Progression-free survival by investigator versus blinded independent central review in newly diagnosed patients with high-grade serous ovarian cancer: Analysis of the VELIA/GOG-3005 trial

Abstract BackgroundThe interaction between BRCA2 BRC repeats and RAD51 is one of the great important factors affecting the homologous recombination in DNA damage repair of tumor cells. We investigated the effect of BRCA2 BRC repeat mutations on outcome in patients with high grade serous ovarian cancer (HGSOC) who received platinum-based chemotherapy.MethodsWe identified the type and location of BRCA2 BRC repeat mutations by PCR and DNA sequencing in tumor and peripheral blood leukocytes (PBL) samples of 113 patients with stage IIIC/IV high grade serous ovarian cancer (HGSOC), and assessed chemotherapy-free interval (CFI), progression-free survival (PFS) and overall survival (OS).Results24 (21.23%) cases with somatic mutation were identified in 113 HGSOC patients. Among them, 8 (7.1%) cases with nonsense mutation resulting in BRCA2 truncation significantly prolonged median CFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); Interestingly, 16 (14.13%) cases with missense mutation also prolonged median CFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS ( 38 vs 31 months, P=0.037). ConclusionsSomatic mutations in BRCA2 BRC5-8 repeat motifs are associated with platinum-based chemotherapy sensitivity and a better outcome in patients with HGSOC.

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A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer

Nature Communications ◽

10.1038/s41467-021-25904-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Panagiotis A. Konstantinopoulos ◽

Alexandre André B. A. da Costa ◽

Doga Gulhan ◽

Elizabeth K. Lee ◽

Su-Chun Cheng ◽

...

Keyword(s):

Ovarian Cancer ◽

Progression Free Survival ◽

Replication Stress ◽

Inhibitor Therapy ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival ◽

Rb Pathway ◽

Pathway Regulation ◽

Stress Biomarker

AbstractIn a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.

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Frizzled class 7 receptor is differentially expressed in high-grade serous ovarian cancer and based on patient survival.

10.31219/osf.io/aqzj9 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

Global Gene Expression ◽

Differentially Expressed ◽

Published Data ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival

High-grade serous ovarian cancer (HGSC) is the most common type of the most lethal gynecologic malignancy (1). To identify genes whose expression was associated with survival outcomes in HGSC, we used published data from patients enrolled in the ICON7 trial to compare the global gene expression profiles of primary HGSC tumors from women with the best and worst progression-free survival (PFS) (2). We found that the Frizzled class 7 (Fzd7) receptor was among the genes most differentially expressed in HGSC tumors when comparing tumor transcriptomes based on superior or inferior PFS. In two independent datasets, Fzd7 was among the genes most differentially expressed in HGSC tumors when comparing primary tumor to the normal ovary (3, 4). Wnt pathway signaling through Fzd7 may be relevant to the biology of high-grade serous ovarian cancers.

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Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2018-000035 ◽

2019 ◽

Vol 29 (2) ◽

pp. 325-333 ◽

Cited By ~ 3

Author(s):

Saul Eugene Rivkin ◽

James Moon ◽

Desiree S Iriarte ◽

Erik Bailey ◽

Heather L Sloan ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Complete Remission ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival ◽

Phase Ib ◽

Experienced Grade

ObjectiveOur goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.MethodsIn this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1–3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis.ResultsThe maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 BRCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3–4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1–2 non-hematologic toxicities.ConclusionsOlaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt.Trial registration numberNCT01650376.

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Management of the Elderly Patients with High-Grade Serous Ovarian Cancer in the REAL-WORLD Setting

Current Oncology ◽

10.3390/curroncol28020110 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1143-1152

Author(s):

Michalis Liontos ◽

Alkistis Papatheodoridi ◽

Angeliki Andrikopoulou ◽

Nikolaos Thomakos ◽

Dimitrios Haidopoulos ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Elderly Patients ◽

Cancer Patients ◽

Progression Free Survival ◽

Optimal Treatment ◽

High Grade ◽

Serous Ovarian Cancer ◽

Debulking Surgery ◽

Free Survival

Treatment of elderly patients with neoplasia is challenging. Age is a known prognostic factor in ovarian cancer but the optimal treatment of elderly patients has not been determined. We undertook a retrospective analysis to determine clinical practice in advanced-stage ovarian cancer patients older than 70 years of age. Methods: Medical records of women with high-grade serous ovarian cancer, stage III and IV were retrospectively analyzed. Results: A total of 735 patients were identified with a median age of 61.5 years. 22.4% among them were older than 70 years of age at diagnosis. First-line Progression-Free Survival (PFS) and Overall Survival (OS) were significantly worse in elderly patients in comparison to the younger ones [mPFS 11.3 months vs. 14.8 months, (p < 0.001) and mOS 30.2 months vs. 45.6 months (p < 0.001)]. However, elderly patients were characterized by worse ECOG-Performance Status and they were more frequently treated with Neoadjuvant Chemotherapy followed by Interval Debulking Surgery, while often they were more frequently denied debulking surgery compared to patients under 70 years of age. Moreover, elderly patients received more frequently monotherapy with platinum as frontline treatment. In contrast, there was no significant difference in the outcome of the debulking surgery in comparison to the younger patients or the frequency that gBRCA test was performed. Age over 70 years did not retain its significance for either Progression-Free Survival or Overall Survival when adjusted for all other reported prognostic factors. Conclusions: Elderly ovarian cancer patients have a worse prognosis. Comprehensive geriatric assessment should be performed for the optimal treatment of these patients.

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Germline BRCA2 mutation is associated with greater progression-free survival in korean women with advanced high-grade serous ovarian cancer

European Journal of Gynaecological Oncology ◽

10.31083/j.ejgo.2020.05.5255 ◽

2020 ◽

Vol 41 (5) ◽

pp. 675

Keyword(s):

Ovarian Cancer ◽

Brca2 Mutation ◽

Progression Free Survival ◽

High Grade ◽

Serous Ovarian Cancer ◽

Korean Women ◽

Free Survival

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Interleukin-16 expression associates with patient survival in high-grade serous ovarian cancer.

10.31219/osf.io/d9hws ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Expression Profiles ◽

Gynecologic Cancer ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

Global Gene Expression ◽

High Grade ◽

Serous Ovarian Cancer ◽

Significant Differential Expression ◽

Free Survival

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with enhanced survival in high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of tumors from women diagnosed with HGSC with the best and worst progression-free survival (2). We found significant differential expression of the gene encoding the cytokine interleukin-16 (IL-16) when comparing tumor transcriptomes based on progression-free survival. IL-16 was expressed at significantly lower levels in high-grade serous ovarian tumors of women with the longest progression-free survival.

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Expression of the interleukin-1 receptor antagonist associates with patient survival in high-grade serous ovarian cancer.

10.31219/osf.io/vtxak ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Ovarian Cancer ◽

Receptor Antagonist ◽

Expression Profiles ◽

Interleukin 1 ◽

Gynecologic Cancer ◽

Progression Free Survival ◽

High Grade ◽

Serous Ovarian Cancer ◽

Significant Differential Expression ◽

Free Survival

Ovarian cancer is the most lethal gynecologic cancer (1). We sought to identify genes associated with enhanced survival in high-grade serous ovarian cancer (HGSC) by comparing global gene expression profiles of tumors from women diagnosed with HGSC with the best and worst progression-free survival (2). We found significant differential expression of the gene encoding the receptor antagonist for the cytokine interleukin-1 (IL-1) (IL-1RN) when comparing tumor transcriptomes based on progression-free survival. IL-1RN was expressed at significantly lower levels in high-grade serous ovarian tumors of women with the longest progression-free survival.

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ATL

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31829527bd ◽

2013 ◽

Vol 23 (5) ◽

pp. 846-852 ◽

Cited By ~ 12

Author(s):

Angeles Alvarez Secord ◽

Jason Cory Barnett ◽

Jonathan A. Ledermann ◽

Bercedis L. Peterson ◽

Evan R. Myers ◽

...

Keyword(s):

Ovarian Cancer ◽

Adverse Events ◽

Parp Inhibitor ◽

Progression Free Survival ◽

Cost Effective ◽

Mutation Testing ◽

High Grade ◽

Serous Ovarian Cancer ◽

Free Survival ◽

Platinum Sensitive

Objectives(1) To determine whether use of a PARP inhibitor or (2) BRCA1/2 mutation testing followed by a PARP inhibitor for test positives is potentially cost-effective for maintenance treatment of platinum-sensitive recurrent high-grade serous ovarian cancer.MethodsA modified Markov decision analysis compared 3 strategies: (1) observe; (2) olaparib to progression; (3) BRCA1/2 mutation testing; treat mutation carriers with olaparib to progression. Progression-free survival and rates of adverse events were derived from a phase 2 randomized trial. Key assumptions are as follows: (1) 14% of patients harbor a BRCA1/2 mutation; (2) progression-free survival of individuals treated with olaparib is improved for BCRA1/2 carriers compared with noncarriers (estimated hazard ratio, approximately 0.4). Costs derived from national data were assigned to treatments, adverse events, and BRCA1/2 test. Monte Carlo probabilistic sensitivity analysis was performed.ResultsGlobal olaparib was the most effective strategy, followed by BRCA1/2 testing and no olaparib. BRCA1/2 testing had an incremental cost-effectiveness ratio (ICER) of $193,442 per progression-free year of life saved (PF-YLS) compared to no olaparib, whereas global olaparib had an ICER of $234,128 per PF-YLS compared to BRCA1/2 testing. At a 52% lower-than-baseline olaparib cost estimate of $3000 per month, BRCA1/2 testing became potentially cost-effective compared with observation, with an ICER of $100,000 per PF-YLS. When strategy (1) was removed from the analysis, BRCA1/2 testing was the preferred strategy.ConclusionsThe use of maintenance olaparib in women with high-grade serous ovarian cancer is not cost-effective regardless of whether BRCA1/2 testing is used to direct treatment. However, BRCA1/2 testing is a preferred strategy compared to global maintenance olaparib alone.

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