ERBB2 (HER2)

  • ERBB2 (erb-b2 receptor tyrosine kinase 2), also called HER2 or neu, encodes a transmembrane receptor tyrosine kinase of the epidermal growth factor receptor (EGFR) family.1,2
  • Gene Location: Chromosome 17 (17q12).1

Biology

  • HER2 is a proto-oncogene product with no ligand-binding domain of its own; it heterodimerizes with ligand-bound family members, enhancing MAPK and PI3K signaling that drives proliferation, differentiation, and resistance to apoptosis.2,3
  • In urothelial carcinoma, HER2 expression is associated with luminal/urothelial-like and genomically unstable subtypes and is enriched in micropapillary histology.4,5

Etiology and Epidemiology

  • HER2 expression is common but varies by series: overexpression is reported in 9% to 61% of bladder cancers; in one series of 284 patients, 44% had IHC 2+/3+ (51% bladder vs 38% upper tract).6
  • IHC 3+: 41% of 105 specimens scored IHC 3+ with gastric (upper GI) criteria vs 34% with breast criteria in a 2026 series; IHC 3+ was enriched in micropapillary (79%) and plasmacytoid (60%) tumors and brain metastases (40%).5
  • ERBB2 amplification: 7.4% of 820 cystectomy specimens by FISH (micropapillary 19%, conventional urothelial carcinoma 8%) and 12.4% of nodal metastases.7

Testing

When to Test:

  • Patients with unresectable or metastatic urothelial carcinoma who have received prior systemic therapy and are being considered for trastuzumab deruxtecan.8

Testing Methodologies:

  • Immunohistochemistry (IHC): there is no urothelial-specific HER2 scoring system. DESTINY-PanTumor02 used ASCO/CAP gastric cancer scoring criteria with central HercepTest testing; breast and gastric criteria give divergent scores in a meaningful subset of urothelial tumors.5,9
  • Heterogeneity: HER2 expression varies spatially within tumors (multiple biopsies improve accuracy), and nodal metastases can show higher expression and amplification than primaries.4,7
  • Local vs central concordance: in DESTINY-PanTumor02, local and central results agreed for 58.6% of IHC 3+ and 54.5% of IHC 2+ cases.10
  • Companion diagnostic: none. The label states that an FDA-authorized test for HER2-positive (IHC 3+) solid tumors is not currently available. NGS can detect ERBB2 amplification or mutation but does not replace IHC.8

Guideline Recommendations

  • NCCN (Bladder Cancer, V.2.2026): lists fam-trastuzumab deruxtecan as biomarker-directed therapy for HER2-positive (IHC 3+) disease and notes it may be useful in certain circumstances for IHC 2+ disease without other satisfactory options; gastric IHC scoring is recommended.11

Targeted Therapy

Approved Agents

Tumor-Agnostic Approval:

Fam-Trastuzumab Deruxtecan-nxki (Enhertu)

FDA-Approved Indication:

  • As monotherapy for adults with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative options (accelerated approval, April 5, 2024).8

Mechanism of Action:

  • Humanized anti-HER2 IgG1 antibody linked through a cleavable tetrapeptide linker to deruxtecan, a topoisomerase I inhibitor. After internalization, the linker is cleaved and the payload causes DNA damage and apoptosis.8

Drug Information: Learn more about Fam-Trastuzumab Deruxtecan ›

Patient Resources: https://www.enhertu.com/

Investigational Agents

  • Disitamab vedotin: HER2-directed ADC, not FDA approved. It received Breakthrough Therapy designation (2020) for previously treated HER2-positive urothelial carcinoma. In the phase 3 RC48-C016 trial in China, disitamab vedotin plus toripalimab improved PFS (13.1 vs 6.5 months; HR, 0.36) and OS (31.5 vs 16.9 months; HR, 0.54) vs chemotherapy in first-line HER2-expressing urothelial carcinoma. The global phase 3 SGNDV-001 trial with pembrolizumab (NCT05911295) is ongoing.12,13

References

  1. HGNC. ERBB2 (HGNC:3430). Accessed October 2026.
  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. Dernbach G, Eich ML, Dragomir MP, et al. Spatial expression of HER2, NECTIN4, and TROP-2 in muscle-invasive bladder cancer and metastases: implications for pathological and clinical management. Mod Pathol. 2025;38(7):100753. doi:10.1016/j.modpat.2025.100753
  5. Bhardwaj S, Morris E, Halthore A, et al. Assessing human epidermal growth factor receptor 2 in urothelial carcinoma: insights from clinical practice into scoring criteria, histologic subtypes, and genomic characteristics across disease sites. Arch Pathol Lab Med. Published online June 30, 2026. doi:10.5858/arpa.2025-0386-OA
  6. Zhou L, Shao Z, Liu Y, et al. HER2 expression associated with clinical characteristics and prognosis of urothelial carcinoma in a Chinese population. Oncologist. 2023;28(8):e617-e624. doi:10.1093/oncolo/oyad070
  7. Cheville JC, Tekin B, Orme JJ, et al. ERBB2 copy number alterations and protein expression in bladder cancer treated by cystectomy. Hum Pathol. 2026;176:106217. doi:10.1016/j.humpath.2026.106217
  8. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection. Prescribing information. Daiichi Sankyo, Inc; revised 05/2026. Accessed October 2026.
  9. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  10. Makker V, Lee JY, Oh DY, et al. Post hoc analysis of the phase II DESTINY-PanTumor02 study: local and central HER2 IHC concordance and trastuzumab deruxtecan efficacy by HER2 IHC status in HER2-expressing solid tumors. Clin Cancer Res. 2026;32(13):2628-2636. doi:10.1158/1078-0432.CCR-25-4702
  11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.
  12. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. 2025;393(23):2324-2337. doi:10.1056/NEJMoa2511648
  13. ClinicalTrials.gov. SGNDV-001 (NCT05911295). Accessed October 2026.