Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer

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.

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OC-0399 Co-occurrence of APOBEC3B and Homologous Recombination Deficiency is Rare in Breast Cancer

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)06886-9 ◽

2021 ◽

Vol 161 ◽

pp. S296-S297

Author(s):

P. Span ◽

M. Jarvis ◽

J. Martens ◽

R. Harris ◽

P. Roelofs

Keyword(s):

Breast Cancer ◽

Homologous Recombination ◽

Homologous Recombination Deficiency

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Rucaparib in patients presenting a metastatic breast cancer with Homologous Recombination Deficiency, without germline BRCA1/2 mutation

10.21203/rs.3.rs-78109/v1 ◽

2020 ◽

Author(s):

Anne Patsouris ◽

M'boyba Khadija DIOP ◽

Olivier Tredan ◽

Daniel Nenciu ◽

Anthony Goncalves ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Homologous Recombination ◽

Statistical Significance ◽

Objective Response ◽

Metastatic Breast ◽

Parp Inhibitors ◽

Small Subset ◽

Durable Response ◽

Homologous Recombination Deficiency

Abstract Breast cancer may present genomic alterations leading to homologous recombination deficiency. PARP inhibitors have proved their efficacy in patients with HER2-negative metastatic breast cancer (mBC) harboring germline (g) BRCA1/2 mutations. We conducted the phase 2 RUBY trial to assess the efficacy of rucaparib in HER2-negative mBC with high genomic loss of heterozygosity (LOH) score or somatic, without gBRCA1/2 mutation. 220 of 711 patients with mBC screened for LOH presented high LOH score which was associated with a higher likelihood of death (HR = 1.39, 95% CI: 1.11-1.75, p = 0.005). The primary objective was not reached with a clinical benefit rate (objective response or SD>16 weeks) of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (14 and 32 months). HRDetect tended to be associated with response to rucaparib, whithout reaching statistical significance (median HRDetect responders versus non responders: 0.465 versus, 0.040, p = 0.2135). Our data suggests that a small subset of patients with high LOH score could derive benefit from PARP inhibitors.

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Identification of a Novel Gene Model-Based Homologous Recombination Deficiency Score to Improve Survival Prediction of TNBC.

10.21203/rs.3.rs-472194/v1 ◽

2021 ◽

Author(s):

Wenxiang Zhang ◽

Bolun Ai ◽

Xiangyi Kong ◽

Xiangyu Wang ◽

Jie Zhai ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Homologous Recombination ◽

Risk Score ◽

Cox Regression ◽

Roc Curves ◽

Cox Regression Analysis ◽

Homologous Recombination Deficiency ◽

Ajcc Stage ◽

Kaplan Meier

Abstract Background Triple-negative breast cancer (TNBC) is a specific histological type of breast cancer with a poor prognosis, early recurrence, which lacks durable chemotherapy responses and effective targeted therapies. We aimed to construct an accurate prognostic risk model based on homologous recombination deficiency (HRD) - gene expression profiles for improving prognosis prediction of TNBC. Methods Triple-negative breast cancer RNA sequencing data and sample clinical information were downloaded from the breast invasive carcinoma (BRCA) cohort in the Cancer Genome Atlas (TCGA) database. Combined with the HRD database, tumor samples were divided into two sets. We screened differentially expressed genes (DEGs) and then identified HRD-related prognostic genes using weighted gene co-expression network analysis (WGCNA) and Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were used to identifying key prognostic genes. Risk scores were calculated and compared with HRD score, Kaplan–Meier (KM) survival analysis were used to assess its prognostic power. GSE103091 dataset from GEO (Gene Expression Omnibus) database was used to validate the signature. Univariate and multivariate Cox regression were performed to independently verify the prognosis of the risk score. A nomogram was constructed and revealed by time-dependent ROC curves to guide clinical practice. Results We found that HRD tumor samples (HRD score > = 42) in TNBC patients were associated with poor overall survival (p = 0.027). We identified a total of 147 differential genes including 203 up-regulated and 213 down-regulated genes, among which 29 were prognosis-related genes. Through the LASSO method, 6 key prognostic genes ((MUCL1, IVL, FAM46C, CHI3L1, PRR15L, and CLEC3A) were selected and a 6-gene risk score was constructed. We found risk score was negatively associated with homologous recombination deficiency (HRD) scores (r = -0.22, p = 0.019). Compared with the low-risk group, Kaplan-Meier survival analysis shows that the high-risk group has an obvious poorer prognosis (P < 0.0001). Finally, we integrated the risk score model and clinical factors of TNBC (AJCC-stage, HRD score, T stage, and N stage) to construct a compound nomogram. Time-dependent ROC curves showed the risk score performed better in 1-, 3- and 5-year survival predictions compared with AJCC-stage. Conclusions Based on HRD gene expression data, our six HRD-related gene signature and nomogram could be practical and reliable tools for predicting OS in patients with TNBC.

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