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Taselisib is a potent β‐sparing phosphatidylinositol 3‐kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA)‐mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression‐free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co‐)alterations on outcomes with one of the largest clinico‐genomic datasets of ER+, HER2−, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.

Abstract 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.

Preemergence herbicides are herbicides that are applied prior to weed seed germination. Control of weeds using preemergence herbicides is most successful when the correct herbicide is applied in the correct manner to a weed-free growing medium prior to weed seed germination. This revised 60-page fact sheet was written by Robert H. Stamps, Heidi M. Savage, Diane K. Rock, and Jeffrey G. Norcini, and published by the UF Department of Environmental Horticulture, March 2012.

Preemergence herbicides are herbicides that are applied prior to weed seed germination. Control of weeds using preemergence herbicides is most successful when the correct herbicide is applied in the correct manner to a weed-free growing medium prior to weed seed germination. This revised 60-page fact sheet was written by Robert H. Stamps, Heidi M. Savage, Diane K. Rock, and Jeffrey G. Norcini, and published by the UF Department of Environmental Horticulture, March 2012.

Preemergence herbicides are herbicides that are applied prior to weed seed germination. Control of weeds using preemergence herbicides is most successful when the correct herbicide is applied in the correct manner to a weed-free growing medium prior to weed seed germination. This revised 60-page fact sheet was written by Robert H. Stamps, Heidi M. Savage, Diane K. Rock, and Jeffrey G. Norcini, and published by the UF Department of Environmental Horticulture, March 2012.