Abstract P3-04-11: Implications of somatic <i>TP53</i> and <i>PIK3CA</i> mutations in patients with metastatic breast cancer who underwent germline <i>BRCA</i> testing
Authors: C Yam, A Gutierrez Barrera, D Huang, X Lin, JK Litton, B Arun
Journal: Cancer Research (2018)

Abstract Background: TP53 and PIK3CA are the most frequently mutated genes in breast cancer. However, there is limited data evaluating the impact of somatic mutations in TP53 and/or PIK3CA patients (pts) with metastatic breast cancer (MBC) who have undergone germline testing for BRCA mutations. Here, we report the frequency of somatic TP53 and PIK3CA mutations in MBC pts who previously underwent germline BRCA (gBRCA) testing and evaluate their impact on long-term outcomes. Methods: We identified pts with MBC from our prospectively maintained high risk genetics database who underwent gBRCA testing and had somatic mutation testing performed for TP53 and/or PIK3CA through hotspot sequencing of single genes or as part of a next generation sequencing panel. Univariable logistic regression was used to evaluate associations between clinicopathological characteristics, including gBRCA status, and the presence of somatic TP53 and PIK3CA mutations. Overall survival (OS) was defined as the time from diagnosis to death from any cause. Multivariable cox regression analysis was used to identify independent predictors of OS. Results: 104 pts met all inclusion criteria. Somatic mutations in TP53 and PIK3CA were found in 46% (39/84) and 23% (24/104) of tested pts, respectively. Associations between clinicopathological characteristics and somatic TP53 and PIK3CA mutation status are summarized in Table 1. Pts with hormone receptor positive (HR+) disease were less likely to have TP53 mutations (odds ratio [OR]: 0.28, 95% confidence interval [CI]: 0.11-0.70, p=0.007) but more likely to harbor PIK3CA mutations (OR: 3.27, 95% CI: 1.11-9.62, p=0.031). There were no significant associations between gBRCA mutation status and somatic TP53 or PIK3CA mutations. On multivariable analysis, somatic TP53 mutations (adjusted hazard ratio [aHR]: 1.98, 95% CI: 1.10-3.58, p=0.023) and de novo metastatic disease (aHR=2.88, 95% CI: 1.26-6.58, p=0.012) independently predicted poorer OS, while HR+ disease (aHR: 0.40, 95% CI: 0.21-0.74, p=0.004) and HER2+ disease (aHR: 0.33, 95% CI: 0.13-0.83, p=0.019) were significantly associated with improved OS. PIK3CA mutations (aHR: 1.20, 95% CI: 0.59-2.44, p=0.62) and gBRCA mutations (aHR: 0.78, 95% CI: 0.33-1.83, p=0.57) did not significantly impact OS in this study. Conclusion: In this study, somatic TP53 mutations independently predicted worse OS in pts with MBC after adjusting for significant covariates, including gBRCA mutation status. These findings should be validated in a larger cohort of pts. Table 1: Association between patient characteristics and somatic TP53 and PIK3CA mutation status TP53 PIK3CA TP53 mutant (n=39)TP53 wild type (n=45)p valuePIK3CA mutant (n=24)PIK3CA wild type (n=80)p valueMedian Age – years (Interquartile Range)37 (33-47)39 (36-44)0.93739 (34-46)38 (34-43)0.494gBRCA mutant – n(%)3 (8)11 (24)0.0511 (4)15 (19)0.116ER/PR positive - n(%)17 (44)33 (73)0.00719 (79)43 (54)0.031HER2 positive - n(%)8 (21)6 (13)0.3827 (29)10 (13)0.060De Novo Metastatic – n(%)6 (15)8 (18)0.7693 (13)16 (20)0.409Visceral Disease – n(%)23 (59)26 (58)0.91215 (63)47 (59)0.743 Citation Format: Yam C, Gutierrez Barrera A, Huang D, Lin X, Litton JK, Arun B. Implications of somatic TP53 and PIK3CA mutations in patients with metastatic breast cancer who underwent germline BRCA testing [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-11.