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

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.

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.

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.

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.