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

被引:13
作者
Hutchinson, Katherine E. [1 ]
Chen, Jessica W. [1 ]
Savage, Heidi M. [1 ]
Stout, Thomas J. [2 ]
Schimmoller, Frauke [2 ]
Cortes, Javier [3 ,4 ,5 ]
Dent, Susan [6 ]
Harbeck, Nadia [7 ,8 ]
Jacot, William [9 ]
Krop, Ian [10 ]
Trabucco, Sally E. [11 ]
Sivakumar, Smruthy [11 ]
Sokol, Ethan S. [11 ]
Wilson, Timothy R. [1 ]
机构
[1] Genentech Inc, Oncol Biomarker Dev, 1 DNA Way, South San Francisco, CA 94080 USA
[2] Genentech Inc, Prod Dev Oncol, South San Francisco, CA USA
[3] Pangaea Oncol, Int Breast Canc Ctr IBCC, Quironsalud Grp, Madrid, Spain
[4] Pangaea Oncol, Int Breast Canc Ctr IBCC, Quironsalud Grp, Barcelona, Spain
[5] Univ Europea Madrid, Fac Biomed & Hlth Sci, Dept Med, Madrid, Spain
[6] Duke Univ, Duke Canc Inst, Durham, NC USA
[7] Ludwig Maximilians Univ LMU Hosp, Breast Ctr, Dept Gynecol & Obstet, Munich, Germany
[8] Ludwig Maximilians Univ LMU Hosp, Comprehens Canc Ctr CCC Munich, Munich, Germany
[9] Montpellier Univ, Inst Canc Montpellier ICM Val dAurelle, INSERM, U1194, Montpellier, France
[10] Yale Canc Ctr, New Haven, CT USA
[11] Fdn Med Inc, Cambridge, MA USA
关键词
PIK3CA; Double PIK3CA mutation; Clonal; Taselisib; PI3K inhibitor; Breast cancer; ctDNA; PI3K signaling; HIGH-FREQUENCY; PLACEBO; DNA; RESISTANCE; LANDSCAPE; PATHWAY; GENE;
D O I
10.1186/s13073-023-01181-8
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
BackgroundMutations in the p110 alpha 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 p110 alpha inhibitors.MethodsTo understand the role of multiple PIK3CAmut in predicting response to p110 alpha 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.ResultsctDNA 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.ConclusionsOur study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110 alpha inhibition and provides rationale for further clinical investigation of p110 alpha inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.
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页数:14
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