Genomic Alterations Correlated to Trastuzumab Resistance and Clinical Outcomes in HER2+/HR- Breast Cancers of Patients Living in Northwestern China

Abstract

Anti-HER2 therapy has significantly improved the survival rates of patients with HER2+ breast cancer. However, a subset of these patients eventually experience treatment failure, and the underlying genetic mechanisms remain largely unexplored. This underscores the need to investigate the genomic heterogeneity of HER2+ breast cancer. In this study, we focus on HER2+/HR- breast cancer, as it differs from HER2+/HR+ breast cancer in terms of genetic and biological characteristics. We performed gene-targeted genome sequencing on 45 HER2+/HR- breast cancer samples and identified 650 mutations across 268 cancer-related genes. TP53 (71.1%) and PIK3CA (35.6%) were the most frequently mutated genes in our sample. Additionally, ERBB2 (77.8%), CDK12 (42.2%), and MYC (11.1%) exhibited a high frequency of copy number amplifications (CNAs). Comparative analysis with two other HER2+/HR- breast cancer cohorts revealed that our cohort had higher genetic variation rates in ARID1A, PKHD1, PTPN13, FANCA, SETD2, BRCA2, BLM, STAG2, FAT1, TOP2A, POLE, ATM, KMT2B, FGFR4, and EPAS1. Notably, in our cohort, NF1 and ATM mutations were more prevalent in trastuzumab-resistant patients (NF1, p=0.016; ATM, p=0.006) and were associated with primary trastuzumab resistance (NF1, p=0.042; ATM, p=0.021). Moreover, patients with NF1 mutations (p=0.009) and high histological grades (p=0.028) were more likely to experience early relapse. Ultimately, we identified a unique cancer-related gene mutation profile and a subset of genes associated with primary resistance to trastuzumab and RFS in patients with HER2+/HR- breast cancer in Northwest China. These findings could lay the groundwork for future studies aimed at elucidating the mechanisms of resistance to trastuzumab and improving HER2-targeted treatment strategies.

Keywords: Breast cancer; Genomic profiling; HER2 positive; Trastuzumab resistance.

Figure 1

Summary of the somatic mutations and Indels of all 45 patients with HER2+/HR- breast cancer in Northwestern China. (HER2-TR = HER2+/HR- breast cancer with primary trastuzumab-resistant status, HER2-TS = HER2+/HR- breast cancer with tastuzumab sensitive status).

Figure 2

Comparison of gene mutations and CNAs between our cohort and the two published HER2+/HR- breast cancer cohorts (TCGA PanCancer Atlas and METABRIC): (a) Comparison of the top twenty mutated genes among the three cohorts (the blue, yellow, and green colors represent the top twenty mutated genes of the three cohorts individually); (b) Comparison of top ten CNAs among the three cohorts (the blue, yellow, and green colors indicate the top ten CNAs of the three cohorts individually).

Figure 3

Summary of hot spot mutations of eight highly mutated genes (Containing TP53, PIK3CA, ARID1A, FAT1, NF1, ATM, PKHD1, and FANCA) in the HER2+/HR- breast cancer cohort of Northwestern China. The mutations are shown in the lollipop graphs.

Figure 4

KEGG enrichment of mutation pathway(a) and gene association and mutual exclusion (b) in the HER2+/HR- breast cancer cohort of Northwestern China.

Figure 5

Comparison of mutation genes(a)and KEGG pathway(b) between primary trastuzumab-resistant and non-resistance groups of the HER2+/HR- breast cancer cohort in Northwestern China.

Figure 6

The Kaplan-Meier curves of mutated NF1 gene (a)and histological grade status(b) on RFS of the patients with HER2+/HR- breast cancer in Northwestern China.