PI3K/PTEN/mTOR Pathway Dynamic Tracking and Prognostic Value in HR+/HER2− BC Patients with Residual Disease after Neoadjuvant Chemotherapy: a Cohort Study

AimsHormone receptor-positive (HR)+/HER2− breast cancer (BC) is highly heterogeneous, with PI3K/PTEN/mTOR pathway alterations emerging as possible players within this complexity. We longitudinally tracked PI3K/PTEN/mTOR pathway dynamics from baseline biopsy to residual disease (RD)—and to metastases in case of relapse—in HR+/HER2− BC patients receiving neoadjuvant chemotherapy (NACT).MethodsHR+/HER2− BC patients with RD after NACT were identified. We assessedPIK3CAmutational, Pten-loss and phosphorylation levels of mTOR and its substrates (p70S6K and 4EBP1) on baseline biopsies and matched RD samples; in case of disease relapse, we also assessedPIK3CAmutational status on metastatic samples. Recurrence-free survival (RFS) was adopted as endpoint.Results92 patient were included. The conversion rate ofPIK3CAmutational status was 12.8%; 1 patient acquiredPIK3CAmutation at relapse; the rate of Pten conversion was 33.3%; mTOR phosphorylation levels significantly increased from baseline biopsy to RD, while its substrates significantly decreased. Baseline phosphorylated-mTOR significantly predicted poorer RFS in patients withPIK3CAwild-type status; baseline phosphorylated-70S6K was positively associated with RFS.ConclusionsWe observed that PI3K/PTEN/mTOR pathway is highly dynamic under NACT exposure and the assessment ofPIK3CAmutations may capture only a small fraction of such complexity. In this context, mTOR activation trough alternative pathways with respect toPIK3CAsignalling may have a crucial role in shaping the molecular landscape of HR+/HER2− BC with RD after NACT. It is imperative to further elucidate the role ofPIK3CAand mTOR-dependent pathways in shaping chemoresistance and endocrine resistance in high-risk HR+/HER2− early/locally advanced BC patients.