Clinical Outcomes and Efficacy of Human Epidermal Growth Factor Receptor 2–Targeted Therapy in Breast Cancer With Uncommon In Situ Hybridization Patterns or Discordant Immunohistochemistry

Abstract

PURPOSE Human epidermal growth factor receptor 2 (HER2)–targeted therapy improves outcomes in HER2+ breast cancer, but efficacy in cases with discordant immunohistochemistry (IHC) and in situ hybridization (ISH) results or with ASCO/College of American Pathologists (CAP) group 2-4 ISH results remains uncertain. METHODS This retrospective study included patients from the National Cancer Database diagnosed from 2013 to 2021. Cases were classified as classically HER2+ (HER2/centromeric region of chromosome 17 [CEP17] ratio ≥2 with HER2 copy number ≥4, IHC 2-3+), HER2– (ratio <2, copy number <4, IHC 0-2+), discordant ISH/IHC, or HER2+ with ISH group 2 (ratio ≥2, copy number <4), group 3 (ratio <2, copy number ≥6), or group 4 (ratio <2, copy number ≥4 and <6) per ASCO/CAP guidelines. Adjusted odds ratio (aOR) for pathologic complete response (pCR) for these subgroups receiving HER2-targeted therapy was calculated compared with HER2– controls. RESULTS We identified N = 144,013 patients with IHC and dual-probe ISH. Of HER2 IHC 3+ cases (n = 8,579), 8.2%, 2.8%, 4.2%, and 8.8% had ISH categorized as groups 2, 3, 4, and 5 (discordant negative), respectively. Classically, HER2+ (aOR, 2.9 [95% CI, 2.65 to 3.18], P < .001) and group 2 (aOR, 2.38 [95% CI, 1.42 to 3.96], P < .001) treated with HER2-targeted therapy had higher pCR than HER2– controls. Benefit was also seen in group 3 (aOR, 1.63 [95% CI, 1.24 to 2.13], P < .001) and cases with discordant ISH+/IHC– (aOR, 1.61 [95% CI, 1.13 to 2.30], P = .008)—but this was only significant in group 3 cases with copy number ≥8 and discordant ISH+/IHC– cases with HER2/CEP17 ratio ≥3. Group 4 ISH cases and cases with ISH–/IHC+ did not benefit. CONCLUSION Patients with ASCO/CAP group 4, discordant ISH–/IHC+ results, and weakly amplified group 3 and discordant ISH+/IHC– have low benefit from HER2 therapy, and alternative approaches for such patients are needed.