Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer
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Yeon Hee Park1,2,*, Hyun-Tae Shin3,*, Hae Hyun Jung2, Yoon-La Choi3, TaeJin Ahn3, Kyunghee Park3, Aeri Lee4, In-Gu Do5, Ji-Yeon Kim1,2, Jin Seok Ahn1, Woong-Yang Park3, Young-Hyuck Im1,2
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Samsung Genomic Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
4Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
5Center of Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea
*These authors have contributed equally to this work
Young-Hyuck Im, e-mail: firstname.lastname@example.org
Woong-Yang Park, e-mail: email@example.com
Keywords: refractory metastatic breast cancer, next generation sequencing (NGS), targeted sequencing, HER2 mutation, HER pathway
Received: June 26, 2015 Accepted: August 28, 2015 Published: September 11, 2015
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.
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