Large-scale genomic sequencing reveals adaptive opportunity of targeting mutated-PI3Kα in early and advanced HER2-positive breast cancer.

Lin-Wei Guo,Zhi-Ming Shao,Xun-Xi Lu,Yun-Song Yang,Xiang-Chen Han,Guan-Tian Lang,Li Chen,Xin Hu,Xiao-Guang Li

doi:10.1002/ctm2.589

Abstract

BackgroundFew studies have discussed the contradictory roles of mutated‐PI3Kα in HER2‐positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression.MethodsWe conducted prospective clinical sequencing of 1923 Chinese breast cancer patients and illustrated the clinical significance of PIK3CA mutations in locally advanced and advanced HER2+ cohort. A high‐throughput PIK3CA mutations‐barcoding screen was performed to reveal impactful mutation sites in tumour growth and drug responses.Results PIK3CA mutations acted as a protective factor in treatment‐naïve patients; however, advanced/locally advanced patients harbouring mutated‐PI3Kα exhibited a higher progressive disease rate (100% vs. 15%, p = .000053) and a lower objective response rate (81.7% vs. 95.4%, p = .0008) in response to trastuzumab‐based therapy. Meanwhile, patients exhibiting anti‐HER2 resistance had a relatively high variant allele fraction (VAF) of PIK3CA mutations; we defined the VAF > 12.23% as a predictor of poor anti‐HER2 neoadjuvant treatment efficacy. Pooled mutations screen revealed that specific PI3Kα mutation alleles mediated own biological effects. PIK3CA functional mutations suppressed the growth of HER2+ cells, but conferred anti‐HER2 resistance, which can be reversed by the PI3Kα‐specific inhibitor BYL719.ConclusionsWe proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti‐HER2 therapy, while the combination of anti‐HER2 and anti‐PI3Kα treatment was not essential for anti‐HER2 treatment‐naïve patients. These findings improve the understanding of genomics‐guided treatment in the different progressions of HER2+ breast cancer.

Highlights

Breast cancer harbouring gene amplification of epidermal growth factor receptor 2 (ERBB2, which encodes HER2) or overexpression of HER2 is categorised as HER2+ breast cancer, which occurs in approximately 15%–20% of all breast cancer cases.[1]
PIK3CA mutations protect against the development of malignancy in early breast cancer, inhibiting the proliferation of HER2+ cells by the negative feedback of RTK expression and activation; PIK3CA mutations mediated a lower overall response rate (ORR) in the trastuzumab-based neoadjuvant or advanced breast cancers, and enriched in metastatic HER2+ tumours
Among HER2-positive (HER2+) breast cancers, patients with phosphoinositide 3-kinase (PI3K) mutations account for a considerable proportion; the accurate annotations of PI3K mutation in the disease progression will be critical for genomics-guided diagnosis and treatment

Summary

Introduction

Breast cancer harbouring gene amplification of epidermal growth factor receptor 2 (ERBB2, which encodes HER2) or overexpression of HER2 is categorised as HER2+ breast cancer, which occurs in approximately 15%–20% of all breast cancer cases.[1]. Conclusions: We proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti-HER2 therapy, while the combination of anti-HER2 and anti-PI3Kα treatment was not essential for anti-HER2 treatment-naïve patients. These findings improve the understanding of genomics-guided treatment in the different progressions of HER2+ breast cancer

Methods

Results

Conclusion