IHC4 and COMBINE scores for enhanced prognostic stratification in HR+/HER2- breast cancer patients after neoadjuvant chemotherapy.

Background: The prognostic value of pathological complete response (pCR) in HR+/HER2- breast cancer patients following neoadjuvant chemotherapy (NAC) is limited, as many of these patients achieve long-term survival regardless of pCR status. The effectiveness of current tools-residual cancer burden (RCB), the Miller-Payne (MP) score, CPS-EG score and the immunohistochemical 4 (IHC4)-in this subgroup remains uncertain. In this study, we validated the prognostic role of these approaches and developed a COMBINED score capable of more accurately stratifying patients into distinct risk groups, effectively identifying low-risk patients with favorable outcomes who may be suitable for treatment de-escalation.

Methods: This study retrospectively analyzed 601 HR+/HER2- breast cancer patients at Sun Yat-sen Memorial Hospital who did not achieve pCR following NAC. Patients were stratified using the IHC4, RCB, MP, CPS-EG, and a novel COMBINE score (integrating CPS-EG and IHC4). Survival outcomes, including disease-free survival (DFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis and Cox regression, with time-dependent ROC and concordance index (C-index) calculations to assess prognostic performance.

Results: The IHC4 and CPS-EG scores outperformed the RCB and MP scores in predicting DFS and OS for non-pCR HR+/HER2- patients. The COMBINE score further enhanced prognostic accuracy, stratifying patients into four risk groups with significant differences in 5-year DFS (96.5% for low-risk vs. 55.1% for high-risk) and OS (100% for low-risk vs. 63.4% for high-risk). The COMBINE score consistently demonstrated superior AUC and C-index values compared to the CPS-EG and IHC4 scores individually at all time points (all p-values < 0.05).

Conclusion: The IHC4 score adds prognostic value beyond the CPS-EG score in HR+/HER2- breast cancer patients post-NAC. The COMBINE score, integrating both systems, offers superior prognostic stratification, highlighting the importance of combining clinical staging with tumor biology. Future studies with independent datasets are needed to validate these findings. This study provides valuable insights for optimizing treatment decisions in HR+/HER2- breast cancer.