EGFR

  • Epidermal growth factor receptor (EGFR, ERBB1)
  • Gene location: chromosome 7p11.2

Biology

  • The EGFR gene, located on chromosome 7, encodes the epidermal growth factor receptor (ERBB1), a transmembrane receptor tyrosine kinase involved in oncogenic signaling.
  • EGFR regulates key cellular processes including proliferation, survival, adhesion, migration, and differentiation.1
  • Upon activation by ligand binding, EGFR initiates downstream signaling cascades such as RAS/RAF/MEK/ERK and PI3K/AKT, contributing to tumor development and progression.2
  • EGFR is commonly overexpressed or dysregulated in various solid tumors, including gastric and gastroesophageal adenocarcinomas.2-4
  • Activating mutations in EGFR are rare in gastric cancer; dysregulation is more often driven by gene amplification or protein overexpression.5

Etiology and Epidemiology

  • In gastric cancer, EGFR overexpression has been described in approximately 27% to 64% of tumors.2,4
  • EGFR overexpression is more commonly seen in the intestinal subtype of gastric cancer and is associated with advanced stage at diagnosis and lymph node metastasis.3,4
  • EGFR gene amplification occurs in approximately 5% to 10% of gastric cancers and, if present, may have the ability to predict resistance to standard chemotherapy.5,6
  • Prognosis is generally worse in EGFR-positive gastric cancers, particularly in patients with HER2-negative disease, who lack effective targeted treatment options.4,5

EGFR Testing

When to test:

  • Although not mandated for all patients with gastric cancer, EGFR testing is strongly recommended in the research or clinical trial setting.6
  • Those with advanced refractory or HER2-negative disease may be appropriate candidates for EGFR-targeted strategies.6

Available Testing Methods:

  • Immunohistochemistry (IHC) remains the standard approach for evaluating EGFR protein expression in tumor tissue.3
  • Fluorescence in situ hybridization (FISH) and polymerase chain reaction or next-generation sequencing assays are employed to assess EGFR gene amplification or copy number alterations.5,7
  • In clinical trials, tumors exhibiting IHC 2+ or 3+ expression are generally classified as EGFR positive and may qualify for enrollment in EGFR-directed therapeutic studies.8

Guideline Recommendations:

  • National Comprehensive Cancer Network guidelines (2025) recommend no routine EGFR testing in gastric cancer outside clinical trials.6
  • However, when EGFR is the therapeutic target, EGFR testing may be requested as part of biomarker-driven patient stratification for trial eligibility.

Targeted Therapy

Approved Agents:

  • As of 2024, no EGFR inhibitors have received FDA approval for gastroesophageal or gastric cancers.6
  • EGFR-targeted agents like cetuximab, panitumumab, and gefitinib have shown modest clinical benefit in unselected gastric cancer populations.5

Investigational Agents:

  • Nimotuzumab8
    • Nimotuzumab, an EGFR humanized monoclonal antibody, has shown clinical activity in metastatic gastric cancer with overexpression of EGFR.
    • In a phase 2 randomized trial, nimotuzumab and irinotecan showed an objective response rate (ORR) of 33.3% in patients with EGFR IHC 2+/3+ tumors compared with 0% with irinotecan alone.
    • Nimotuzumab is generally well tolerated and may be considered as an investigational option for patients with EGFR-positive tumors when standard therapies are unavailable or exhausted.
  • Mechanism of Action7,8
    • EGFR-targeted drugs inhibit ligand-induced receptor dimerization and autophosphorylation, thereby suppressing downstream oncogenic signaling.
    • Monoclonal antibodies such as nimotuzumab can also induce antibody-dependent cellular cytotoxicity, facilitating immune-mediated killing of tumor cells.
    • Nimotuzumab’s moderate binding affinity is associated with a more favorable safety profile, with reduced skin and gastrointestinal toxicities compared with those associated with other EGFR inhibitors.

Investigational Study:

  • Phase 3 trial9
    • ClinicalTrials.gov: NCT01813253
    • Study design: randomized, open-label, phase 3 study comparing nimotuzumab plus irinotecan vs irinotecan alone in previously treated EGFR-positive advanced gastric or gastroesophageal junction adenocarcinoma. While terminated, it confirms the investigational strategy.

References

  1. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2-16. doi:10.1016/j.gene.2005.10.018
  2. Lordick F, Shitara K, Janjigian YY. New agents on the horizon in gastric cancer. Ann Oncol. 2017;28(8):1767-1775. doi:10.1093/annonc/mdx051
  3. 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
  4. Yoon HH, Shi Q, Sukov WR, et al. Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma. J Clin Oncol. 2012;30(32):3932-3938. doi:10.1200/JCO.2012.43.1890
  5. 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
  6. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2024. Accessed June 19, 2025.https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  7. Spano JP, Fagard R, Soria JC, Rixe O, Khayat D, Milano G. Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives. Ann Oncol. 2005;16(2):189-194. doi:10.1093/annonc/mdi057
  8. Satoh T, Lee KH, Rha SY, et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2015;18(4):824-832. doi:10.1007/s10120-014-0420-9
  9. Phase 3 study of nimotuzumab and irinotecan as second line with advanced or recurrent gastric and gastroesophageal junction cancer. Clinicaltrials.gov. Updated March 26, 2018. Accessed June 19, 2025. https://clinicaltrials.gov/study/NCT01813253