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Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient

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Abstract

HER2 (ERBB2) is an oncogene and 20% of breast cancers display HER2 amplification. The HER2 monoclonal antibody, trastuzumab, is used to treat breast cancers that display HER2 amplification, with good responses in 80–90% of cases; however, 10% of tumours develop resistance to trastuzumab. In this study, we collected data of primary breast cancer patients who treated at hospital during 2004–2014. In our cohort, 205 of 1497 primary breast cancer patients showed HER2-amplification, and 20 experienced recurrence after trastuzumab therapy. Of the 20 recurrent cases, only six patients had metastatic sites, excluding brain metastases, which were resistant to trastuzumab. To examine trastuzumab resistance in HER2-amplified breast cancer, we analysed clinical specimens before and after trastuzumab therapy. The results indicated that an intrinsic activating mutation leads to a valine-to-leucine substitution at codon 777 within the HER2 kinase domain (HER2 V777L). This was identified in one of six cases of a HER2-amplified breast cancer, both pre- and post-treatment; however, HER2 V777L was not identified in 14 responders who were treated with trastuzumab. These results suggest that HER2 V777L mutation is responsible for, and a predictive marker of, trastuzumab resistance. This is the first report to show that HER2 V777L is coincident with HER2-amplification in breast cancers that have developed trastuzumab resistance.

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Acknowledgements

We thank Hideyuki Shigetomo, Yumi Kubota and Ritsuko Yokouchi for their help. We thank all medical and ancillary staff in hospital and the patient for consenting to participate. This study was supported by a Grant-in-Aid for Genome Research Project from the Yamanashi Prefecture (Y.H. and M.O.) and the grant from The YASUDA Medical Foundation (Y.H.).

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Authors and Affiliations

  1. Genome Analysis Center, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Yosuke Hirotsu, Kenji Amemiya, Hitoshi Mochizuki & Masao Omata

  2. Department of Breast Surgery, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Hiroshi Nakagomi & Masayuki Inoue

  3. Pathology Division, Laboratory Department, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Kenji Amemiya & Toshio Oyama

  4. Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Hitoshi Mochizuki & Masao Omata

  5. The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Masao Omata

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  1. Yosuke Hirotsu
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Hirotsu, Y., Nakagomi, H., Amemiya, K. et al. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med Oncol 34, 3 (2017). https://doi.org/10.1007/s12032-016-0857-2

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