Transcriptomic predictors of therapy response across age groups in an omani breast cancer cohort

Breast cancer (BC) exhibits profound heterogeneity influenced by age, intrinsic subtypes, and treatment-induced molecular remodeling. We performed molecular analysis to identify transcriptomic biomarkers predictive of tumor biology, treatment response, and survival outcomes in Omani BC patients. Methods: Archived FFPE tissues from 39 BC patients at Sultan Qaboos University Hospital were analyzed. Transcriptomic profiling using the NanoString Breast Cancer 360 assay was integrated with clinical and pathologic data. Spearman correlations were used to assess the relationships between age and biosignatures. Decision tree models were constructed to identify molecular determinants of (i) treatment allocation across age groups, (ii) pathologic complete response (pCR) versus partial response (pPR), and (iii) survival. Results: Age showed a strong molecular pattern: older patients had higher ESR1, AR, PTEN, stromal, and Claudin-Low expression signatures, while younger patients exhibited higher CD8⁺ T-cell, proliferation, HRD, p53, and BRCAness scores, consistent with a genomically unstable, immune-active phenotype. In early-onset disease, ERBB2 was the dominant treatment classifier, with CDK6 and macrophage signatures further stratifying endocrine versus TNBC chemotherapy; in late-onset tumors, IFN-gamma and SOX2 defined treatment branches, suggesting age-specific immune and stemness programs. Across response strata, pCR was driven by high ERBB2 and CD8⁺-rich immune signatures. In contrast, pPR was characterized by BRCAness and Cell Adhesion, indicating an overlap between HRD-like and adhesion-driven aggressiveness, as well as the impact of targeted therapies, such as trastuzumab, on response. Survival models mirrored this, linking long-term survival to HER2 modulation and immune activation and non-survival to AR and Claudin-Low-like states. Conclusions: In this Omani cohort, age is associated with distinct, contextualized molecular programs. Younger patients exhibit HER2-driven, HRD-enriched, highly proliferative and immune-active biology, while older patients show hormone receptor-dominated, stromal and PTEN-preserved phenotypes. The data obtained indicate that integrating ERBB2 variations, immune metrics, and HRD-like signatures into future risk-adapted strategies in Middle East and North Africa (MENA) populations may be considered for diagnostic and treatment purposes.