PARP inhibitors in BRCA mutation-associated ovarian cancer

e13100 Background: ovarian cancer (OC) with germinal or somatic BRCA mutations responds better to platinum and to PARP-inhibitors. There is great enthusiasm about BRCA somatic screening. Our aim was to analyse the correlation between BRCA somatic and germline mutational profile. Methods: a cohort of 23 pts was obtained by cross-linking OC pts from the South Portuguese Cancer Registry, between 2009-2014 and BRCA mutation carriers identified in our Clinic. Medical records were reviewed: demographic and clinico-pathologic data obtained. Germinal screening: pts were pre-screened for the BRCA2 Portuguese founder mutation (PFM), analysed for BRCA point mutations (different screening methodologies were used in diagnostic timeline: initially CSGE, then CSCE and finally NGS) and for large rearrangements by MLPA. Somatic screening: DNA was extracted from 5 sections of 10µm of FFPE tissue and analysed for BRCA1/2 genes by NGS. Results: clinico-pathological features of the 23 pts revealed mainly high-grade serous histology (96%). Mean age at diagnosis was 54 years old (33-76); BRCA2 were older than BRCA1 carriers (62 vs 51). Most pts presented at advanced stage (70% stages III-IV; 30% stage I-II). Seventeen were BRCA1 carriers and 6 were BRCA2 (5 of those PFM, a large insertion of an Alu element). Somatic correlation: 8 pts (5 BRCA1, 3PFM) were already analysed and 100% correlation was observed for all point mutations. One additional BRCA2 somatic mutation was detected (with a variant allele frequency of 53% whereas 2 others were < 7%); interestingly exclusive somatic mutations were only observed in PFM carriers (known not to be NGS detectable). The remaining 15 pts are under analysis. Conclusions: it was expected that the PFM and other large rearrangements would not be detected with NGS. A specific somatic screening for the PFM may be possible but other rearrangements are found by MLPA in our population (10% of all BRCA mutations). Preliminary data adds to the evidence that NGS OC somatic screening will identify all germinal point mutations and an indeterminate number of additional pts with exclusive somatic mutations. An ideal correlation needs integration of differenttechniques that may increase complexity, time and cost.

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PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

Author(s):

Boussios ◽

Karathanasi ◽

Cooke ◽

Neille ◽

Sadauskaite ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Current Evidence ◽

Repair Pathway ◽

Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

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Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919849753 ◽

2019 ◽

Vol 11 ◽

pp. 175883591984975 ◽

Cited By ~ 15

Author(s):

Jonathan A. Ledermann ◽

Eric Pujade-Lauraine

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Parp Inhibitors ◽

European Medicines Agency ◽

Clinical Safety ◽

Platinum Sensitive ◽

Repair Deficiency ◽

Recombination Repair ◽

Term Tolerability

Poly (ADP-ribose) polymerase (PARP) inhibitors were developed with the intention of treating patients with homologous recombination repair deficiency (HRD), specifically for patients with tumours that harbour a BRCA mutation (BRCAm). Evidence from clinical trials to date has demonstrated that patients with a BRCAm derive the greatest benefit from PARP inhibitors. However, clinical studies have also shown that PARP inhibitors provide benefit to women with ovarian cancer who do not have a BRCAm. The recent updated approvals of olaparib, niraparib and rucaparib by the US Food and Drug Administration and the European Medicines Agency for the treatment of all platinum-sensitive relapsed (PSR) ovarian-cancer populations, regardless of their BRCAm status, support this. Long-term tolerability and efficacy of olaparib have been demonstrated in patients both with and without a BRCAm, with 13% of patients receiving maintenance olaparib for at least 5 years in one study, which is unprecedented in the relapsed ovarian-cancer setting ( versus 1% on placebo). Further studies should be performed to elucidate which non-BRCAm patients are deriving benefit and what molecular processes are enabling this, so that patients continue to receive optimal treatment for their disease. Here, we review clinical and molecular markers of HRD, the long-term clinical safety and efficacy of PARP inhibitors in ovarian cancer, with a focus on olaparib and the current approved indications for PARP inhibitors, as well as guidance on treatment decisions for patients with PSR ovarian cancer.

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Efficacy and safety of PARP inhibitors as the maintenance therapy in ovarian cancer: a meta-analysis of nine randomized controlled trials

Bioscience Reports ◽

10.1042/bsr20192226 ◽

2020 ◽

Vol 40 (3) ◽

Cited By ~ 4

Author(s):

Fengping Shao ◽

Jun Liu ◽

Yaoyun Duan ◽

Li Li ◽

Liqun Liu ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Brca Mutation ◽

Meta Analysis ◽

Brca1 Mutation ◽

Brca2 Mutation ◽

Parp Inhibitors ◽

Incidence Rates ◽

Efficacy And Safety ◽

Grade 3

Abstract Purpose: Poly ADP ribose polymerase (PARP) inhibitors can effectively kill cancer cells by restraining the activity of DNA repair enzymes and utilizing the characteristics of BRCA mutations. This article evaluates the efficacy and safety of PARP inhibitors (PARPis) in the maintenance treatment of ovarian cancer. Method: We searched for clinical trials in electronic databases. PARPis efficacy were evaluated by the hazard ratios (HR) and its 95% confidence intervals (95% CI) of overall survival (OS) and progression-free survival (PFS) between the PARPis groups and placebo groups, while the PARPis’ safety was assessed by relative risk (RR) values of adverse events (AEs) between the two arms. Results: The immature OS data manifested that patients with BRCA mutation receiving PARPis therapy versus placebo therapy appeared to have longer OS (HR = 0.78, 95%CI = 0.61–1.01; P = 0.06). Compared with placebo group, PARP group had a significant advantage in PFS in ovarian cancer patients with BRCA wild-type (BRCAwt), BRCA mutation (BRCAm), BRCA status unclassified, BRCA1 mutation subgroup and the BRCA2 mutation subgroup (BRCAwt: HR = 0.53, 95%CI = 0.42–0.68, P < 0.00001; BRCAm: HR = 0.30, 95%CI = 0.26–0.34, P < 0.00001; BRCA status unclassified: HR = 0.52, 95%CI = 0.41–0.66, P < 0.00001; BRCA1m: HR = 0.38, 95%CI = 0.29–0.48, P < 0.00001; BRCA2m: HR = 0.23, 95%CI = 0.10–0.57, P = 0.001). Our analysis revealed the incidence rates for AEs of grade ≥3 (grades 3 to 4) and serious AEs in PARPis group were 55.19% and 26.29%, respectively. Conclusion: Our meta-analysis demonstrates that PARPis therapy can significantly improve PFS in ovarian cancer patients, but it has no benefit in OS. However, the therapy is associated with a significant increase in the risk of AEs of grade ≥ 3 and serious AEs.

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OTHR-03. Brain Metastasis Among Ovarian Cancer Patients

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.058 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii14-iii15

Author(s):

Dror Limon ◽

Eliya Shachar ◽

Lyri Adar ◽

Shira Peleg Hasson ◽

Tamar Safra

Keyword(s):

Ovarian Cancer ◽

Brain Metastasis ◽

Survival Data ◽

Brca Mutation ◽

Subsequent Development ◽

Disease Recurrence ◽

Parp Inhibitors ◽

Study Cohort ◽

Bevacizumab Treatment ◽

Brca Mutation Carriers

Abstract Background Brain metastasis (BM) are uncommon among ovarian cancer (OC) patients. Their frequency, risk factors and clinical repercussions are not well described. We assessed OC patients who developed BM, the role of BRCA status and survival implications. Methods Study cohort included OC patients treated at our center, from 2002–2020. We retrospectively evaluated clinical parameters, risk for BM development and association with survival data. Results Among 972 OC patients, 28 (2.9%) were diagnosed with BM. Comparing the BM to non-BM group, median age of 60 across both groups, stage III-IV at diagnosis was more common among BM group (96.4% vs. 84.8%, p=0.0065) while platinum sensitivity was similar (92.3% in BM vs. 80.8% in non-BM, p=0.2193). Out of 658 patients tested for BRCA, 33.6% (n=221) were BRCA mutation carriers (BRCA+). Of the patients with BM, 22 tested for BRCA, 13 were carriers. BRCA+ was significantly higher in the BM group compared to the non-BM group (59.1% vs. 32.9%, p=0.0123). Among BRCA+ the rate of BM was higher than among BRCA- (5.8% vs. 2.1%, p=0.0123, HR=3.029; 95%CI: 1.4–6.5). Median time from OC diagnosis to BM and from disease recurrence to BM, was longer for BRCA+ compared to BRCA- (44.3mo vs. 32.3mo and 11.8mo vs. 0.7mo, respectively). Median survival (mOS) was not significantly different among patients with BM compared to those without BM (59.4mo vs. 71.2mo, p=0.36). Following diagnosis of BM, mOS was 20.6mo among BRCA+ and 12.3mo among BRCA- (p=0.4266). No correlation was demonstrated with PARP inhibitors or bevacizumab treatment and subsequent development of BM. Conclusion BM are an infrequent event among OC patients. However, the risk is three-folds higher among BRCA+. Interestingly, BM do not significantly alter survival among OC patients. Our work suggests that the higher rate of BM in BRCA+ may be related to longer survival. Another hypothesis requiring further evaluation, is possible higher brain tropism among this population.

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The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9072239 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2239

Author(s):

Ludivine Dion ◽

Isis Carton ◽

Sylvie Jaillard ◽

Krystel Nyangoh Timoh ◽

Sébastien Henno ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Genetic Alterations ◽

High Grade ◽

Dna Breaks ◽

Brca Mutations ◽

Platinum Based Chemotherapy

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

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Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

Asian Journal of Oncology ◽

10.1055/s-0039-1700619 ◽

2019 ◽

Vol 05 (01) ◽

pp. 01-18

Author(s):

Vikas Goswami ◽

Venkata Pradeep Babu Koyyala ◽

Sumit Goyal ◽

Manish Sharma ◽

Varun Goel ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Germ Line ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Repair Mechanism ◽

Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

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Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.771836 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lili Gao ◽

Rui Chen ◽

Ting Li ◽

Lujin Li ◽

Qingshan Zheng

Keyword(s):

Ovarian Cancer ◽

Combination Therapy ◽

Maintenance Treatment ◽

Brca Mutation ◽

Progression Free Survival ◽

Recurrent Ovarian Cancer ◽

Parp Inhibitors ◽

Quantitative Information ◽

Wild Type ◽

Significant Difference

Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC).Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated.Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively.Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.

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Parp Inhibitors for the Treatment of Ovarian Cancer

Current Cancer Drug Targets ◽

10.2174/1568009618666180308104646 ◽

2018 ◽

Vol 18 (9) ◽

pp. 877-893 ◽

Cited By ~ 6

Author(s):

Laura Cortesi ◽

Angela Toss ◽

Iole Cucinotto

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Advanced Ovarian Cancer ◽

Parp Inhibitors ◽

Comprehensive Treatment ◽

Cycle Arrest ◽

Intraperitoneal Therapy ◽

Surgical Debulking ◽

Cancer Mutations ◽

Interesting Approach

The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologousrecombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCAmutation carriers leads to the persistence of DNA damage usually repaired by the homologousrecombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in “BRCAness” ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice.

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Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

Genes ◽

10.3390/genes12071050 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1050

Author(s):

Masayuki Sekine ◽

Koji Nishino ◽

Takayuki Enomoto

Keyword(s):

Ovarian Cancer ◽

Cancer Risk ◽

Cancer Patients ◽

Brca Mutation ◽

Parp Inhibitors ◽

Individual Risk ◽

Ovarian Cancer Risk ◽

Founder Mutations ◽

Brca Mutations ◽

Germline Brca Mutation

Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

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