Abstract P4-10-34: Plasma sequencing demonstrates that breast cancer patients have a higher prevalence of clonal and multiple PIK3CA mutations than other solid tumor patients

Background: Alpelisib, a PI3Kα inhibitor, was recently approved by the FDA for the treatment of metastatic PIK3CA-mutated HR+ breast cancer in combination with fulvestrant. This therapeutic breakthrough came after years of disappointing efforts to develop solid tumor drugs targeting PIK3CA, one of the most commonly altered oncogenes in cancer, including 40% of HR+ breast and 30% of head and neck squamous cell cancer. The limited success of PI3Kinhibitors outside of breast cancer may be partly because cancers may harbor heterogeneous PIK3CA mutations and/or co-occurring mutations that confer varying degrees of sensitivity to PI3Kα inhibition. Methods: To identify biomarkers of sensitivity and resistance to PI3Kinhibitors, we assessed all plasma samples sent to a CLIA-certified commercial laboratory (Guardant Health) for a targeted NGS assay (Guardant360) from November 2016 to March 2019. The assay included 73 genes for single-nucleotide variants, 23 genes for insertions / deletions, 18 genes for amplifications, and 6 genes for fusions. In total, 53,118 cancer patients were sequenced, of whom 8,464 patients (15.9%) had a PIK3CA point mutation or amplification. This PIK3CA-mutated subset served as our analysis cohort. Results: The four most common tumor types in our PIK3CA-mutated cohort were breast (n=2060), non-small cell lung (n=2667), colorectal (n=999), and prostate cancer (n=713); head and neck cancer patients (n=129) were also included given the high frequency of PIK3CA mutations in this disease. Breast cancer patients had a median of 6 plasma mutations detected (range 1-92) and median maximum variant allele frequency (VAF) of 7.6% (range 0.05-96.5%). PIK3CA mutations were clonal in 68.2% of breast cancer patients (as defined by a VAF>50% of the maximum VAF), compared to 18-44% in patients of other tumor types (p Conclusions: PIK3CA-mutated breast cancer patients were more likely to have clonal PIK3CA mutations and multiple PIK3CA and PI3K pathway mutations compared to patients with other tumor types, which may suggest greater PI3Kpathway dependency and sensitivity to treatment with PI3Kα inhibitors. Ongoing whole exome and RNA sequencing of 21 pairs of pre- and post-treatment tissue biopsies of breast cancer patients treated with PI3Kα inhibitors will provide additional genomic and transcriptomic context to these plasma-based results. Citation Format: Christopher Chen, Avinash Sahu, Kristin Price, Christopher Pinto, Read Allen, Xiaoman Wang, Annamaria Szabolcs, Lipika Goyal, David Ting, Shirley Liu, Dejan Juric. Plasma sequencing demonstrates that breast cancer patients have a higher prevalence of clonal and multiple PIK3CA mutations than other solid tumor patients [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 P4-10-34.