scholarly journals Translational Research Opportunities Regarding Homologous Recombination in Ovarian Cancer

2018 ◽  
Vol 19 (10) ◽  
pp. 3249 ◽  
Author(s):  
Margarita Romeo ◽  
Juan Pardo ◽  
Anna Martínez-Cardús ◽  
Eva Martínez-Balibrea ◽  
Vanesa Quiroga ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Daily Practice ◽  
Parp Inhibitors ◽  
Repair Pathway ◽  
Mechanisms Of Resistance ◽  
First Line ◽  
Ovarian Carcinomas ◽  
Therapeutic Opportunity ◽  
Line Setting

Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations.

scholarly journals Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

2020 ◽  
Author(s):  
Michal M. Hoppe ◽  
Tuan Zea Tan ◽  
Stefanus Lie ◽  
Sherlly Lim ◽  
Joe PS Yeong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Clinical Relevance ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Platinum Resistance ◽  
First Line ◽  
Ovarian Carcinomas ◽  
Increased Sensitivity ◽  
Immune Exclusion

AbstractBackgroundHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. The homologous recombination (HR) mediator RAD51, however, is commonly overexpressed, potentially driving unregulated HR. Due to non-quantitative measurements and heterogeneous cohorts, the clinical relevance of RAD51 expression in ovarian cancer is unclear.MethodsFluorescent immunohistochemistry and multispectral imaging were used to quantitate RAD51 expression, in relation to other markers, in independent cohorts of ovarian carcinomas from British Columbia Cancer (BCC n=284) and the phase III SCOTROC4 trial (n=268). Independent cohorts (TCGA n=566, GSE9891 n=267, GSE26712 n=185 and GSE3149 n=146) were used for mRNA expression and immune infiltration analyses.ResultsRAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in both BCC and SCOTROC4. The negative prognostic significance of high RAD51 was primarily evident in cases classified “HRD negative” by the Myriad genomic scar assay. Unexpectedly, overexpression of RAD51 in ovarian cancer cell lines did not affect sensitivity to platinum or PARP inhibitors, but modified the expression of immune-regulatory genes. Accordingly, tumours with high RAD51 mRNA showed consistent changes in immunomodulatory transcripts across four independent ovarian cancer cohorts. In-situ multiplexed imaging confirmed that high RAD51 tumours correlated with tumour exclusion of cytotoxic-T-cells, possibly explaining their poor outcomes after chemotherapy.ConclusionsHigh RAD51 expression, in conjunction with a HRD score <42, identifies a subgroup of EOC cases with platinum resistance and an immune excluded tumour microenvironment. Tumours with high RAD51 may require alternate or additional adjuvant therapeutic strategies to overcome immune exclusion.Statement of Translational RelevanceHomologous recombination deficiency (HRD) in ovarian cancer confers increased sensitivity to Poly-ADP-Ribose-Polymerase (PARP) inhibitors and platinum. Currently, methods to identify patients who do poorly on first-line platinum based chemotherapy in ovarian cancer represent an unmet clinical need. In this report we show that RAD51 expression can identify patients with primary platinum resistance in two large cohorts, including a unique phase-III trial of carboplatin as adjuvant monotherapy. The clinical relevance of a positive genomic scar HRD score, a biomarker for assessing HRD status, in predicting benefit to PARP inhibitors has been established following recent phase 3 trials in first line and 2nd line maintenance treatment of ovarian cancer. Our findings suggest that HRD negative ovarian tumours may be further stratified by RAD51 expression status in the context of platinum sensitivity, and may serve to guide future trials of HRD targeted agents.

Poly-(ADP-ribose) polymerase inhibitors: paradigm shift in the first-line treatment of newly diagnosed advanced ovarian cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 721-727
Author(s):  
Fady Gh Haddad ◽  
Elias Karam ◽  
Elissar Moujaess ◽  
Hampig Raphael Kourie
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Excision Repair ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
First Line ◽  
Free Survival ◽  
Base Excision ◽  
Breast Cancer Gene

Debulking surgery associated with chemotherapy represent the backbone of ovarian cancer therapy. Adding bevacizumab has improved survival. Recently, PARP inhibitors were added in the first line as maintenance treatment for the patients who achieve a complete or partial response. These drugs act by blocking the activity of the PARP enzyme responsible for base-excision repair, and have shown positive responses when used for tumors lacking homologous recombination. Olaparib, niraparib and veliparib were evaluated and showed an increase in the duration of progression-free survival: 22.1 months (hazard ratio [HR] = 0.59), 13.8 (HR = 0.62) and 23.5 (HR = 0.68) with olaparib, niraparib and veliparib, respectively. This review describes the benefit of PARP inhibitors as maintenance therapy and discusses the efficacy according to breast cancer gene and homologous recombination status.

scholarly journals Preventing and Overcoming Resistance to PARP Inhibitors: A Focus on the Clinical Landscape

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 44
Author(s):  
Rosario Prados-Carvajal ◽  
Elsa Irving ◽  
Natalia Lukashchuk ◽  
Josep V. Forment
Keyword(s):  
Ovarian Cancer ◽  
Targeted Therapies ◽  
Patient Population ◽  
Maintenance Treatment ◽  
Parp Inhibitors ◽  
Mechanisms Of Resistance ◽  
First Line ◽  
Clinical Models ◽  
Cancer Types

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are now a first-line maintenance treatment in ovarian cancer and have been approved in other cancer types, including breast, pancreatic and prostate. Despite their efficacy, and as is the case for other targeted therapies, resistance to PARPi has been reported clinically and is generating a growing patient population of unmet clinical need. Here, we discuss the mechanisms of resistance that have been described in pre-clinical models and focus on those that have been already identified in the clinic, highlighting the key challenges to fully characterise the clinical landscape of PARPi resistance and proposing ways of preventing and overcoming it.

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

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
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.

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.

Poly (ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer

2021 ◽  
Author(s):  
Olivia Le Saux ◽  
Hélène Vanacker ◽  
Fatma Guermazi ◽  
Mélodie Carbonnaux ◽  
Clémence Roméo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Advanced Ovarian Cancer ◽  
Cost Effective ◽  
Preclinical Study ◽  
The Body ◽  
Synergistic Activity ◽  
High Grade ◽  
First Line ◽  
Homologous Recombination Deficiency

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Laboratory cross-comparison of homologous recombination repair mutation analysis in tumor in a multicenter epithelial ovarian cancer series: The BORNEO GEICO 60-0 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17550-e17550
Author(s):  
Ignacio Romero ◽  
Ana Oaknin ◽  
Zaida Garcia-Casado ◽  
Raul Marquez ◽  
Alfonso Yubero Esteban ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Epithelial Ovarian Cancer ◽  
Mutational Analysis ◽  
Figo Stage ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Class 1 ◽  
Uncertain Significance

e17550 Background: In epithelial ovarian cancer (EOC), the identification of mutations in homologous recombination repair (HRR) genes on tumor is prognostic, predictive of response to PARP inhibitors, and a tool to identify individuals at genetic cancer risk. The aim of this study is to compare the concordance between two laboratories in identifying and classifying genetic variants in HRR genes. Methods: In a multicentre ambispective series of unselected, non mucinous EOC of all stages formalin-fixed and paraffin embedded tumors were collected. These samples underwent the same mutational analysis of 15 HRR genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) in two different Laboratories (Lab1, Lab2) that used their own validated multi-gene NGS panels. Variant allele frequency (VAF) threshold was 5% for single nucleotide polymorphism and 10% for indels. Large rearrangements were not analyzed. Variants were classified into three categories based on ACMG criteria: non-mutated (class 1-2), Variants of Uncertain Significance (VUS: class 3) and likely pathogenic/pathogenic (class 4-5). Results: A total of 81 cases were sent for the analysis. One had low DNA quality and therefore 80 cases were finally studied (85% high grade serous and 74% FIGO stage III-IV). Results reported by Lab1 and Lab2 (lab1/Lab2) were the following: 21/19 (26%/24%) cases had BRCA1/2 mutations, 7/8 (8.7%/10%) mutations on other HRR genes including two in ATM and RAD51D, one in CHEK1, CHEK2, and FANCL and one RAD51C reported in Lab2 only while the rest were either VUS 23/27 (29%/34%) or non-mutated 29/26 (36%/33%). Concordance between laboratories in classifying patients was 93.75% (kappa coefficient 0.86). Discrepancies (DC) on variants were classified into arbitrary categories, namely 0= complete concordance, category 1 meaning DC in detection assumed to be due to tumor heterogeneity (VAF nearby the threshold) or technique (1A), or caused by laboratories performance and avoidable (1B) and the category 2 identified DC in interpretation without clinical relevance (2A) or clinically relevant (2B), the results of total number of variants are shown in table. Overall, regarding clinically relevant DC in HRR genes, 9 DC in variants were observed including six 2B, two 1A and one 1B and they affect 5 (6.3%) patients since some were overlapping. Conclusions: In our EOC series the concordance of two Laboratories in the identification of clinically relevant HRR mutations on tumor is high but discrepancies in interpretation remain a challenge that needs further harmonization.[Table: see text]

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