Résumé
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 (
PIK3CA
mut) 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
PIK3CA
mut 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
PIK3CA
mut 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
PIK3CA
mut 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
PIK3CA
mut ctDNA. Altogether, we demonstrated the impact of genomic (co‐)alterations on outcomes with one of the largest clinico‐genomic datasets of ER+, HER2−,
PIK3CA
mut breast cancer patients treated with a PI3K inhibitor.