HER2

  • Human epidermal growth factor receptor2 (HER2); erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERB-B2) 
  • Gene location: chromosome 17 (17q12)

Biology

  • The HER2 oncogene 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.

Etiology and Epidemiology

  • 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

Testing for HER2 Amplification

When to Test:

  • All patients with metastatic CRC should receive molecular testing for HER2 amplification at the time of diagnosis.9,10

Available Testing Methods:

  • Testing for HER2 overexpression is generally performed via immunohistochemistry (IHC) assays, with positivity defined as 3+ staining in greater than 50% of tumor cells.9,10
  • 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.9,10
  • Next generation sequencing (NGS) may also be used to identify HER2 amplification.9,10

Guideline Recommendations for Testing:

  • All patients with mCRC should undergo testing for KRAS/NRAS and BRAF mutations, HER2 amplifications, and MSI/MMR status; testing may be performed individually or via NGS (preferred).9,10

HER2 Targeted Therapy

Approved Agents:

  • The FDA has approved two targeted therapies for HER2+ metastatic CRC, tucatinib in combination with trastuzumab and trastuzumab deruxtecan.11,12
  • On January 19, 2023, the FDA granted accelerated approval to tucatinib 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 (NCT03043313).

Tumor Agnostic Approval:

  • On April 5, 2024, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.14
  • Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).14

Trastuzumab Deruxtecan (T-DXd)12:

  • FDA-Approved Indication:
    • Adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
  • Mechanism of Action:
    • Trastuzumab deruxtecan (T-DXd) is a HER2-directed 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 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.12
  • Drug Information:
  • Patient Resources:

Tucatinib11:

  • FDA-Approved Indication:
    • In combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
  • Mechanism of Action:
    • Tucatinib is a tyrosine kinase inhibitor of HER2.
    • In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells.
    • In vivo, tucatinib inhibited the growth of HER2 expressing tumors.
    • The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
  • Drug Information:
  • Patient Resources:

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). Prescribing information. Bothell, WA, USA: Seagen Inc., 2023. https://docs.seagen.com/TUKYSA_Full_Ltr_Master.pdf
  12. ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Basking Ridge, NJ, USA: Daiichi Sankyo, Inc., 2024. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
  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