Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers

Springer Science and Business Media LLC - Tập 15 - Trang 1-14 - 2023
Katherine E. Hutchinson1, Jessica W. Chen1, Heidi M. Savage1, Thomas J. Stout2, Frauke Schimmoller2, Javier Cortés3,4, Susan Dent5, Nadia Harbeck6, William Jacot7, Ian Krop8, Sally E. Trabucco9, Smruthy Sivakumar9, Ethan S. Sokol9, Timothy R. Wilson1
1Oncology Biomarker Development, Genentech Inc., South San Francisco, USA;
2Product Development Oncology, Genentech, Inc, South San Francisco, USA
3International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Madrid & Barcelona, Spain
4Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
5Duke Cancer Institute, Duke University, Durham, USA
6Breast Center, Department Gynecology and Obstetrics and Comprehensive Cancer Center (CCC) Munich, Ludwig-Maximilians-University (LMU) Hospital, Munich, Germany
7Institut du Cancer de Montpellier (ICM) Val d’Aurelle, Montpellier University, Montpellier, France
8Yale Cancer Center, New Haven, USA
9Foundation Medicine, Inc., Cambridge, USA

Tóm tắt

Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35–40% of patients with HR+/HER2– breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors. To understand the role of multiple PIK3CAmut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2– metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes. ctDNA samples with clonal multiple PIK3CAmut had fewer co-alterations in receptor tyrosine kinase (RTK) or non-PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CAmut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CAmut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CAmut. Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.

Tài liệu tham khảo

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