scholarly journals PARP inhibitors for BRCA wild type ovarian cancer; gene alterations, homologous recombination deficiency and combination therapy

2019 ◽  
Vol 49 (8) ◽  
pp. 703-707 ◽  
Author(s):  
Koji Matsumoto ◽  
Meiko Nishimura ◽  
Takuma Onoe ◽  
Hideki Sakai ◽  
Yusaku Urakawa ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Susceptibility ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
Current Status ◽  
Wild Type ◽  
Homologous Recombination Deficiency ◽  
Cancer Susceptibility Genes ◽  
Gene Alterations

Abstract After a brief summary of the current status of poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer, we summarize the current status of PARP inhibitors for BRCA wild type ovarian cancer, especially regarding gene alterations other than BRCA, homologous recombination deficiency (HRD), and combinations. Discussion of gene alterations other than BRCA include the results of multiple gene panels studying homologous recombination repair deficiency genes and cancer susceptibility genes, and influences of these alterations on efficacy of PARP inhibitors and cancer susceptibility. Discussions of HRD include the results of phase three trials using HRD assay, the definition of HRD assays, and the latest assays. Discussions of combinations include early phase trial results and ongoing trials combining PARP inhibitors with immune checkpoint inhibitors, anti-angiogenic agents, and triplets.

Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17543-e17543
Author(s):  
Xiaoxiang Chen ◽  
Jing Ni ◽  
Xia Xu ◽  
Wenwen Guo ◽  
Xianzhong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Regression Analysis ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Real World ◽  
Cox Regression ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Homologous Recombination Deficiency ◽  
Polymerase Inhibitors

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.

AcornHRD: A novel tool to identify homologous recombination deficiency events in whole genome sequencing data.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15078-e15078
Author(s):  
Kai Liu ◽  
Xueyu Hao ◽  
Mengmeng Zhang ◽  
Mingwei Li ◽  
Wang Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Whole Genome Sequencing ◽  
Cell Line ◽  
Cell Lines ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Wild Type ◽  
Homologous Recombination Deficiency

e15078 Background: Recently, homologous recombination deficiency (HRD) scores are associated with the efficacy of Poly‐(ADP‐Ribose)‐Polymerase (PARP) inhibition and platinum-based chemotherapy in a variety of cancers. Evaluating HRD level in patients with cancers is becoming far more important and influential, so far, there is no standard method to be used in clinical. In this study, we developed an algorithm to detect HRD from next-generation sequencing (NGS) for finding additional patients may potentially benefit from target therapy. Methods: Forty-eight patients were enrolled, including breast cancer, ovarian cancer, prostatic cancer. Fifteen cell lines with breast cancer and endometrial carcinoma were collected from Cobioer biosciences co., LTD. Forty-eight Formalin-fixed, paraffin embedded (FFPE) samples and 15 cell lines were performed by DNA extracting. We developed an HRD score algorithm, termed as AcornHRD algorithm. HRD score was analyzed by whole-genome sequencing, and GATK mutect2 software was used to detect BRCA1/2mutation by deep sequencing. Results: BRCA1/2 deleterious mutations were observed in 20 patients (41.7%). HRD was explained by deficiencies in 17 patients (85.0%) with BRCA mutation, whereas eight HRD-high tumors were non- BRCA related (28.6%). Among BRCA wild-type patients, the corresponding percentage of HRD positive patients in breast cancer, ovarian cancer and prostate cancer were 36.3%, 37.5% and 11.1%, respectively. Similar results were also verified in the cell line datasets. The findings showed that 100% (3/3) BRCA1/2 deficient cell lines are also HRD-high. Furthermore, HRD scores were highly correlated with standard results in the cell line datasets. Conclusions: We here report the NGS-based HRD scores to distinguish similarly well between BRCA mutant and BRCA wild-type cases in a cohort of Chinese population. AcornHRD scores were highly associated with BRCA1/2 deficiency. AcornHRD algorithm can be a useful tool to detect HRD events in clinical settings.

Homologous recombination deficiency in ovarian cancer and beyond

2016 ◽  
Vol 4 (2) ◽  
pp. 17-22
Author(s):  
Ilary Ruscito ◽  
Susana Banerjee
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cell Transformation ◽  
Parp Inhibitors ◽  
Molecular Signature ◽  
Current Evidence ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Homologous Recombination Deficiency ◽  
Response To Chemotherapy

It has been well established that failure in the homologous recombination repair (HRR) mechanism for DNA double strand repair causes genomic instability and increases the risk for cell transformation. Mutations in BRCA1 and BRCA2 are currently known to be the most frequent responsible for homologous recombination deficiency (HRD) but HRD can occur through other processes including mutations and epigenetic aberration of HRD-related genes and the indirect interaction of BRCA proteins with other proteins involved in the DNA repair. Current efforts in this field are concentrating in identifying an HRD molecular signature able to predict response to chemotherapy and PARP inhibitors, thus allowing to extend novel targeted treatments beyond germline BRCA mutated ovarian cancer patients. The aim of this brief review is to summarize the current evidence regarding HRD beyond germline BRCA mutations and therapeutic approaches.

scholarly journals Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1315 ◽  
Author(s):  
Michela Camilla Milanesio ◽  
Silvia Giordano ◽  
Giorgio Valabrega
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Parp Inhibitors ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Ovarian Cancers ◽  
Mutational Status

Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.

scholarly journals Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Renata Colombo Bonadio ◽  
Maria del Pilar Estevez-Diz
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Current Knowledge ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Treatment Resistance ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Inhibitor Activity ◽  
Secondary Resistance

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors’ efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

scholarly journals Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying-Cheng Chiang ◽  
Po-Han Lin ◽  
Wen-Fang Cheng
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Epithelial Ovarian Cancer ◽  
Recurrent Disease ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Current Status ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Future Direction

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of BRCA mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

An optimized homologous recombination deficiency (HRD) algorithm ASGAD for predicting PARP inhibitor response in ovarian cancer patient.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17077-e17077
Author(s):  
Yang Jiao ◽  
Dong Ju Chen ◽  
Bo Liu ◽  
Pei Meng ◽  
Lei Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cancer Patient ◽  
Large Scale ◽  
Clustering Algorithm ◽  
Ovarian Cancer Patient ◽  
Parp Inhibitor ◽  
Gynecologic Cancer ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency

e17077 Background: Homologous recombination deficiency (HRD) results less efficient and error-prone DNA double strand break (DSB) repair, thus causes genomic in stability and impacts on cancer susceptibility to Poly‐(ADP‐Ribose)‐Polymerase (PARP) inhibitors. Evaluating HRD level in gynecologic cancer patients is becoming far more important and influential, so far, there is no standard method to be used in clinical. Methods: Here, we optimized an HRD score algorithm, termed as ASGAD, which combines three classic factors, including loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI), large-scale state transition score (LST), along with tumor ploidy to predict PARP inhibitor response in ovarian cancer patient. Results: Traditional global optimization strategy for purity and ploidy calculation is usually sensitive to initial values and may lead to incorrect convergences. Here we designed a two-step optimization manner to avoid this problem. Firstly, a density-based clustering algorithm was applied on BAF and CN, and the genotype was assigned to the most legible cluster. Then the rectified BAF and CN was calculated and used to find the maximum likelihood genotype of each segment. The segmentation processed was also improved by applying a series of statistical test to merge similar adjacent segments. The accuracy of allele-specific copy-number detection is significantly improved vie this algorithm, deriving stable and reliable HRD scores especially on aneuploid and hyperploid tumor cases. In this study, we assessed ASGAD algorithm in almost 150 ovarian cancer patient samples, who had treated with platinum effectively. BRCA1/2 deficient was defined as either one deleterious mutation in BRCA1/2, with LOH in the wild type copy or two deleterious mutations in the same gene. The results showed that the 19/23 BRCA1/2 deficient samples are also HRD-high, giving the sensitivity of 82.61%. Besides, we identify 58 HRD-high samples with intact BRCA1/2, who might benefit from PARP inhibitors, by the ASGAD algorithm. Interestingly, we analyzed 4 HRD-high samples by using whole-exome sequencing (WES), and found other HR genes mutations in these samples, including PARP4, FANCM, MSH2, MSH6, ATR, POLD1. Conclusions: The expanded use of PARP inhibitors in HRD tumors using the ASGAD algorithm requires more validation.

High prevalence of actionable germline variants in unselected endometrial cancer (EC) patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5577-5577
Author(s):  
Monica Levine ◽  
Rachel Pearlman ◽  
Heather Hampel ◽  
Casey Cosgrove ◽  
David E. Cohn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Prevention ◽  
Cancer Susceptibility ◽  
Checkpoint Inhibitors ◽  
Clinical Care ◽  
Type Ii ◽  
Genetic Syndrome ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing

5577 Background: The use of upfront germline genetic testing for cancer patients to identify hereditary syndromes and to aid in treatment decision making has increased dramatically. Recent evidence suggests that such testing should be considered for all solid tumors. In EC, mismatch repair deficiency (MMRd) has emerged as an important molecular marker for treatment with checkpoint inhibitors. MMRd is the hallmark of Lynch syndrome (LS), the most common hereditary cause of EC. Therefore, identifying LS not only affords opportunities for cancer prevention but also for making treatment decisions for women who already have EC. Although tumor-based screening is highly effective, some LS diagnoses will be missed. Upfront multi-gene panel testing (MGPT) for EC has been evaluated as an alternative approach to identifying LS with the potential to simultaneously find actionable germline variants in other cancer susceptibility genes (CSGs). Our objective was to determine the frequency and types of actionable germline variants in a large, unselected group of women with EC. Methods: Prospective germline MGPT for 47 CSGs was performed for 961 unselected EC cases. Patients diagnosed from 2017-2020 were enrolled at nine different institutions. Clinicopathologic data were abstracted from patients’ records. Results: 101 likely pathogenic (LP) or pathogenic variants (PV) were identified in 98 women (10.2%). LP/PVs in LS genes were most common: 29 LS cases were identified (3.02%, 95% CI 2.1 - 4.3%). MGPT found 9 cases (one-third of LS cases) that were not identified by tumor screening: 6 were from institutions that do not perform tumor screening and 3 had normal immunohistochemistry. There were 72 LP/PVs found in 17 different CSGs. 21 patients (2.1%) had LP/PVs in high penetrance CSGs other than the LS genes, 19 of which were in genes associated with breast and/or ovarian cancer (4 in BRCA1, 6 in BRCA2, 6 in BRIP1, 2 in PALB2, 1 in RAD51C). BRCA1/2 PVs (1.04% of the study population, 95% CI 0.6 - 1.9%) were significantly more frequent in women with type II cancers than the rest of the cohort (P =.005, HR 2.00, 95% CI 1.16 - 4.75). 21 additional LP/PVs were found in moderate risk CSGs ( ATM, CHEK2, NBN, NF1). Conclusions: Upfront MGPT in an unselected EC population improved LS diagnosis and identified an additional 2% of patients with LP/PVs in highly penetrant CSGs. The enrichment of germline BRCA1/2 PVs in type II cancers is consistent with prior reports that non-endometrioid tumors are frequently deficient in homologous recombination. Germline BRCA mutation is a known predictive biomarker in ovarian cancer and an attractive therapeutic target in EC. Knowing germline status at the time of diagnosis facilitates further delineation of germline/phenotype associations, and it defines a genetic syndrome allowing for cancer prevention. Upfront MGPT in EC provides clinically impactful information and should be adopted into routine clinical care. Clinical trial information: NCT03460483.

scholarly journals Clinical Implications of Genomic Loss of Heterozygosity in Endometrial Carcinoma

2021 ◽  
pp. 1013-1023
Author(s):  
Bethany Bustamante ◽  
Risha Sinha ◽  
Briana Rice ◽  
Aaron Nizam ◽  
Weiwei Shan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Loss Of Heterozygosity ◽  
Molecular Subtype ◽  
Retrospective Chart Review ◽  
High Grade ◽  
Homologous Recombination Deficiency ◽  
Molecular Features ◽  
Significant Difference ◽  
Gene Alterations

PURPOSE Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number–high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. METHODS Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture–based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability–high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. RESULTS PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. CONCLUSION The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.20-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS.

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