HER2

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

HER2 Biology

  • ERBB2, commonly referred to as HER2, is a proto-oncogene found on chromosome 17q12 that encodes a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor family.1,2
  • When activated following phosphorylation, the HER2 receptor triggers signaling pathways associated with cell division, proliferation, differentiation, and antiapoptosis.3

Etiology and Epidemiology

  • HER2 alterations in biliary tract cancer (BTC) are associated with shorter disease-free survival, but their impact on overall survival remains unclear.4
  • HER2 overexpression and/or amplification are present in approximately 5% to 20% of cholangiocarcinomas (CCAs) and 15% to 30% of gallbladder cancers.5-12
  • Among CCAs, HER2 overexpression has been reported more frequently among patients with extrahepatic CCA (≈17%) compared to intrahepatic CCA (≈5%).12
  • A strong correlation (75%) between HER2 overexpression and gene amplification has been demonstrated in BTCs.13

HER2 Testing

When to Test:

  • Patients with unresectable or metastatic BTCs who are eligible for systemic therapy should undergo comprehensive molecular profiling at the time of diagnosis.14

Available Testing Methods:

  • HER2 amplification can be identified through immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS) techniques.
  • NGS testing provides the capability to evaluate multiple molecular alterations concurrently and additionally allows for the detection of HER2 activating mutations. This method can be considered as an initial strategy when diagnostic tissue is limited; however, IHC and FISH continue to be the most widely utilized methodologies.
  • While most HER2 alterations are identified as overexpression or amplification, activating missense mutations also represents a significant subset of HER2-altered tumors. These mutations, however, can be missed when relying solely on standard IHC and FISH techniques.
  • Additionally, hepatobiliary malignancies, unlike breast and gastric tumors, lack defined guideline cutoff points and standardized algorithms for assessing HER2 positivity based on protein expression or ERBB2 amplification.14

Guideline Recommendations for Testing:

  • The National Comprehensive Cancer Network (NCCN) guidelines recommend testing for HER2 overexpression and/or amplification in patients with unresectable or metastatic gallbladder cancer, intrahepatic CCA, or extrahepatic CCA.14

HER2-Targeted Therapy

Approved Agents and Tumor Agnostic Approval:

  • In April 2023, T-DXd was granted accelerated approval for previously treated unresectable or metastatic HER2+ (IHC 3+) solid tumors, including biliary tract cancers, with no satisfactory alternative treatment options, marking it as the first tumor-agnostic approved antibody-drug conjugate (ADC).
  • Accelerated approval was based on findings from 3 clinical trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831).15,16

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.13
  • 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.16

Learn more about Fam-Trastuzumab Deruxtecan nxki (T-DXd) >

References

  1. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ERB-B2 receptor tyrosine kinase 2; ERBB2. MIM Number: 164870. Updated September 25, 2024. Accessed October 4, 2024. https://omim.org/entry/164870
  2. Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12(suppl 1):S3-S8. doi:10.1093/annonc/12.suppl_1.s3
  3. 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. doi:10.1038/312513a0
  4. Ayasun R, Ozer M, Sahin I. The role of HER2 status in the biliary tract cancers. Cancers (Basel). 2023;15(9):2628. doi:10.3390/cancers15092628
  5. Lee H, Wang K, Johnson A, et al. Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets. J Clin Pathol. 2016;69(5):403-408. doi:10.1136/jclinpath-2015-203394
  6. Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122(24):3838-3847. doi:10.1002/cncr.30254
  7. Jacobi O, Ross JS, Goshen-Lago T, et al. ERBB2 pathway in biliary tract carcinoma: clinical implications of a targetable pathway. Oncol Res Treat. 2021;44(1-2):20-27. doi:10.1159/000511919
  8. Xian ZH, Zhang SH, Cong WM, Wu W-Q, Wu M-C. Overexpression/amplification of HER-2/neu is uncommon in hepatocellular carcinoma. J Clin Pathol. 2005;58:500-503. doi:10.1136/jcp.2004.023556
  9. Hiraoka N, Nitta H, Ohba A, et al. Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer. Hum Pathol. 2020;105:9-19. doi:10.1016/j.humpath.2020.08.006
  10. Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015;34(1):157-164. doi:10.1007/s10555-015-9552-6
  11. Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9(12):e115383. doi:10.1371/journal.pone.0115383
  12. Galdy S, Lamarca A, McNamara MG, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev. 2017;36(1):141-157. doi:10.1007/s10555-016-9645-x
  13. Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206(3):356-365. doi:10.1002/path.1779
  14. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 4.2024. Accessed October 4, 2024. https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf
  15. FDA.gov. FDA grants 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
  16. ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo; 2024. Accessed October 4, 2024. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true