Integrating PIK3CA Testing into Clinical Practice for Advanced HR+/HER2- Breast Cancer: An Expert Consensus

AbstractBackground Alterations in the PI3K/AKT/mTOR signaling pathway represent a mechanism of resistance to endocrine therapy in advanced HR+/HER2- breast cancer. The identification of activating mutations in PIK3CA has gained therapeutic relevance, guiding the use of PIK3CA-targeted inhibitors such as alpelisib and inavolisib. Methods A multidisciplinary panel of Italian experts conducted a structured consensus process to develop shared recommendations for molecular testing of PIK3CA in advanced HR+/HER2- breast cancer, addressing preanalytical, analytical, and clinical-therapeutic areas of concern. Results A total of 23 out of 29 statements reached complete agreement (100%). The resulting recommendations encompass sample selection, analytical methodologies, sensitivity thresholds, result reporting, and clinical interpretation and integration. Additional guidance is provided for the management of non-canonical gene variants and for other genes involved in the PI3K/AKT/mTOR pathway. Conclusions This consensus document provides operational and interpretative guidelines aimed at standardizing PIK3CAtesting and assessing related genes in clinical practice. These recommendations promote a harmonized approach to patient care, in line with the latest scientific evidence.