Endocrine treatment of high grade serous ovarian carcinoma; quantification of efficacy and identification of response predictors

Abstract

Objectives. The role of endocrine therapy (ET) in high grade serous ovarian carcinoma (HGSOC) is poorly defined due to the lack of phase III data and significant heterogeneity of clinical trials performed. In this study, we sought to identify predictive factors of endocrine sensitivity in HGSOC. Methods. HGSOC patients who received at least four weeks of ET for relapsed disease following one line of chemotherapy at the Edinburgh Cancer Centre were identified. Exclusion criteria were use of endocrine therapy as maintenance therapy or of unknown duration. Duration of therapy and best CA125 response as per modified GCIG criteria were recorded. Oestrogen receptor (ER) histoscore, treatment free interval, prior lines of chemotherapy, and type of ET were evaluated as predictive factors. Results. Of 431 patients identified, 269 were eligible (77.0 % letrozole, 18.6% tamoxifen, 2.2% megesterol acetate, 2.2% other). The median duration of therapy was 126 days (range 28-1427 days). 32.7% remained on ET for ≥180 days and 14.1% for ≥365 days. The CA125 response and clinical benefit rates (response or stable disease) were 8.1% and 40.1% respectively. ER histoscore >200 (P=0.0016) and a treatment free interval of ≥180 days (P<0.0001) were independent predictive factors upon multivariable analysis. Conclusions. ET should be considered as a viable strategy to defer subsequent chemotherapy for relapsed HGSOC. Patients with an ER histoscore >200 and a treatment free interval of ≥180 days are most likely to derive benefit. 7 2.5 Statistical analysis Duration of therapy according to ER histoscore, TFI, prior lines of chemotherapy, best CA125 response and type of ET was evaluated using the Kaplan-Meier method and Cox regression models for univariable and multivariable analyses. Comparisons of CA125 ORR and CBR1 between groups were assessed using Chi-squared and Fisher's exact tests as appropriate. Statistical analyses were performed using R version 3.3.3. 3. RESULTS 431 patients received at least one line of ET. 162 patients were excluded (figure 1). 269 received ET as treatment for relapsed disease. 143(53.2%) were confirmed as HGSOC through contemporary pathology review conducted through other research studies, and 118(43.9%) and 8(3.0%) had a historical diagnosis of grade 3 and grade 2 serous carcinomas, respectively. The median age of diagnosis was 65 years (range 28-91 years). 3.1 First endocrine therapy for relapse Of 269 patients, 209 (77.7%), 55 (20.4%) and five (1.9%) patients received one, two and three lines of ET, respectively. 207 (77.0%), 50 (18.6%) and six (2.2%) patients received letrozole, tamoxifen and megesterol acetate, respectively. 156 (58.0%) patients received ET after one prior line of chemotherapy, 87 (32.3%) after two lines, and 26 (9.7%) after three or more lines. 229 (85.1%) and 36 (13.4%) patients last received chemotherapy in the platinum sensitive and platinum resistant setting, respectively. ER histoscores were available in 225 (83.6%) patients. The range of ER scores are illustrated in table 1. The ma...

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

“…Two recent reports have described studies evaluating the use of endocrine therapy in their respective centers and provide interesting insight into HGSOC outside of a trial setting [ 77 , 78 ]. An analysis of 97 patients treated at the Royal Marsden Hospital, London, investigated the use of tamoxifen and letrozole in high grade ovarian cancer (of which 91% were HGSOC) [ 77 ].…”

“…In an analysis of 269 HGSOC patients studied within Edinburgh over a 25-year period, letrozole and tamoxifen had comparable overall responses (8% and 11%, respectively) and clinical benefit rates (41% and 33%, respectively) [ 78 ]. Patients with a high ER score (discussed further below) and a longer treatment-free interval were most likely to benefit [ 78 ].…”

“…In an analysis of 269 HGSOC patients studied within Edinburgh over a 25-year period, letrozole and tamoxifen had comparable overall responses (8% and 11%, respectively) and clinical benefit rates (41% and 33%, respectively) [ 78 ]. Patients with a high ER score (discussed further below) and a longer treatment-free interval were most likely to benefit [ 78 ]. The conclusion from both of these analyses is in line with the clinical trial results and is that treatment with either tamoxifen or letrozole is a rational treatment option for patients with ER-positive HGSOC, producing a comparable overall response rate, CBR and disease stability.…”

Management of recurrent ovarian cancer: when platinum-based regimens are not a therapeutic option

“…A recent retrospective study enrolling 269 patients with high-grade serous ovarian carcinoma treated with hormonal therapy (letrozole, tamoxifen, and megestrol acetate) investigated factors associated with endocrine sensitivity. At multivariable analysis, an estrogen receptor histoscore >200 and a TFI >180 were independent prognostic factors for survival 40 44…”

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

“…Therefore, the use of endocrine disrupting agents in HGSOC could be promising [15]. Indeed, treatment of women with recurrent HGSOC using the antiestrogen tamoxifen or the aromatase inhibitor letrozole resulted in response rates between 10% and 15% and disease stabilization rates of 30% to 40% [16].…”