Abstract PS18-20: Frequency and Spectrum of Doublepik3casomatic Mutations in Metastatic Breast Cancer Patients

Abstract Background: PIK3CA is the most frequently mutated oncogene in breast cancer (BC). These mutations are considered drivers, indeed, several novel PI3K inhibitors are under evaluation in clinical trials. Recently, alpelisib, a PI3Kα inhibitor, combined with hormonotherapy has improved progression-free survival in mutated advanced luminal BC. As a result, alpelisib has been FDA-approved for this setting. In some tumors, double PIK3CA mutations in cis demonstrated increasing oncogenicity and sensitivity to PI3Kα inhibitors compared to those tumors with single-hotspot mutations. We aim at assessing the proportion and distribution of PIK3CA double mutations of a monocentric genomic screening program to select patients for trials with experimental targeted agents. Methods: We assessed PIK3CA mutation in a cohort of 345 consecutive metastatic BC patients diagnosed at Hospital Clínico València-INCLIVA from Jan-13 to Apr-20. Molecular screening of hotspot mutations was performed in primary (36.2%, 125/345) and metastatic tissue (63.8%, 220/345), with either MassArray or Next-Generation Sequencing. Hotspots were selected according to public published databases. To be considered mutant, tumors needed to harbor at least 5% of mutant alleles. Our cohort is enriched in luminal BC, according to clinical trials developing PI3K inhibitors. Results: Patients with PIK3CA mutations represented 34.8% (120/345) of the whole cohort. The distribution of BC subtypes was: 80.5% Luminal, 12.0% HER2, and 7.5% triple-negative. The most frequent metastatic site was liver (32.8%) followed by nodes (21.4%), and bone (11.4%). We detected 27 different hotspots, of which three comprised 73% of all PIK3CA mutations: H1047R (32%), E545K (27%), and E542K (14%). Others hotspots were: E545D (4%), H1047L (3%), M1043I (2%), N345K (2%), C420R (1%), E545A (1%), R88Q (1%). Furthermore, 12% PIK3CA mutations were unique (<1%): R38C, R93Q, R93W, P104R, G106V, E110K, K111E, R115Q, V344G, N345D, N345S, E418K, P539R, E542Q, E453Q, M1043V, and H1047L. In our series, 19 patients (15.8%) of all mutant tumors presented a double PIK3CA mutation. In almost all double-PIK3CA mutated tumors (89%, 17/19), one of the hotspots was either a helical or kinase domain (E542, E545, and H1047). Interestingly, E545D was never detected among tumors with a single-mutations. Conclusions: In our cohort, a wide spectrum of PIK3CA mutations was found in patients with metastatic breast cancer, suggesting the clinical relevance of molecular screening. Double PIK3CA mutations were identified in 15.8% of mutant tumors and maybe related to higher sensitivity to PI3K inhibitors. E545D mutation was always associated with a second mutation suggesting a different biological behavior. Citation Format: Juan Miguel Cejalvo, Santiago Moragón, Valentina Gambardella, Belén Ortega, Cristina Hernando, Maria Teresa Martinez, Noelia Tarazona, Octavio Burgués, Soraya Simón, Jesús Poveda, Alba Viala, Jorge Martín, Pilar Rentero-Garrido, Sheila Zúñiga-Trejos, Ana Lluch, Begoña Bermejo, Desamparados Roda, Andrés Cervantes. Frequency and spectrum of doublePIK3CAsomatic mutations in metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-20.