Abstract
In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted.
Highlights
Correspondence to: Keywords: refractory metastatic breast cancer, generation sequencing (NGS), targeted sequencing, HER2 mutation, HER pathway
Wild-type HER2 overexpression occurs in 20–30% of breast cancers, Bose et al estimated that about 1.6% of breast cancer patients possess a HER2 mutation [13]. They found that seven HER2 mutations activated the protein, as reflected in its enzyme activity, and downstream HER2 signaling in mouse xenografts
metastatic breast cancer (MBC) that was refractory to conventional treatments were enrolled, and fresh frozen tumour tissues were collected from metastatic sites for targeted sequencing, CancerSCANTM analysis, and RNA sequencing
Summary
Whole-transcriptome sequencing (RNA-Seq) to evaluate the HER pathway in patients with refractory MBC. Approaches in The Cancer Genome Atlas (TCGA) suggest that primary BCs are mutationally heterogeneous [9, 10] This heterogeneity of MBCs and refractoriness to conventional treatments represent a significant treatment challenge, and there is a pressing need to understand better the biology of these aggressive cancers and to develop more effective therapies. Wild-type HER2 overexpression occurs in 20–30% of breast cancers, Bose et al estimated that about 1.6% of breast cancer patients possess a HER2 mutation [13] They found that seven HER2 mutations activated the protein, as reflected in its enzyme activity, and downstream HER2 signaling in mouse xenografts.
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