Abstract 2934: Pattern of PIK3CA co-alterations in endometrial cancer

Abstract

Abstract Purpose: Aberrant PI3K pathway activation drives tumor proliferation and survival. The aim of this study was to identify PI3K pathway activation patterns in endometrial cancer by profiling mutational prevalence and co-mutation with PTEN and TP53. Methods: Molecular profiles of 1,180 unique cancer (endometrial, breast, lung, and colorectal) patients’ formalin-fixed paraffin-embedded tissue samples were analyzed. Samples were evaluated using a 323 gene NGS panel utilizing the QIAseq targeted DNA chemistry. Fisher's exact test was used for statistics. Results: The most frequent PIK3CA mutations were found in the kinase domain (KD) in both endometrial and breast cancers (predominately p.H1047). In lung and colorectal cancers, helical domain alterations were predominant. There were significantly more PIK3CA adaptor binding domain mutations and PIK3CA/PTEN co-mutations in endometrial cancer compared to other tumor types. Among PIK3CA/PTEN co-mutations in endometrial cancer, there were significantly fewer TP53 mutations when compared to those with no PTEN co-mutation (17.2% vs. 70.7%; p<0.0001). Conclusions: In endometrial cancer, PTEN is more frequently mutated upon PI3K/AKT pathway hyperactivation, abrogating its normal inhibitory effect on PI3K resulting in increased cell proliferation and survival. When PTEN is not mutated, alternations downstream of AKT, such as TP53 mutations, may serve as alternative cell survival regulators. This may account for the relationship between PTEN/PIK3CA KD co-mutation and TP53 mutation. While PIK3CA KD mutations are similarly predominant in breast and endometrial cancer, the PTEN feedback loop is disrupted in endometrial cancer. This study provides insight into the patterns of molecular alterations present within PIK3CA-mutated patients, which could be instrumental in stratifying patient populations. PIK3CA Mutation Prevalence Adapter binding domain Helical domain Kinase domain Hotspot H1047 PTEN co-mutation + any PIK3CA mutation Endometrial (n=99) 21.2% 26.3% 42.4% 27.3% 58.6% Breast (n=278 ) 3.6% (p<0.0001) 37.8% (p=0.0386) 55.4% (p=0.0258) 46.8% (p=0.0007) 7.2% (p<0.0001) Lung (n=452) 8.8% (p=0.0004) 50.2% (p<0.0001) 24.6% (p=0.0003) 8.4% (p<0.0001) 5.5% (p<0.0001) Colorectal (n=342) 9.9% (p=0.0027) 51.5% (p<0.0001) 25.1% (p=0.0008) 16.4% (p=0.0147) 8.2% (p<0.0001) Citation Format: Madhuri Paul, Frank J. Scarpa, Rachel Daringer, Sally Agersborg, Vincent Anthony Funari, Forrest Blocker. Pattern of PIK3CA co-alterations in endometrial cancer [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 2934.