Data from Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer
Year: 2023
Type: other
Abstract: Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI). Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04). Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.
Authors: Eric Y. Zhao, Yaoqing Shen, Erin Pleasance, Katayoon Kasaian, Sreeja Leelakumari, Martin Jones, Pinaki Bose, Carolyn Ch'ng, Caralyn Reisle, Peter Eirew, Richard Corbett, Karen L. Mungall, Nina Thiessen, Yussanne Ma, Jacqueline E. Schein, Andrew J. Mungall, Yongjun Zhao, Richard A. Moore, Wendie Den Brok, Sheridan Wilson, Diego Villa, Tamara Shenkier, Caroline Lohrisch, Stephen Chia, Stephen Yip, Karen Gelmon, Howard Lim, Daniel Renouf, Sophie Sun, Kasmintan A. Schrader, Sean Young, Ian Bosdet, Aly Karsan, Janessa Laskin, Marco A. Marra, Steven J.M. Jones
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4361945598