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Research Paper|Volume 12, Issue 2|pp 1577—1590

PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies

Yu Tang1,2, Jing Li1,2, Ning Xie1,2, Xiaohong Yang1,2, Liping Liu1,2, Hui Wu1,2, Can Tian1,2, Ying He1,3, Xiao Wang4, Qiongzhi He5, Zhe-Yu Hu1,2, Quchang Ouyang1,2
  • 1The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha 410000, China
  • 2Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha 410000, China
  • 3The 2nd Department of Breast Cancer Surgical Oncology, Hunan Cancer Hospital, Changsha 410000, China
  • 4ICF, Atlanta, GA 30329, USA
  • 5Beijing Geneplus Institute, Beijing 102200, China
Received: November 6, 2019Accepted: December 27, 2019Published: January 24, 2020
https://doi.org/10.18632/aging.102701

Copyright: © 2020 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Nearly half of metastatic breast cancers (MBC) have genetic aberrations in the PI3K/AKT pathway. To investigate the distinct effect of these aberrations on MBC, 193 MBC patients who progressed after the early line (≤2) salvage treatment voluntarily received next generation sequencing (NGS) for a panel of 1,021 genes. 93 (48%) patients had genetic aberrations in the PI3K/AKT pathway. The number of patients with PIK3CA mutations in kinase domain (KD), helical domain (HD) and other domain (OD), were 36 (18.7%), 26 (13.5%), 10 (5.2%), respectively. 21 (10.9%) patients had mutations in PI3K/AKT pathway genes other than PIK3CA (P/A). Compared to PI3K/AKT-wild type (WT) patients, PIK3CA-HD patients had a significantly shorter progression-free survival (PFS) (Logrank p-value < 0.0001). PIK3CA-KD, PIK3CA-OD and other P/A mutations showed similar PFS to WT patients (Logrank p-value = 0.63). PIK3CA-HD patients had a distinct ctDNA mutation profile to patients with other PI3K/AKT mutations. PIK3CA-HD patients had a higher rate of FGFR and NF1 aberrations. In addition, more PIK3CA-HD carriers were TMB-high. Cox regression analyses suggested that PIK3CA-HD mutations, FGFR aberrations and high TMB were all significant risk factors for poor PFS. In conclusion, future research needs to focus more on the treatment strategies targeting PIK3CA-HD mutations.