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Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-,
Katherine E Hutchinson1, Jessica W Chen1, Heidi M Savage1
1Oncology Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Clonal multiple PIK3CA mutations in breast cancer predict better response to p110α inhibitors. This finding highlights clonal PIK3CA mutations as a key biomarker for targeted therapy selection.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Mutations in the PIK3CA gene, encoding the p110α subunit of PI3K, are found in 35-40% of HR+/HER2- breast cancers, leading to PI3K pathway dysregulation.
- Preclinical studies show that cancer cells with multiple PIK3CA mutations exhibit increased PI3K pathway activation and heightened sensitivity to p110α inhibitors.
Purpose of the Study:
- To investigate the role of multiple PIK3CA mutations in predicting response to p110α inhibition.
- To analyze the clonality of multiple PIK3CA mutations in ctDNA and correlate it with co-alterations and clinical outcomes in HR+/HER2- metastatic breast cancer.
Main Methods:
- Estimated clonality of multiple PIK3CA mutations in ctDNA from patients with HR+/HER2- metastatic breast cancer treated with fulvestrant ± taselisib.
- Analyzed ctDNA subgroups for co-altered genes and pathways, and correlated findings with response rates and progression-free survival.
- Validated findings in an independent cohort of breast cancer tumor specimens using comprehensive genomic profiling.
Main Results:
- ctDNA samples with clonal multiple PIK3CA mutations showed fewer co-alterations in RTK or non-PIK3CA PI3K pathway genes, suggesting a stronger reliance on the PI3K pathway.
- This reliance was confirmed in an independent cohort.
- Patients with clonal multiple PIK3CA mutations in ctDNA had significantly higher response rates and longer progression-free survival compared to those with subclonal mutations.
Conclusions:
- Clonal multiple PIK3CA mutations are established as a significant molecular determinant for response to p110α inhibition.
- The findings provide a rationale for further clinical investigation of p110α inhibitors in breast cancer and other solid tumors, potentially in combination with other therapies.
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