The evolution and prognostic impact of HER2‐low, HER2‐ultralow, and HER2‐null status in HER2‐negative early breast cancer: A pre– to post–neoadjuvant chemotherapy study

Abstract Background The prognostic relevance of HER2‐low, HER2‐ultralow, and null status in HER2‐negative early breast cancer (eBC), and its evolution during neoadjuvant chemotherapy (NAC), remains unclear. Methods The authors analyzed 810 HER2‐negative eBC patients (2011–2021) with centrally confirmed pre‐ and post‐NAC HER2 status. Pathologic complete response (pCR, ypT0/is ypN0) rates were analyzed using logistic regression, and invasive disease‐free survival (iDFS) and overall survival (OS) were evaluated via multivariable Cox proportional hazards models. Results HER2‐null tumors demonstrated significantly higher rates of hormone receptor negativity, grade III histology, and Ki‐67 ≥20% compared to HER2‐low subgroup ( p < .05 for all). The pCR rates were 8.4% (HER2‐low), 20.4% (HER2‐ultralow), and 25.0% (HER2‐null), respectively. HER2 expression inversely correlated with pCR rates across the entire cohort (odds ratio, 0.75; 95% confidence interval CI, 0.58–0.98; p for trend = .033). After a median follow‐up of 70.8 months, survival analysis indicated that higher HER2 expression was associated with significantly improved iDFS (hazard ratio, 0.72; 95% CI, 0.62–0.83) and OS (hazard ratio, 0.67; 95% CI, 0.57–0.80) in the overall population ( p for trend <.001 for both). Following NAC, nearly 41.0% of baseline HER2‐null tumors converted to HER2‐low or ultralow status. Notably, post‐NAC HER2 status remained predictive of improved survival in patients with residual disease (iDFS, hazard ratio, 0.72; 95% CI, 0.62–0.84; OS, hazard ratio, 0.65; 95% CI, 0.55–0.78; p for trend <.001 for both). Conclusion HER2 expression levels (low/ultralow/null) stratify prognosis in HER2‐negative eBC. The dynamic evolution of HER2 status following NAC and its prognostic utility highlights the importance of reassessing HER2 status in residual disease in HER2‐negative eBC.