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.

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], < .001) and group 2 (aOR, 2.38 [95% CI, 1.42 to 3.96], < .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], < .001) and cases with discordant ISH+/IHC- (aOR, 1.61 [95% CI, 1.13 to 2.30], = .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.