Tailoring treatment in early-stage breast cancer: The identification of prognostic and predictive biomarkers in HER2-negative and triple-negative breast cancer

Abstract

This thesis focuses on identifying prognostic and predictive biomarkers that may guide treatment decisions for patients with early-stage HER2-negative breast cancer (BC) or triple-negative BC (eTNBC). We studied the value of histopathologic tumor traits, in addition to stromal-compartment tumor infiltrating lymphocyte (sTIL) levels, in the risk stratification of young patients with node-negative eTNBC who did not receive adjuvant systemic treatment. Lymphovascular invasion and fibrotic focus showed independent prognostic value for breast cancer-specific survival. Furthermore, we described that BCs with the expression of the meiotic DNA break regulator HORMAD1 are associated with homologous recombination deficiency (HRD) and show clinicopathological and genomic instability characteristics resembling those of BRCA1-mutated BCs. Moreover, we observed that in the early disease setting, HORMAD1-positivity was predictive for benefit of high-dose platinum-based chemotherapy (HDCT) compared to conventional non-platinum-based chemotherapy in a subgroup of patients with high-risk HER2-negative BC participating in the N4plus Dutch trial. Last, we studied a subgroup of patients with eTNBC participating in the phase III FinXX trial, randomized between adjuvant capecitabine-containing and conventional chemotherapy. Adjuvant capecitabine appeared to improve recurrence-free survival in patients with non-BRCA1-like tumors, while this survival benefit was less clear in patients with BRCA1-like tumors. Together, the work described in this thesis may, if confirmed in independent series, contribute to optimizing risk stratification of patients with eTNBC and may help to guide the allocation of (neo)adjuvant treatment strategies for individual patients.