A Five-Biomarker IHC-Based Signature Predicting Outcome in Breast Cancer Patients Following Adjuvant...

Background/Objectives: Breast cancer remains the leading cause of cancer-related death among women worldwide. While tools such as Adjuvant Online, PREDICT, OncotypeDx and Mammoprint identify patients at higher risk of relapse who should therefore be offered chemotherapy, there are currently no tools to accurately predict response to chemotherapy, with varied response rates (regardless of subtypes, etc.) of 8-70% reported. Accurately stratifying patients based on their likelihood of benefiting from SoC chemotherapy is therefore critical to guide personalised treatment decisions. Methods: A retrospective cohort of 293 breast cancer patients treated with SoC adjuvant anthracycline-based regimen was analysed. Five biomarkers (TOP2A, PTEN, EGFR, IGF1R, and phospho-mTOR), selected for their prognostic and therapeutic relevance, were assessed using immunohistochemistry (IHC) combined with digital pathology. Results: Biomarker expression was quantified using the digital pathology platform, QuPath, with each marker, when stratified based on high/low expression, demonstrating a significant association with relapse-free survival following SoC chemotherapy in specific subtypes of breast cancer. A composite five-biomarker signature was then generated by integrating the individual biomarker scores to improve prognostic precision. Patients with a five-biomarker signature score greater than zero exhibited a significantly higher likelihood of favourable outcomes following anthracycline-based chemotherapy compared with those with a score of zero or below. Conclusions: This study establishes a novel IHC-based five-biomarker signature capable of predicting patient outcome in the context of SoC chemotherapy. As the signature relies exclusively on IHC, it is simple, cost-effective and readily integratable into routine diagnostic workflows. In addition to its prognostic value, several biomarkers within the panel are potentially actionable, offering opportunities to guide targeted therapies in patients predicted to have poor response to conventional chemotherapy.