Abstract P4-09-15: A large study of PIK3CA mutations in the community setting identifies varying degree of mutation positivity rates across age groups in advanced HR+, HER2- breast cancer patients using an FDA RT-PCR cleared test

Background: The phosphatidylinositol 3-kinase (PI3K) gene encoding the catalytic component p110, PIK3CA, is one of the most frequently mutated genes in breast cancer. [1] PIK3CA mutational status and prevalence have been studied in various clinical trial settings but not sufficiently studied in the community setting. In the SOLAR-1 trial, PIK3CA mutations were detected in approximately 40% of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients where the mutation rate in exon 20 was similar to that in exon 9 (33.7% vs 29.9%). [2-3] In other HER2-positive breast cancer trials, the PIK3CA mutation rate was 21.4% in the GeparStudies, 22.5% in NeoALTTO, and 20.4% in the CHERLOB study, where mutations in exon 20 were twice as high as in exon 9 (14.5% vs 7.2%). [4-6] Methods: An unselected female cohort of 1281 patients with advanced stage HR-positive, HER2-negative breast cancer seen in the community setting was included in this study, with an average age of 62.9 years. Age groups by the decade ranged from 80 years old respectively: 6, 46, 124, 274, 390, 332, 109 patients. The breast tumor tissues used in this study were formalin-fixed, paraffin-embedded (FFPE). Mutational status was determined by an U.S. Food & Drug Administration (FDA) cleared test kit, and processed in accordance with the labeling instructions. [7-8] This PIK3CA kit was a real-time qualitative PCR test for the detection of 11 mutations in the PIK3CA gene (Exon 7: C420R; Exon 9: E542K, E545A, E545D [1635G>T only], E545G, E545K, Q546E, Q546R; and Exon 20: H1047L, H1047R, H1047Y) using genomic DNA (gDNA) extracted from (FFPE) breast tumor tissue. Results: PIK3CA mutations were detected at 37.5% (N=481) of patient samples. Mutation positivity rates differed depending on the patient age groups. For patients under the age of 30 or in their 30s, mutation positivity rates were 16.7% and 17.4% respectively while the positivity rates were substantially higher in older age groups: 37.9% (40s), 31% (50s), 41.3% (60s), 39.2% (70s) and 45% (> 80 years old). The specific mutations identified varied for the different age groups. Patients under the age of 30 or in their 30s, the p.E545K variant appeared to be the predominant point mutation. In contrast, patients in the 50 years old age group and older had mutations across all detectable mutational hotspots in exon 7, 9 and 20. Conclusion: PIK3CA is one of the most frequently mutated genes in breast cancer. This study marks the first large cohort assessment of PIK3CA mutation status within the community setting using an FDA-cleared assay. In this study, the mutation positivity rate of 37.5% in the community setting is similar to the ~40% in clinical trial settings. Refernces: 1. Cancer Genome Atlas Network: Nature 490:61-70, 2012 2. Andre F, et al. N Engl J Med 2019;380: 1929-40 3. Rugo H, et al. Cancer Res 2019;79(13 Suppl):Abstract CT142 4. Loibl S, et al. Annals of Oncology 27: 1519–1525, 2016 5. Majewski IJ, et al. J Clin Oncol 2015; 33: 1334–1339 6. Guarneri V, et al. Oncologist 2015; 20: 1001–1010 7. P190001 - therascreen® PIK3CA RGQ Kit Instructions for Use (Handbook). Accessed August 29, 2019 8. P190004 - therascreen® PIK3CA RGQ PCR Kit Instructions for Use (Handbook). Accessed August 29, 2019 Citation Format: Alex C Chan, Lawrence M Weiss, Ryan Bender. A large study of PIK3CA mutations in the community setting identifies varying degree of mutation positivity rates across age groups in advanced HR+, HER2- breast cancer patients using an FDA RT-PCR cleared test [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-15.