scholarly journals Prevalence of homologous recombination deficiency (HRD)-related signatures indicates that a wider range of prostate cancer patients may benefit from PARP-inhibitor therapy

2019 ◽  
Vol 30 ◽  
pp. vii14
Author(s):  
Z. Sztupinszki ◽  
M. Diossy ◽  
M. Krzystanek ◽  
J. Borcsok ◽  
M. Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Homologous Recombination Deficiency

scholarly journals Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

2019 ◽  
Author(s):  
Zsofia Sztupinszki ◽  
Miklos Diossy ◽  
Marcin Krzystanek ◽  
Judit Borcsok ◽  
Mark Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Next Generation Sequencing Data ◽  
Parp Inhibition ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Homologous Recombination Deficiency ◽  
Platinum Based Chemotherapy ◽  
Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

scholarly journals Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors

2018 ◽  
Author(s):  
M. Diossy ◽  
L. Reiniger ◽  
Zs. Sztupinszki ◽  
M. Krzystanek ◽  
K. M. Timms ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Brain Metastases ◽  
Primary Breast Cancer ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Published Data ◽  
Data Set ◽  
Primary Tumors ◽  
Homologous Recombination Deficiency

AbstractDue to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.Key messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the “my choice” HRD score in collaboration with Myriad Genetics.These confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.

scholarly journals Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles

2021 ◽  
Author(s):  
Miklos Diossy ◽  
Viktoria Tisza ◽  
Hua Li ◽  
Jia Zhou ◽  
Zsofia Sztupinszki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Homologous Recombination ◽  
African American Men ◽  
Parp Inhibitor ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Mutational Signatures ◽  
Homologous Recombination Deficiency ◽  
Aggressive Disease

AbstractBackgroundAfrican American (AA) men have significantly higher mortality rates from prostate cancer (PC) than individuals of European ancestry (EA). Therapeutically targetable molecular differences may hold the potential to reduce this disparity.ObjectiveTo investigate chromodomain helicase DNA-binding protein 1 (CHD1) deletion both as a cause of aggressive disease and therapeutic vulnerability in the prostate cancer of AA men.Design, setting, and participants91 AA and 109 EA prostate cancer cases were analyzed by fluorescence in situ hybridization (FISH) for the deletion of CHD1. Whole exome and whole genome sequencing data from prostate adenocarcinoma cases were analyzed for mutational signatures from AA and EA individuals.Outcome measurements and statistical analysisAssociations with biochemical recurrence were evaluated using Cox proportional hazard regression models. Association between mutational signatures and CHD1 deletion were assessed by Wilcoxon ranked sum tests.Results and limitationsSubclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of men than in EA men. CHD1 deletion is associated with some of the homologous recombination deficiency associated mutational signatures in prostate cancer. In a cell line model CHD1 deletion induced 1-10 kb deletions resembling those induced by BRCA2 deficiency. CHD1 deficient cells showed markedly increased sensitivity to both talazoparib and the radiomimetic bleomycin.ConclusionsCHD1 is more frequently deleted in the prostate cancer of AA men. This deletion is both associated with and induces mutational signatures characteristic of BRCA2 deficiency. CHD1 deficient prostate cancer is more sensitive to talazoparib or bleomycin treatment.Patient summarySubclonal deletion of CHD1 is more frequent in the prostate cancer of AA men and this could be one of the reasons behind more aggressive disease. CHD1 deletion, however, also constitutes a therapeutic vulnerability to the PARP inhibitor talazoparib. This treatment may significantly improve the outcome of disease in AA men.

A transcriptomic model for homologous recombination deficiency in prostate cancer

2021 ◽  
Author(s):  
Adam B. Weiner ◽  
Yang Liu ◽  
Matthew McFarlane ◽  
Pushpinder S. Bawa ◽  
Eric V. Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Homologous Recombination Deficiency

scholarly journals Pan-cancer landscape of homologous recombination deficiency

2020 ◽  
Author(s):  
Luan Nguyen ◽  
John Martens ◽  
Arne Van Hoeck ◽  
Edwin Cuppen
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cancer Genomics ◽  
Strand Break ◽  
Diagnostic Value ◽  
Cancer Type ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
A Genome ◽  
Pan Cancer

AbstractHomologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we developed a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n=3,504) and primary (n=1,854) pan-cancer cohort revealed HRD was most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. Biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 was the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. While the specific genetic cause of HRD was cancer type specific, biallelic inactivation was predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

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.

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