J. Madore, S. Fereday, J. George, L. Galletta, G. Lurie, L.R. Wilkens, M.E. Carney,
P.J. Thompson, R.K. Matsuno, S.K. Kjær, A. Jensen, C. Høgdall, K.R. Kalli, B.L. Fridley,
G.L. Keeney, R. a Vierkant, J.M. Cunningham, L. a Brinton, H.P. Yang, M.E. Sherman,
M. García-Closas, J. Lissowska, K. Odunsi, C. Morrison, S. Lele, W. Bshara, L.
Sucheston, M. Jimenez-Linan, K. Driver, J. Alsop, M. Mack, V. McGuire, J.H.
Rothstein, B.P. Rosen, M.Q. Bernardini, H. Mackay, A. Oza, E.L. Wozniak, E. Benjamin,
A. Gentry-Maharaj, S. a Gayther, A.V. Tinker, L.M. Prentice, C. Chow, M.S. Anglesio,
S.E. Johnatty, G. Chenevix-Trench, A.S. Whittemore, P.D. Pharoah, E.L. Goode, D.G.
Huntsman, S.J. Ramus, Hormone-receptor expression and ovarian cancer survival:
an ovarian tumor tissue analysis consortium study, Lancet Oncol. 14 (2013)
853–862, https://doi.org/10.1016/S1470-2045(13)70253-5.
[19] S. Stadlmann, U. Gueth, U. Reiser, P.-A. Diener, A.G. Zeimet, E. Wight, M. Mirlacher, G.
Sauter, M.J. Mihatsch, G. Singer, Epithelial growth factor receptor status in primary
and recurrent ovarian cancer, Mod. Pathol. 19 (2006) 607–610, https://doi.org/10.
1038/modpathol.3800575.
[20] M. Goldman, B. Craft, T. Swatloski, M. Cline, O. Morozova, M. Diekhans, D. Haussler, J.
Zhu, The UCSC cancer genomics browser: update 2015, Nucleic Acids Res. 43 (2015)
D812–7, https://doi.org/10.1093/nar/gku1073.
[21] M.S. Cline, B. Craft, T. Swatloski, M. Goldman, S. Ma, D. Haussler, J. Zhu, Exploring
TCGA pan-cancer data at the UCSC cancer genomics browser, Sci Rep 3 (2013),
2652. https://doi.org/10.1038/srep02652.
[22] caArray_EXP-485: TCGA Analysis of Gene Expression for Ovarian Serous
Cystadenocarcinoma Using Affymetrix HT_HG-U133A, (n.d.).
[23] R.W. Tothill, A.V. Tinker, J. George, R. Brown, S.B. Fox, S. Lade, D.S. Johnson, M.K.
Trivett, D. Etemadmoghadam, B. Locandro, N. Traficante, S. Fereday, J.A. Hung, Y.-
E. Chiew, I. Haviv, Australian Ovarian Cancer Study Group, D. Gertig, A. DeFazio,
D.D.L. Bowtell, Novel molecular subtypes of serous and endometrioid ovarian cancer
linked to clinical outcome, Clin. Cancer Res. 14 (2008) 5198–5208, https://doi.org/
10.1158/1078-0432.CCR-08-0196.
[24] NCCN Guidelines, Ovarian Cancer Including Fallopian Tube Cancer and Primary Peri-
toneal Cancer Version 1.2016, NCCN.org 2016.
[25] S.A. Weiner, D.S. Alberts, E.A. Surwit, J. Davis, D. Grosso, Tamoxifen therapy in recur-
rent epithelial ovarian carcinoma, Gynecol. Oncol. 27 (1987) 208–213http://www.
ncbi.nlm.nih.gov/pubmed/3570058.
[26] C.A. Papadimitriou, S. Markaki, J. Siapkaras, G. Vlachos, E. Efstathiou, I. Grimani, G.
Hamilos, M. Zorzou, M.-A. Dimopoulos, Hormonal therapy with letrozole for re-
lapsed epithelial ovarian cancer. Long-term results of a phase II study, Oncology
66 (2004) 112–117, https://doi.org/10.1159/000077436.
85
[27] E. Senkus, S. Kyriakides, F. Penault-Llorca, P. Poortmans, A. Thompson, S. Zackrisson,
F. Cardoso, ESMO Guidelines Working Group, Primary breast cancer: ESMO Clinical
Practice Guidelines for diagnosis, treatment and follow-up, Ann. Oncol. (24 Suppl. 6)
(2013) vi7–23, https://doi.org/10.1093/annonc/mdt284.
[28] N.G. Version, N. Clinical, P. Guidelines, N. Guidelines, Breast Cancer2012.
[29] C. Falandry, B. Weber, A.-M. Savoye, F. Tinquaut, O. Tredan, E. Sevin, L. Stefani, F.
Savinelli, M. Atlassi, J. Salvat, E. Pujade-Lauraine, G. Freyer, Development of a geriat-
ric vulnerability score in elderly patients with advanced ovarian cancer treated with
first-line carboplatin: a GINECO prospective trial, Ann. Oncol. 24 (2013) 2808–2813,
https://doi.org/10.1093/annonc/mdt360.
[30] C. Davies, H. Pan, J. Godwin, R. Gray, R. Arriagada, V. Raina, M. Abraham, V.H.
Medeiros Alencar, A. Badran, X. Bonfill, J. Bradbury, M. Clarke, R. Collins, S.R. Davis,
A. Delmestri, J.F. Forbes, P. Haddad, M.-F. Hou, M. Inbar, H. Khaled, J. Kielanowska,
W.-H. Kwan, B.S. Mathew, I. Mittra, B. Müller, A. Nicolucci, O. Peralta, F. Pernas, L.
Petruzelka, T. Pienkowski, R. Radhika, B. Rajan, M.T. Rubach, S. Tort, G. Urrútia, M.
Valentini, Y. Wang, R. Peto, Adjuvant Tamoxifen: Longer Against Shorter (ATLAS)
Collaborative Group, Long-term effects of continuing adjuvant tamoxifen to
10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive
breast cancer: ATLAS, a randomised trial, Lancet 381 (2013) 805–816, https://doi.
org/10.1016/S0140-6736(12)61963-1.
[31] D. Zhao, F. Zhang, W. Zhang, J. He, Y. Zhao, J. Sun, Prognostic role of hormone recep-
tors in ovarian cancer: a systematic review and meta-analysis, Int. J. Gynecol. Cancer
23 (2013) 25–33, https://doi.org/10.1097/IGC.0b013e3182788466.
[32] B.J. Monk, H. Dalton, J.H. Farley, D.M. Chase, I. Benjamin, Antiangiogenic agents as a
maintenance strategy for advanced epithelial ovarian cancer, Crit. Rev. Oncol.
Hematol. 86 (2013) 161–175, https://doi.org/10.1016/j.critrevonc.2012.09.012.
[33] P.S.G. Linda, R. Mileshkin, Richard J. Edmondson, Rachel O'Connell, Katrin Marie
Sjoquist, David Cannan, Rema Jyothirmayi, Philip James Beale, Tony Bonaventura,
Jeffrey C. Goh, Marcia Hall, Andrew R. Clamp, John A. Green, Rosemary Lord,
James Scurry, Michael Fried, Phase II study of anastrozole in recurrent estrogen
(ER)/progesterone (PR) positive endometrial cancer: the PARAGON trial—ANZGOG
0903, J. Clin. Oncol. 34 (2016) (Suppl; Abstr 5520) (n.d.).
[34] B. Thurlimann, A. Keshaviah, A.S. Coates, H. Mouridsen, L. Mauriac, J.F. Forbes, R.
Paridaens, M. Castiglione-Gertsch, R.D. Gelber, M. Rabaglio, I. Smith, A. Wardley,
K.N. Price, A. Goldhirsch, A comparison of letrozole and tamoxifen in postmeno-
pausal women with early breast cancer, N. Engl. J. Med. 353 (2005) 2747–2757,
https://doi.org/10.1056/NEJMoa052258.