Abstract B008: Evaluating ctDNA as a risk-stratifying biomarker in non-metastatic triple-negative breast cancer treated with neoadjuvant chemotherapy
Authors: Brianese Rafael Canfield , Santiago Karina Miranda , de Angelis de Carvalho Nathalia , de Brot Andrade Marina , Torrezan Giovana Tardin , Cordeiro de Lima Vladmir Claudio , Sanches Solange Moraes , Nirvana da Cruz Formiga Maria , Alves Makdissi Fabiana Baroni , Carraro Dirce Maria 
Published: November 2024

Abstract
Introduction: Patients with triple-negative breast cancer (TNBC) who respond well to neoadjuvant chemotherapy (NACT) generally experience favorable outcomes. However, those with residual disease after NACT face a higher risk of relapse and exhibit varying outcomes. Therefore, additional tools for assessing relapse risk are critical for guiding personalized treatment strategies. We aim to investigate the role of circulating tumor DNA (ctDNA) in conjunction with homologous recombination deficiency (HRD) as a risk-stratifying biomarker in TNBC patients with residual disease. Methods: TNBC were classified as HRD-Hereditary or Sporadic using multi-gene genetic testing. Comprehensive Genomic Profiling (CGP) was performed and tumor acquired small variants were tracked in plasma samples by a personalized-amplicontarget-sequencing (PATS) approach. Plasma samples were collected at six key time points: before treatment (BT), after the first block of NACT (ab1Neo), post-completion of NACT (aNeo), after tumor resection (aSur), and at two monitoring intervals every three months (M3m and M6m). Results: Of 105 TNBC patients tested for germline variants, 26% were classified as HRD-Hereditary, primarily due to BRCA1 mutations. 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% (69/73) of cases, with TP53 variants being the most frequent (84%). Regarding response to NACT, 55% (58/105) achieved pathological complete response (RCB=0), while 11% (12/105) had RCB=I, 16% (17/105) RCB=II, 10% (11/105) RCB=III and 7% (7/105) unavailable RCB score. ctDNA analysis was feasible for 62% (65/105) of cases. Positive ctDNA (ctDNApos) was detected in 66.2% (43/65) at BT, 48.4% (30/62) at ab1Neo, 25.4% (15/59) at aNeo, 32.8% (20/61) at aSur, 18.6% (11/59) at M3m and 28.6% (14/49) at M6m. Interestingly, sporadic tumor patients exhibited significantly higher ctDNApos rates compared with HRD-Hereditary tumors at BT, aNeo, and aSur. No significant association was found between ctDNApos at any timepoint and RCB scores. Strong negative predictive value of RCB=0/1 and ctDNAneg aSur for progression was observed (94.2% - 65/69 and 85.4% - 35/41, respectively; mean follow-up 39.7 months, median 36.9 months). In contrast, the positive predictive value for both RCB=2/3 and ctDNApos aSur was relatively low (50% - 14/28; 50% - 10/20, respectively). However, when ctDNApos at aSur were combined with RCB=2/3, the PPV improved to 77.8%. Moreover, ctDNApos was significantly associated with clinical progression at BT (p=0.0359) and aSur (p=0.0053) and consistently anticipated progression detected by standard imaging, with a mean lead-time of 4.7 months. Patients with ctDNApos also demonstrated worse progression-free survival, strongly suggesting its potential as a prognostic marker. Conclusions: ctDNA appears to be a promising risk-stratifying biomarker for TNBC patients with residual cancer, offering valuable insights for tailoring patient management and improving outcomes.
Citation Format: Rafael Canfield Brianese, Karina Miranda Santiago, Nathalia de Angelis de Carvalho, Marina de Brot Andrade, Giovana Tardin Torrezan, Vladmir Claudio Cordeiro de Lima, Solange Moraes Sanches, Maria Nirvana da Cruz Formiga, Fabiana Baroni Alves Makdissi, Dirce Maria Carraro. Evaluating ctDNA as a risk-stratifying biomarker in non-metastatic triple-negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B008.