Discussion
tumor, Breast Cancer, breast cancer, TNBC, breast cancer-related
DISEASE PROGRESSION, BREAST CANCER, METASTASIS, TUMOR, RECURRENCE, BREAST CANCER, DISEASE, REGRESSION, EVENTS
In this exploratory analysis of the NACATRINE trial, we employed a commercial human breast cancer-specific gene expression assay to establish candidate biomarkers for pCR and long-term outcomes in women with TNBC treated with two different schedules of NAC. This assay of 776 genes, which targets various biological mechanisms, has been successfully employed in other pivotal studies, such as the Finland Capecitabine (FinXX) trial, in which patients were randomized to receive anthracycline-/taxane-based adjuvant chemotherapy with or without capecitabineWe identified 24 differentially expressed genes that appeared to indicate higher odds of pCR in the entire study cohort (i.e., independent of the treatment arm). These genes, according to the nCounter® Breast Cancer 360™ panelOther studies have investigated the predictive role of gene signatures in early-stage TNBC with variable resultsIn the present study, the multivariate logistic regression model with the genes Furthermore, we identified gene signatures potentially predictive of the response to carboplatin, with 10 (By annotating the KEGG pathway, we identified several alterations with potential clinical implications. The Notch signaling pathway, for instance, has been considered important in breast cancer because of its potential role in drug resistanceRegarding individual gene alterations found in this study, we highlight those related to genes whose upregulation has been historically associated with a worse prognosis because of their role in disease progression, invasion, and metastasis. On the other hand, the upregulation of aldehyde dehydrogenase 1A1 (Fibrinogen-like protein 2 (Among the limitations of this study, we highlight the limited sample size, the fact that the analyses were exploratory in nature (i.e., not a primary outcome of the study), and the fact that genes/pathways not covered by the commercial assay employed were potentially not covered. Additionally, it is important to note that the correction for False Discovery Rate (FDR) was not feasible due to resource limitations and the exploratory nature of the analysis. However, as strengths of the study, we emphasize that this translational research analysis was prospectively planned and methodologically robust. We employed a standardized, breast cancer-specific, and widely recognized assay, and the tumor samples were derived from a prospective randomized clinical trial. Furthermore, the inclusion of participants with advanced disease stage and young age led to several early recurrence events, which allowed for the OS and DFS analyses presented herein, despite the relatively short follow-up time.The identification of clinically useful biomarkers has been challenging owing to various limitations, such as tumor heterogeneity, which is why single biomarkers tend to have insufficient sensitivity and specificity to predict response to therapy and tumor behavior. In recent years, with the advancement of research and technology, it has become possible to identify gene expression signatures, some of which are now commercially available in standardized gene assaysIn summary (Fig. Graphical summary of the identification of differentially expressed genes as a pCR biomarker in a tissue biopsy specimen in the NACATRINE study. Step 1, genetic material was separated from tissue biopsy samples. Step 2 involved using a composite panel of breast cancer-related genes for gene expression profiling. Step 3 in the NACATRINE trial population, we identified a signature of 10 downregulated genes that have potential as accurate biomarkers for paclitaxel + carboplatin treatment, allowing differentiation between patients achieving pCR and those with RD. Furthermore, for the paclitaxel treatment arm, we identified 3 upregulated genes as potential pCR biomarkers.