Ottavia Amato1,2, Laurence Buisseret1, Géraldine Gebhart3, Nicolas Plouznikoff4, Denis Larsimont5, Ahmad Awada1, Martine Piccart1 and Philippe Aftimos6 1Oncology Medicine Department, Institut Jules Bordet—Université Libre de Bruxelles, Brussels, 1070, Belgium; 2Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, 35128, Italy; 3Nuclear Medicine Department, Institut Jules Bordet—Université Libre de Bruxelles, Brussels, 1070, Belgium; 4Department of Nuclear Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec H2X 354, Canada; 5Pathology Department, Institut Jules Bordet—Université Libre de Bruxelles, Brussels, 1070, Belgium; 6Clinical Trials Conduct Unit, Institut Jules Bordet—Université Libre de Bruxelles, Brussels, 1070, Belgium Corresponding author: philippe.aftimosbordet.be

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%–15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%–20%, and are listed as “likely gain-of-function” alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

Received November 9, 2022. Accepted February 6, 2023.