Assessment of Circulating Tumor DNA as a Risk-Stratification Biomarker in Non-Metastatic Triple-Negative Breast Cancer Undergoing Neoadjuvant Chemotherapy

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All articles of this category (opens in new window) Address for correspondence Dirce Maria Carraro (e-mail: dirce.carraro@accamargo.org.br) Introduction: Patients with triple-negative breast cancer (TNBC) who respond favorably to neoadjuvant chemotherapy (NACT) typically exhibit improved outcomes. In contrast, those with residual disease are at higher risk of relapse and show varying outcomes. Therefore, additional biomarkers are needed to refine relapse risk assessment and guide personalized therapeutic strategies. We evaluated the circulating tumor DNA (ctDNA) as a potential risk-stratifying biomarker in TNBC patients characterized for germline homologous recombination deficiency (HRD). Methods: TNBC were classified as HRD-Hereditary or Sporadic by multi-gene genetic testing. Comprehensive Genomic Profiling (CGP) was performed and tumor-acquired variants were tracked in plasma samples by a personalized-amplicon-target-sequencing (PATS) approach. Plasma samples were collected at six timepoints: before treatment (BT), post first block of NACT (pb1N), post-NACT (pN), post-Surgery (pSur), and at two monitoring intervals every three months (M3m and M6m). Results: Among 105 TNBC, 26% were HRD-Hereditary, primarily due to BRCA1 mutations (20%). CGP was performed on 73 tumors, with 12.5% displaying high tumor mutation burden (TMB), not associated with HRD-Hereditary status. Tumor-specific variants were identified in 95% of cases, most frequently in TP53 (84%). Regarding response to NACT, 55% achieved pathological complete response (RCB=0), while 11% had RCB=I, 16% RCB=II, 10% RCB=III and 7% missing RCB score. ctDNA analysis was feasible for 66% (69/105) of cases. Positive ctDNA (ctDNApos) was detected in 63% at BT, 23% at pb1N, 21% at pN, 14% at pSur, 18% at M3m and 24% at M6m. Sporadic tumors had significantly higher ctDNApos rates at BT than HRD-Hereditary tumors. ctDNApos at pN and M6m was associated with RCB=II/III and with disease progression at pNeo, M3m and M6m. RCB=0/1 had high negative predictive value (NPV, 94.1%) for disease progression while RCB=II/III had poor positive predictive value (PPV, 50%). However, combining ctDNApos at pSur with RCB=II/III increased PPV to 80%. Moreover, ctDNApos anticipated progression detection by standard imaging, with a mean lead-time of 4.7 months and was associated with worse progression-free survival, underscoring its potential as a prognostic marker. Conclusions: The combination of ctDNA detection and RCB score improves risk stratification in TNBC patients with residual disease, enhancing prediction of progression and supporting personalized management. Publication History Article published online: 26 June 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil Bibliographical Record Rafael Canfield Brianese, Karina Miranda Santiago, Nathalia de Angelis Carvalho, Marina de Brot, Giovana Tardin Torrezan, Vladmir Claudio Cordeiro de Lima, Solange Moraes Sanches, Maria Nirvana da Cruz Formiga, Fabiana Baroni Alves Makdissi, Dirce Maria Carraro. Assessment of Circulating Tumor DNA as a Risk-Stratification Biomarker in Non-Metastatic Triple-Negative Breast Cancer Undergoing Neoadjuvant Chemotherapy. Brazilian Journal of Oncology 2026; 22. DOI: 10.1055/s-0046-1825211

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