Abstract PD18-04: Prognostic implications of PIK3CA mutation by hormone receptor status and intrinsic subtype in early stage HER2-positive breast cancer: a correlative analysis from CALGB 40601

Background PIK3CA mutations have been described in 20-25% of early-stage HER2-positive breast tumors [1], and are associated with reduced pathologic complete response (pCR) rate after chemotherapy and anti-HER2 agents [2]. However, the independence of this finding and association with long-term outcomes within HER2+ patients is still largely unknown. Here, we studied the prognostic implications of PIK3CA mutations by hormone receptor (HR) status and intrinsic subtype in patients with early stage HER2+ breast cancer enrolled in CALGB 40601. Method In CALGB 40601, gene expression profiling by RNA sequencing (RNAseq) with PAM50-determined intrinsic subtype and PIK3CA mutations from whole exome sequencing (WES) were obtained from 184/305 (60%) pretreatment core biopsies. We examined the association of PIK3CA mutations with pCR and event free survival (EFS) by HR status and intrinsic subtype using logistic and Cox regression analyses. Results PIK3CA mutations were found in 32 patients (32/184, 17%). The most frequent mutation was H1047R (12/32,38%), followed by E545K (7/32,22%) and E542K (5/32,16%). PIK3CA mutations were present in 20% and 15% of HR-positive and HR-negative BC subpopulations, respectively. Within Luminal-B, Luminal-A and HER2-Enriched breast tumors, PIK3CA mutations occurred in 36%, 10% and 19% respectively. In the overall population there was lower rate of pCR in mutated-PIK3CA patients than wild-type (34% vs 49%). Using only the subset of patients treated with neoadjuvant trastuzumab-based therapy as standard of care (excluding the lapatinib plus paclitaxel arm), we found a statistically significant lower pCR rate among PIK3CA-mutated tumors using logistic regression model (30% vs 54%, OR=0.30, p=0.045). At a median follow-up of 9.1 years, the presence of PIK3CA mutation was significantly associated with worse EFS in the overall study population (HR 2.58, 95% CI 1.24- 5.35, p=0.011). In a multivariable model including pCR status, HR status and intrinsic subtype (HER2-E vs. not), PIK3CA mutation was independently and significantly associated with worse EFS (HR 2.18, 95% CI 1.04- 4.56, p=0.039). The negative impact of PIK3CA mutation on EFS was statistically significant only in patients with HR-positive (HR 3.6, 95% CI 1.45-8.96, p=0.06) and luminal breast tumors (HR 4.84, 95% CI 1.08-21.7, p=0.039), but not in HR-negative and non-luminal subtypes. Conclusion In our study, the presence of PIK3CA mutation was significantly associated with lower pCR rates in patients treated with chemotherapy plus trastuzumab. Moreover, in uni- and multivariable Cox models, PIK3CA mutations were associated with worse long-term survival, which appeared to be driven by HR-positive and luminal HER2-positive breast tumors. References 1. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature 2012;490:61–70. 2. Loibl S, Majewski I, Guarneri V, Nekljudova V, Holmes E, Bria E, et al PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. Ann Oncol 2016;27:1519–25. Citation Format: Paola Zagami, Aranzazu Fernandez-Martinez, Naim U. Rashid, Katherine A Hoadley, Patty Spears, Charles M. Perou, Lisa Carey. Prognostic implications of PIK3CA mutation by hormone receptor status and intrinsic subtype in early stage HER2-positive breast cancer: a correlative analysis from CALGB 40601. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-04.