Molecular profile of residual triple-negative breast cancer: opportunities for post-neoadjuvant therapeutic interventions

A subset of triple negative breast cancer (TNBC) patients shows resistance to standard neoadjuvant chemotherapy (NAC), resulting in high relapse and mortality risk. This highlights the need for predictive biomarkers and alternative treatment strategies. Targeted molecular profiling was performed on post-NAC resection specimens from 138 TNBC patients, diagnosed across multiple centers between 2013 and 2022, all exhibiting extensive poor response, defined as >50% residual tumor and the development of distant metastasis. Integrated immunohistochemistry and genomic analyses were conducted to identify potentially targetable alterations. Most post-NAC TNBCs (60%) were HER2-ultralow or HER2-low. Among 85 patients with successful DNA sequencing, 2640 variants were detected, with TP53 mutations being most frequent (94%). Mutation count ranged from 3 to 1668 per patient (median n = 11). Several altered genes, including ERBB2, BRCA1/2, PIK3CA, and RB1, have been associated with favorable responses to targeted therapeutics in clinical trials. Moreover, 208 potential neo-peptide targets (median per patient n = 3) were detected across recurrently mutated genes such as ATM, CREBBP, IRS2, KEAP1, MSH6, NOTCH1, NOTCH2, POLD1, TP53, and TSC2. Molecular profiling of residual disease in extensively poor responding TNBC post-NAC revealed multiple potentially targetable variant, supporting the use of next-generation sequencing to guide personalized strategies for these high-risk TNBC patients.