HER2

Human epidermal growth factor receptor2 (HER2); erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERB-B2) 

HER2 Biology

The HER2 oncogene, located on chromosome 17q12, encodes a transmembrane tyrosine kinase receptor that is part of the epidermal growth factor receptor family.1,2 HER2 initiates downstream signaling pathways related to cell proliferation by forming homodimers or heterodimers with other EGFR family members.3 Amplification or overexpression of HER2 results in the increased activation of mitogenic signaling, leading to uncontrolled cell proliferation and tumorigenesis. In colorectal cancer (CRC) HER2 amplification is more frequently observed in distal (rectal) and left-sided tumors, while being less common in proximal and right-sided CRC.4-7 HER2-amplified CRC is also associated with a greater number of metastatic sites, particularly lung and brain metastases. While the prognostic significance of HER2 amplification in CRC remains unclear, it may serve as a predictive marker for resistance to anti-EGFR therapies.7,8 HER2 amplification or overexpression occurs in approximately 3-5% of metastatic CRC, with a higher reported prevalence in RAS/BRAF wild type tumors.3,9

HER2 Testing

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in colon and rectal cancer, recommend testing for HER2 amplification in patients with metastatic CRC and no KRAS/NRAS or BRAF mutations.9,10 Testing for HER2 overexpression is generally performed via immunohistochemistry (IHC) assays, with positivity defined as 3+ staining in greater than 50% of tumor cells. Reflex testing with fluorescence in situ hybridization (FISH) is recommended in patients with IHC 2+ to identify HER2 amplification, with positivity defined as a HER2:CEP17 ratio greater than or equal to 2 in more than 50% of tumor cell. Next generation sequencing (NGS) may also be used to identify HER2 amplification.

HER2 Targeted Therapy

The FDA has approved two targeted therapies for HER2+ metastatic CRC.11,12 The first of these, tucatinib, is a HER2-targeted tyrosine-kinase inhibitor. Tucatinib received accelerated approval in combination with the anti-HER2 monoclonal antibody, trastuzumab, for RAS wild-type HER2+ unresectable or metastatic CRC that has progressed on chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan.13 This approval was based on findings from the phase 2 MOUNTAINEER study.Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 antibody linked to the topoisomerase I inhibitor payload, deruxtecan, via a cleavable tetrapeptide linker.12 Upon binding of HER2 on tumor cells, T-DXd undergoes internalization and intracellular linker cleavage, thereby releasing the DXd payload and subsequently causing DNA damage and apoptotic cell death. T-DXd was granted accelerated approval for previously treated unresectable or metastatic HER2+ (IHC 3+) solid tumors with no satisfactory alternative treatment options, marking it as the first tumor-agnostic approved ADC. Accelerated approval was based on findings from three clinical trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).14

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References

  1. Rubin I and Yarden, Y. The basic biology of HER2. Ann Oncol. 2001;12(supp1):S3-S8.
  2. Schechter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513‐516.
  3. Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in colorectal cancer: the long and winding road from negative predictive factor to positive actionable target. Am Soc Clin Oncol Educ Book.2022;42:1-14. doi: 10.1200/EDBK_351354.
  4. Sartore-Bianchi A, Lonardi S, Martino C, et al. Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial. ESMO Open. 2020;5:e000911.
  5. Siena S, Di Bartolomeo M, Raghav K, et al; DESTINY-CRC01 investigators. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2021;22:779-789.
  6. Strickler JH, Ng K, Cercek A, et al. MOUNTAINEER: open-label, phase II study of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017, trial in progress). J Clin Oncol. 2021;39:3s (suppl; abstract TPS153).
  7. Sartore-Bianchi A, Amatu A, Porcu L, et al. HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist. 2019;24:1395-1402.
  8. Raghav K, Loree JM, Morris JS, et al. Validation of HER2 amplification as a predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. JCO Precis Oncol.2019;3:1-13. doi: 10.1200/PO.18.00226.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in colon cancer, version 1.2024. Accessed April 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in rectal cancer, version 1.2024. Accessed April 22, 2024. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf 
  11. TUKYSA (tucatinib) [package insert].Bothell, WA, USA: Seagen Inc., 01/2023.
  12. ENHERTU (fam-trastuzumab deruxtecan-nxki) [package insert].Basking Ridge, NJ, USA: Daiichi Sankyo, Inc., 02/2024.
  13. FDA.gov. FDA grant accelerated approval to tucatinib with trastuzumab for colorectal cancer.Updated January 19, 2023. Accessed April 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer 
  14. FDA.gov. FDA grant accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. Updated April 5, 2024. Accessed April 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2