Ki‐67 Dynamics and Biomarker Conversion as Prognostic Factors in Residual Breast Cancer

BACKGROUND: Neoadjuvant chemotherapy (NAC) exerts selective pressure on tumor biology, frequently altering the expression of ER, PR, and HER2 in residual disease. While guidelines mandate re-biopsy to guide adjuvant therapy, whether these biomarker conversions represent a true prognostic deterioration or a manageable adaptation remains controversial. This study investigates the relative prognostic weight of biomarker conversion and proliferative dynamics (Ki-67) in determining patient survival. METHODS: We retrospectively analyzed 338 patients with invasive breast cancer who had residual disease following standard NAC and curative surgery. Paired biomarker status (pre-NAC vs. post-NAC) for ER, PR, HER2, and Ki-67 was evaluated. Adjuvant therapy was adapted according to the residual tumor profile, including targeted therapy for patients acquiring HER2 positivity. Survival outcomes were analyzed using Cox regression models. RESULTS: Biomarker conversion was substantial, with conversion rates of 13.9% for ER, 18% for PR, and 27% for HER2. However, despite this high frequency of receptor conversion, changes in receptor status (loss or gain) did not translate into statistically significant differences in disease-free survival (DFS) or overall survival (OS) (all p > 0.05). In sharp contrast, Ki-67 dynamics emerged as the significant independent prognostic factor. Patients who converted from high-to-low proliferation (Ki-67 < 18%) achieved significantly superior DFS (HR: 0.45, 95% CI: 0.24-0.84, p = 0.011) and OS (HR: 0.36, 95% CI: 0.15-0.85, p = 0.020) compared to those with persistent high expression. CONCLUSION: While biomarker conversion is a frequent event in residual breast cancer, it does not compromise survival outcomes when adjuvant treatment is adjusted according to the post-NAC immunohistochemical (IHC) profile. Instead, prognosis is predominantly driven by the tumor's proliferative response. These findings suggest that persistent high Ki-67, rather than biomarker conversion, should be the primary marker for escalating adjuvant therapy and risk stratification.