Details

Autor(en) / Beteiligte

• Zhao, Eric Y
• Shen, Yaoqing
• Pleasance, Erin
• Kasaian, Katayoon
• Leelakumari, Sreeja
• Jones, Martin
• Bose, Pinaki
• Ch'ng, Carolyn
• Reisle, Caralyn
• Eirew, Peter
• Corbett, Richard
• Mungall, Karen L
• Thiessen, Nina
• Ma, Yussanne
• Schein, Jacqueline E
• Mungall, Andrew J
• Zhao, Yongjun
• Moore, Richard A
• Den Brok, Wendie
• Wilson, Sheridan
• Villa, Diego
• Shenkier, Tamara
• Lohrisch, Caroline
• Chia, Stephen
• Yip, Stephen
• Gelmon, Karen
• Lim, Howard
• Renouf, Daniel
• Sun, Sophie
• Schrader, Kasmintan A
• Young, Sean
• Bosdet, Ian
• Karsan, Aly
• Laskin, Janessa
• Marra, Marco A
• Jones, Steven J M

Titel

Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer

Ist Teil von

• Clinical cancer research, 2017-12, Vol.23 (24), p.7521-7530

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response. 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 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). HRDetect predicted 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; = 0.006) with the same optimal threshold, even after adjusting for mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT ( = 0.0003) and 1.3-year extended median OS ( = 0.04). 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 mutation status and hope this work will guide the development of clinical trials. .