Abstract 1239: Prognostic and predictive value of PIK3CA mutations in metastatic CRC (mCRC)

Abstract Background: Molecular aberrations including MSI, RAS, RAF, and HER2 have been used to guide the management of mCRC. However, the role of PIK3CA mutations is unclear in mCRC. In this study, we aimed to determine the prognostic value of PIK3CA mutations and their predictive value of response to anti-EGFR therapy in mCRC patients (pts). Methods: Pts with mCRC and clinical next generation sequencing were identified from the Clinical Genomics Action Committee database at Moffitt Cancer Center. Clinical and molecular aberration data were retrospectively collected. Progression-free survival (PFS) was the time from treatment initiation to clinical or radiographic disease progression. Overall survival (OS) was the time from diagnosis of metastatic disease to death. Kaplan Meier method and log-rank test were used for survival analysis. A parametric exponential model was implemented for PIK3CA exon analysis to account for small sample size. Pearson correlation coefficient was determined for correlation between PIK3CA and co-mutations. An additional meta-analysis was performed including prior studies of pts with KRAS wild-type (wt) PIK3CA mutant (mut) mCRC receiving anti-EGFR therapy using random effects model. Results: Among 639 pts with mCRC, PIK3CA mutation was positively correlated with KRAS mutation (r=0.11, p=0.006) and negatively correlated with TP53 mutation (r=-0.18, p=<0.001). It was not correlated with BRAF or APC mutations. Among 335 pts with KRAS wt mCRC, 174 were PIK3CA wt without anti-EGFR therapy; 111 were PIK3CA wt with anti-EGFR therapy; 33 were PIK3CA mut without anti-EGFR therapy; and 16 were PIK3CA mut with anti-EGFR therapy. Median OS of PIK3CA mut pts was 35.5 months, significantly shorter (HR 2.0, 95%CI 1.2-3.1) that median OS of 55.3 months in PIK3CA wt mCRC pts. The same was observed in pts (n=10) with PIK3CA exon 20 mutation (mOS: 18.5 months, HR 2.6, 95%CI 1.1-6.0) and pts (n=18) with PIK3CA exon 9 mutation (mOS: 38 months, HR 2.15, 95%CI 1.1-4.3). Among 166 pts evaluable for response rate, 44% PIK3CA wt pts responded to anti-EGFR therapy compared to 56% PIK3CA mut pts (p=0.51). Median PFS between PIK3CA mut and PIK3CA wt pts receiving anti-EGFR therapy was 10.3 versus 7.2 months (p=0.6), respectively. Our study and previously published 12 studies from 2005 to 2015 were examined in a meta-analysis where the included studies lacked significant heterogeneity (I2=0%, p=0.6). Among 1047 pts with KRAS wt mCRC who received anti-EGFR therapy, 104 of them were PIK3CA mut. The estimated risk ratio for response to anti-EGFR therapy was 0.77 (95%CI 0.5-1.1) with prediction interval between 0.4 and 1.6. Conclusion: PIK3CA mutation has positive correlation with KRAS mutation and negative correlation with TP53 mutation in mCRC. PIK3CA mutation confers a worse prognosis but is not predictive for response to anti-EGFR therapy in pts with KRAS wt mCRC. The latter finding was confirmed in an updated meta-analysis of 13 studies including ours. Citation Format: Elaine Tan, Wenyi Fan, Michael Schell, Ibrahim Sahin, Jason Fleming, Todd Knepper, Hao Xie. Prognostic and predictive value of PIK3CA mutations in metastatic CRC (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1239.