Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: A meta-analysis and bioinformatic analysis of TCGA‑BRCA data

Abstract

Background: This study aimed to comprehensively explore the clinical significance of PIK3CA mutation in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with anti-HER2 therapy.

Methods: We systematically searched PubMed, Embase, and the Cochrane databases for eligible studies assessing the association between PIK3CA mutation and outcomes in patients with HER2-positive breast cancer receiving anti-HER2 therapy. The main outcomes included: (1) pathological complete response (pCR) or disease-free survival (DFS) for the neoadjuvant setting; (2) DFS or invasive DFS for the adjuvant setting; (3) objective response rate (ORR), progression-free survival (PFS), time-to-progression (TTP), or overall survival (OS) for the metastatic setting. The mutational landscape of HER2-positive breast cancer according to PIK3CA mutation status was examined based on TCGA breast cancer dataset.

Results: Totally, 43 eligible studies, covering 11,099 patients with available data on PIK3CA mutation status, were identified. In the neoadjuvant setting, PIK3CA mutation was significantly associated with a lower pCR rate (OR=0.23, 95% CI 0.19-0.27, p<0.001). This association remained significant irrespective of the type of anti-HER2 therapy (single-agent or dual-agent) and hormone receptor status. There were no significant differences in DFS between PIK3CA mutated and wild-type patients in either the neoadjuvant or adjuvant settings. In the metastatic setting, PIK3CA mutation predicted worse ORR (OR=0.26, 95%CI 0.17-0.40, p<0.001), PFS (HR=1.28, 95%CI 1.03-1.59, p = 0.024) and TTP (HR=2.27, 95%CI 1.54-3.34, p<0.001). However, no significant association was observed between PIK3CA mutation status and OS. Distinct mutational landscapes were observed in HER2-positive breast cancer between individuals with PIK3CA mutations and those with wild-type PIK3CA.

Conclusions: PIK3CA mutation was significantly associated with a lower pCR rate in HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy. In the metastatic setting, PIK3CA mutation was predictive of worse ORR, PFS and TTP. These results suggest the potential for developing PI3K inhibitors as a therapeutic option for these patients.

Keywords: Anti-HER2 therapy; Breast cancer; HER2-positive; PIK3CA mutation; Predictive.

Fig. 1

Flow diagram of study selection. HER2, human epidermal growth factor receptor 2.

Fig. 2

Forest plot of association between PIK3CA mutation and pathological complete response for HER2-positve breast cancer patients treated with anti-HER2 therapy in the neoadjuvant setting. HER2, human epidermal growth factor receptor 2.

Fig. 3

Forest plot of association between PIK3CA mutation and pCR for HER2-positve breast cancer patients treated with anti-HER2 therapy according to anti-HER2 agents. (A) Association between PIK3CA mutation and pCR for patients receiving neoadjuvant single-agent anti-HER2 therapy; (B) Association between PIK3CA mutation and pCR for patients receiving neoadjuvant dual-agent anti-HER2 therapy. pCR, pathological complete response; HER2, human epidermal growth factor receptor 2.

Fig. 4

Forest plot of association between PIK3CA mutation and pCR for HER2-positve breast cancer patients treated with anti-HER2 therapy according to hormone receptor status. (A) Association between PIK3CA mutation and pCR for hormone receptor-negative patients; (B) Association between PIK3CA mutation and pCR for hormone receptor-positive patients. pCR, pathological complete response; HER2, human epidermal growth factor receptor 2.

Fig. 5

Forest plot of association between PIK3CA mutation and outcome measures for HER2-positve breast cancer patients treated with anti-HER2 therapy in the metastatic setting. (A) Association between PIK3CA mutation and ORR; (B) Association between PIK3CA mutation and PFS; (C) Association between PIK3CA mutation and OS. HER2, human epidermal growth factor receptor 2; ORR, objective response rate; PFS, progression-free survival; OS, overall survival.

Fig. 6

Somatic mutations and signaling pathways in HER2-positive breast cancer from TCGA dataset. (A) The oncoprint of somatic mutations for PIK3CA mutated patients (left side, n = 48) and that for PIK3CA wild-type patients (right side, n = 112); (B) The bar-graph showing comparisons of ten canonical signaling pathways between PIK3CA mutated patients and PIK3CA wild-type patients. An asterisk (*) indicates the significant difference in mutational frequencies of the signaling pathway between PIK3CA mutated and wild-type patients. HER2, human epidermal growth factor receptor 2; TCGA, The Cancer Genome Atlas.