Abstract 1412: Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer
Authors: Kook Yoonwon , Kim Kyungsoo , Jang Ji Soo , Baek Seung Ho , BAe Soong June , Jeong Joon , Ahn Sung Gwe 
Published: June 2023

Background: PIK3CA mutation is commonly found in estrogen receptor (ER)+ human epidermal growth factor receptor-2 (HER2)- breast cancer (BC) and can be therapeutically targeted by alpelisib, an alpha-specific PIK3CA inhibitor. While previous studies presented conflicting results on the prognostic influence of PIK3CA mutation among ER+HER2- breast cancer, few have been able to address causes of the prognostic discrepancy on a clinical level. In this study, we investigated clinical and genomic features according to a coexistence of TP53 mutation in PIK3CA mutated ER+HER2- breast cancer.

Methods: Tumor tissue based next generation sequencing (NGS) was analyzed for 224 HR+ HER2- BC patients from April 2017 to August 2021 in Gangnam Severance Hospital, Seoul, South Korea. Matching clinical records with patient information were reviewed retrospectively. Clinicopathologic features including age, tumor size, histologic grade (HG), TNM stage, estrogen receptor (ER) expression, progesterone (PgR) expression, Ki-67, and Oncotype Dx Recurrence Score (RS) were analyzed. Further analysis was carried out using The Cancer Genome Atlas (TCGA) to explore the relationship of mutation status with intrinsic subtype and risk of recurrence (ROR) score.

Results: We identified PIK3CA mutation (PIK3CA m) in 105 (46.9%) of 224 patients, and of these, TP53 co-mutation was found in 25 (23.8%). None of clinicopathologic features were different according to PIK3CA mutation. When PIK3CA m cohort was analyzed according to TP53 mutation (TP53 m) status, tumors with TP53 m presented unfavorable features such as higher HG (p&lt;0.001), lower PgR expression (TP53 wt: Median 7 versus TP53 m: Median 5, p=0.027), and higher N stage (p=0.008). It also displayed a significantly higher proliferative profiles with Ki-67 (TP53 wt: Median 15 versus TP53 m: Median 20, p&lt;0.001) and Oncotype Dx RS (TP53 wt: Median 15 versus TP53 m: Median 26.5, p=0.002). In the 539 ER+HER2- breast cancer from the TCGA database, PIK3CA and TP53 co-mutation was found in 33 (6.1%). Distribution of intrinsic subtypes revealed a higher rate of Luminal B in PIK3CA and TP53 co-mutant tumors (51.5%) than in PIK3CA m and TP53 wt tumors (14.3%, p&lt;0.001). The ROR score was found to be higher in the PIK3CA-TP53 co-mutation compared to PIK3CA m alone (p&lt;0.001).

Conclusion: Unlike PIK3CA mutation, PIK3CA and TP53 co-mutation clearly divided multiple clinicopathologic features of HR+ HER2- BC including with. Poorer prognosis of co-mutation was also corroborated by TCGA analysis of intrinsic subtype and ROR score. These findings indirectly suggest that co-mutation of TP53 gene may be associated with less sensitivity to PIK3CA targeted therapy in PIK3CA m ER+HER2- breast cancers. Further research is warranted to improve an efficacy of PIK3CA targeted therapy for PIK3CA m ER+ breast cancer with endocrine-resistant factors.

Citation Format: Yoonwon Kook, Kyungsoo Kim, Ji Soo Jang, Seung Ho Baek, Soong June BAe, Joon Jeong, Sung Gwe Ahn. Co-existence of TP53 mutation confers endocrine resistance in PIK3CA-mutated ER+HER2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1412.