Abstract
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.
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The authors would like to thank Boaz Kuiper, Evy Verstraaten, Tara Love, Shweta Venkatakrishan and Leendert Vermeulen from Roche for their guidance during the DNA sequencing process, and Zeliha Ozgur and Zakia Azmani for helping with the DNA processing and sequencing. Moreover, we would like to thank Angelique van der Made, Thierry van den Bosch and Karishma Lila from Erasmus MC Pathology Research and Trial Service (PARTS) for helping with cutting and staining of all FFPE slides. We thank ZonMW for funding this project. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.
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Roche delivered the materials for DNA isolation and sequencing; however, this did not have any influence on the substantive matters within this article. C.H.M. van Deurzen has received research funding from AstraZeneca, which was unrelated to this project. R. Debets received research support from MSD and Bayer, personal fees from Bluebird Bio, Genticel, other support from Pan Cancer T, which was unrelated to the submitted work (all paid to the Erasmus MC Cancer Institute), as well as European patent application nos. 21152822.9, 24192717.7, and 25163944.9 (pending to Erasmus MC). J.W.M. Martens received research funding from Menarini, Tzu genomics, MSD, and Pfizer, and a consultancy fee from Novartis; these were all unrelated to this project. All the other authors declare no potential competing interests.
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van den Ende, N.S., Smid, M., Martens, J.W.M. et al. Molecular profile of residual triple-negative breast cancer: opportunities for post-neoadjuvant therapeutic interventions. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00964-7
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DOI: https://doi.org/10.1038/s41523-026-00964-7
