Abstract 2796: ctDNA prognosis in adjuvant triple-negative breast cancer
Authors: Molinero Luciana , Renner Derrick , Wu Hsin-Ta , Qi Nina , Patel Rajesh , Chang Ching-Wei , Sethi Himanshu , Aleshin Alexey , Bais Carlos , Cameron David 
Published: June 2022

Abstract
Background: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, even in early stages. Evidence of molecular residual disease (MRD), after treatment with curative intent (surgery, chemotherapy), predating macroscopic recurrence can provide rationale for early therapeutic intervention, potentially improving patient outcomes. Longitudinal evaluation of circulating tumor DNA (ctDNA) is emerging as a promising early marker of treatment efficacy and recurrence, validated to pre-date recurrence by radiological imaging. However, data in early TNBC (eTNBC) are limited. Here we investigate the prognostic value of longitudinal ctDNA monitoring in eTNBC patients post-surgery and after adjuvant chemotherapy (ACT) using a custom bespoke ctDNA assay.
Methods: Tumor tissue and longitudinal post-surgical plasma samples were collected and analyzed from 186 patients enrolled in the phase 3 BEATRICE clinical study (NCT00528567). Samples from each patient were whole exome sequenced to identify up to 16 SNVs for ctDNA monitoring. ctDNA status was measured longitudinally and correlated with baseline prognostic factors as well as invasive disease free survival (iDFS) and overall survival (OS).
Results: Baseline ctDNA (b-ctDNA), evaluated post-surgery and prior to chemotherapy was detected in 19.9% (36/181) of patients. b-ctDNA was positively associated with large tumors and lymph node (LN) involvement, and negatively correlated with presence of stromal tumor infiltrating lymphocytes (TILs). b-ctDNA presence was a stronger predictor of shorter IDFS and OS compared to LN involvement (HR IDFS: 4.36 [2.47-7.7] vs 1.86 [1.08-3.19]; HR OS: 4.01 [1.6-10.07] vs 2.89 [1.39-6]]), respectively). Remarkably, b-ctDNA prognostic value was restricted to LN+ pts (HR IDFS: 10.94 [3.2-37.41]) vs LN- pts (HR IDFS 1.61 [0.49-5.36]). ctDNA positivity after ACT was observed in 21.5% (40/186) of patients and was associated with reduced IDFS and OS (HR: 8.36 [4.62-15.1] and 18.45 [6.79-50.17]), independent of LN involvement. Upon chemotherapy treatment, the median time to first ctDNA positivity occurrence was 13 months (range 3-42.3 mo) and the median lead time from ctDNA detection to radiographic recurrence was 6.1 months (range 0-30.5 mo). Akaike information criterion (AIC, p&lt;0.05) indicated that ctDNA detected post-surgery or post-chemotherapy identifies patients at the highest risk of disease progression even after adjustment for LN and TILs status as well as the tumor size.
Conclusions: ctDNA, both at post-surgery and post-ACT, provides additional prognostic value beyond the known risk factors of LN involvement, tumor size and TILs. Post-op ctDNA+ provides an independent and stronger indicator of poor prognosis than any other evaluated baseline covariates. Our data show that TNBC pts that are ctDNA+ post-surgery are at the highest risk of recurrence and death and are underserved by current SOC treatment.
Citation Format: Luciana Molinero, Derrick Renner, Hsin-Ta Wu, Nina Qi, Rajesh Patel, Ching-Wei Chang, Himanshu Sethi, Alexey Aleshin, Carlos Bais, David Cameron. ctDNA prognosis in adjuvant triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2796.