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

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.