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A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer

British Journal of Cancer volume 129, pages 1176–1183 (2023)Cite this article

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Abstract

Background

This study aimed to elucidate the clinicopathological and molecular features of HER2-amplified and HER2-low colorectal cancers (CRCs). We also characterised HER2 expression statuses in CRCs focusing on their intratumoral heterogeneity and alterations in metastatic lesions to establish practical HER2 status assessment.

Methods

We evaluated 1009 CRCs for HER2 expression and HER2 amplification by immunohistochemistry and FISH, respectively, and correlated the results to clinicopathological and molecular data. For HER2-positive tumours, HER2 expression in metastatic lesions was also assessed.

Results

Twenty-five HER2-amplified (2.5%) and 46 HER2-low tumours (4.6%) were identified. HER2-amplified tumours consistently lacked a mucinous component and HER2-low tumours tended to be in the right colon, but no other clinicopathological features were noted. KRAS, NRAS or BRAF mutations were detected in only two HER2-amplified tumours (8%), whereas 23 HER2-low tumours (50%) had one of these mutations. Most HER2-amplified and HER2-low tumours showed a homogeneous or mosaic HER2 expression pattern and a clustered heterogeneous expression pattern was rather rare. HER2 expression was maintained in most metastatic lesions in both HER2-amplified (93%) and HER2-low tumours (81%).

Conclusions

These results suggest that biopsy-based assessment of primary lesions is appropriate for the identification of CRC patients eligible for systemic HER2-targeted therapy.

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Fig. 1: HER2 expression pattern classification.
Fig. 2
Fig. 3: HER2 expression in primary and metastatic tumours.
Fig. 4: HER2 expression status in primary and metastatic tumours.
Fig. 5: HER2 mRNA expression by HER2 immunohistochemistry (IHC)/FISH status.

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Data availability

All data and materials generated and/or analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Hitoshi Ichikawa, Dr. Masahiro Gotoh, Ms. Sachiko Miura, Ms. Toshiko Sakaguchi, Ms. Chizu Kina, Ms. Maiko Matsuda, Ms. Yoko Shimada, Ms. Sachiyo Mitani and Mr. Hiroki Kakishima for their skilful technical assistance.

Funding

None.

Author information

Authors and Affiliations

  1. Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan

    Taiki Hashimoto, Junpei Yonemaru, Tomoaki Naka, Yasushi Yatabe & Shigeki Sekine

  2. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

    Daisuke Takayanagi, Erika Machida, Takashi Kohno & Kouya Shiraishi

  3. Department of Medicine, Division of Medical Oncology, Showa University School of Medicine, Tokyo, Japan

    Daisuke Takayanagi

  4. Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan

    Daisuke Takayanagi

  5. Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan

    Kengo Nagashima

  6. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Yasushi Yatabe & Shigeki Sekine

  7. Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan

    Yukihide Kanemitsu

  8. Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan

    Ryuji Hamamoto

  9. Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Atsuo Takashima

  10. Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan

    Kouya Shiraishi

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Contributions

TH, KS, EM, TK and SS carried out experiments and analysed data. TH, JY, TN, YY and SS performed histological analyses. KN conducted the statistical analysis. TH and SS wrote the manuscript. DT, YK and AT provided clinicopathological and mutation data. RH reviewed the paper. All authors provided critical revisions of the final manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shigeki Sekine.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the National Cancer Center Tokyo, Japan. The study was performed in accordance with the Declaration of Helsinki.

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Hashimoto, T., Takayanagi, D., Yonemaru, J. et al. A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer. Br J Cancer 129, 1176–1183 (2023). https://doi.org/10.1038/s41416-023-02382-z

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