HER2

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

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 anti-apoptosis.

Etiology and Epidemiology

  • Studies suggest that between 7% and 38% of gastroesophageal adenocarcinomas (GEAs) exhibit HER2 amplification or overexpression.3-6
  • Overexpression rates are slightly higher in cancers at the gastroesophageal junction compared to those in the stomach, with variations based on histologic type and differentiation.7
  • In contrast to breast carcinomas, GEA typically displays greater heterogeneity in immunostaining and tiered scoring systems, such as the one used in the ToGA trial (NCT01041404), have been proposed to better define GEA-associated HER2 expression.3,8-10

HER2 Testing

When to Test:

  • HER2 testing should be performed at diagnosis in patients with gastric cancer patients if metastatic disease is confirmed or suspected.7,11

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.7,11
  • 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 cells.7,11
  • Next generation sequencing (NGS) may also be used to identify HER2 amplification.7,11

Testing Guideline Recommendations:

  • Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample.7,11
  • In these cases, comprehensive genomic profiling via a validated NGS assay is advised.7,11
  • Key biomarkers for interrogation include HER2 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, NTRK fusion, RET fusion, and BRAF V600E mutation.7,11
Figure

HER2 Targeted Therapy

Approved Agents:

  • The FDA has approved 2 targeted therapies for HER2+ metastatic CRC.12,13
  • The first of these, trastuzumab, received approval in combination with chemotherapy for use in patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma based on findings from the phase 3 ToGA study (NCT01041404).14,15
  • T-DXd was granted approval for locally advanced or metastatic HER2+ gastric or gastroesophageal (GEJ) adenocarcinoma patients who have received a prior trastuzumab-based regimen, based on findings from DESTINY-Gastric01 (NCT03329690).16

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.17
  • 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).17

Trastuzumab Deruxtecan (T-DXd)13:

  • FDA-Approved Indication:
    • Adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ ISH positive) gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
    • 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.
    • 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.
  • Drug Information:
  • Patient Resources:

Trastuzumab12:

  • FDA-Approved Indication:
    • The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
  • Mechanism of Action:
    • Trastuzumab is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.
    • Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2.
    • Trastuzumab is a mediator of antibody-dependent cellular cytotoxicity (ADCC). In vitro, trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
  • Drug Information:
  • Patient Resources:

References

  1. 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
  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. doi:10.1038/312513a0
  3. Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345-1363. doi:10.5858/arpa.2016-0331-CP
  4. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X
  5. Tanner M, Hollmén M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase II alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16(2):273-8. doi:10.1093/annonc/mdi064
  6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523-1529. doi:10.1093/annonc/mdn169
  7. National Comprehensive Cancer Network. Clinical Practice Guidelines in gastric cancer, version 2.2024. May 29, 2024. Accessed June 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  8. Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Adv Anat Pathol. 2011;18(1):53-59. doi:10.1097/PAP.0b013e3182026d72
  9. Pirrelli M, Caruso ML, Di Maggio M, Armentano R, Valentini AM. Are biopsy specimens predictive of HER2 status in gastric cancer patients? Dig Dis Sci. 2013;58(2):397-404. doi:10.1007/s10620-012-2357-3
  10. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52(7):797-805. doi:10.1111/j.1365-2559.2008.03028.x
  11. National Comprehensive Cancer Network. Clinical Practice Guidelines in esophageal and esophagogastric junction cancers, version 2.2024. April 26, 2024. Accessed June 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
  12. HERCEPTIN (trastuzumab). Prescribing information. Genentech; 2021. Accessed June 12, 2024. https://www.gene.com/download/pdf/herceptin_hylecta_prescribing.pdf
  13. ENHERTU (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo; 2024. Accessed June 12, 2024.https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true
  14. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X
  15. FDA approves Herceptin for HER2-positive metastatic stomach cancer. FiercePharma.com. Updated October 21, 2010. Accessed April 22, 2024. https://www.fiercepharma.com/pharma/fda-approves-herceptin-for-her2-positive-metastatic-stomach-cancer
  16. FDA approved fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA.gov. Updated January 15, 2021. Accessed April 22, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
  17. 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

Additional Reading

Lei YY, Huang JY, Zhao QR, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. World J Surg Oncol. 2017;15(1):68. doi:10.1186/s12957-017-1132-5

Li W, Zhang X, Du Y, et al. HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives. Biomark Res. 2022;10(1):71. doi:10.1186/s40364-022-00416-x

Phillips BE, Tubbs RR, Rice TW, et al. Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction. Dis Esophagus. 2013;26(3):299-304. doi:10.1111/j.1442-2050.2012.01369.x

Radford M, Abushukair H, Hentzen S, Cavalcante L, Saeed A. Targeted and immunotherapy approaches in HER2-positive gastric and gastroesophageal junction adenocarcinoma: a new era. J Immunother Precis Oncol. 2023;6(3):150-157. doi:10.36401/JIPO-22-36

Rüschoff J, Hanna W, Bilous M, et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol. 2012;25(5):637-650. doi:10.1038/modpathol.2011.198

Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476-484. doi:10.1007/s10120-014-0402-y

Wang HB, Liao XF, Zhang J. Clinicopathological factors associated with HER2-positive gastric cancer: a meta-analysis. Medicine (Baltimore). 2017;96(44):e8437. doi:10.1097/MD.0000000000008437