LAUSR

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 analyzed circulating tumor DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation detected (NMD) per baseline ctDNA. The top mutated genes and tumor fraction estimates identified were analyzed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib+fulvestrant, tumor 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 harboring a neurofibromin 1 (NF1) alteration or high baseline tumor fraction estimate experienced improved PFS upon treatment with taselisib+fulvestrant compared to placebo+fulvestrant. Broadly, alterations in estrogen 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.