Abstract P2-01-06: Detection of circulating tumor DNA post neoadjuvant chemotherapy using a personalized assay is associated with disease relapse
Authors: Elisa Agostinetto, Frédéric Cailleux, Matteo Lambertini, Françoise Rothé, Hsin-Ta Wu, Mustafa Balcioglu, Himanshu Sethi, Delphine Vincent, Giulia Viglietti, Andrea Gombos, Andreas Papagiannis, Isabelle Veys, Ahmad Awada, Christos Sotiriou, Ekaterina Kalashnikova, Alexey Aleshin, Denis Larsimont, David Venet, Michail Ignatiadis
Journal: Cancer Research (2022)

Abstract Background: Approximately 30% of patients with early breast cancer present disease relapse after surgery, and technologies that enable the detection of circulating tumor DNA (ctDNA) were shown to identify them earlier than standard imaging. In the present study, we aimed to interrogate the value of the SignateraTM personalized ctDNA assay for early detection of disease relapse. Methods: The study included 52 early breast cancer patients undergoing neoadjuvant chemotherapy from an ongoing translational, single-center study at Jules Bordet Institute, Brussels, Belgium. From each patient, primary tumor tissue sections, blood sample for normal DNA, and serial plasma samples were sent to NATERA Inc for ctDNA detection using the SignateraTM assay. Plasma samples were collected before the initiation of neoadjuvant chemotherapy (baseline), after neoadjuvant chemotherapy, before surgery (pre-surgery), and at follow-up post-surgery. Whole exome sequencing (WES) was performed on the primary tumor tissue and matched normal DNA to design a patient-specific ctDNA assay. The unique set of SNV’s identified in WES were tracked in serial plasma samples. Associations between baseline ctDNA detection and standard clinicopathological characteristics and primary tumor point mutations or copy number aberrations were evaluated. Association between ctDNA detection, pathological complete response (pCR) and event-free survival (EFS) were explored. Fisher, Mann-Whitney and Kruskal-Wallis tests were used to compare variables. Log-rank tests and Cox regressions were used for survival analyses. Hazard ratios (HRs) and confidence intervals (CIs) were obtained from Cox regressions. For multivariable tests, logistic regressions were used for binary outcomes and Cox regressions for survival outcomes. P-values were obtained by comparing models with and without the variable of interest using Chi-square test in ANOVAs. Results: Forty-four out of 52 (85%) initially selected patients had the required tumor cellularity (≥ 20%) and adequate tumor DNA quantity and quality and had personalized ctDNA assays designed. In these 44 patients, 154 plasma samples were successfully processed including 38, 41, 75, 38 at baseline, pre-surgery, follow-up (any timepoint) and last follow-up timepoint, respectively. Twenty (45%) patients had hormone receptor positive/HER2-negative, 13 (30%) triple-negative and 11 (25%) HER2-positive breast cancers. Detection of ctDNA was observed in 22 of 38 (58%) patients at baseline and was significantly associated with Ki67&amp;gt;20% and MYC copy number gain in the primary tumor. ctDNA detection at pre-surgery and at last follow-up was observed in 2 of 41 (5%) and 2 of 38 (5%) patients respectively. All patients who achieved pCR were ctDNA-negative at the pre-surgical time point. With a median follow-up of 3.03 years (range 0.39 - 5.85), we observed 8 relapses (7 distant and 1 local, respectively). After adjusting for pCR, ctDNA detection was associated with shorter EFS at pre-surgery and at last follow-up time points (HR: 53, 95% CI: 4.5-624, p&amp;lt;0.01, and HR: 31, 95% CI: 2.7-352, p&amp;lt;0.01, respectively), but not at baseline (HR: 1.4, 95% CI: 0.3-5.9, p=0.67). Conclusions: The detection of ctDNA post neoadjuvant chemotherapy is associated with disease relapse in early breast cancer supporting interventional trials in this setting. Citation Format: Elisa Agostinetto, Frédéric Cailleux, Matteo Lambertini, Françoise Rothé, Hsin-Ta Wu, Mustafa Balcioglu, Himanshu Sethi, Delphine Vincent, Giulia Viglietti, Andrea Gombos, Andreas Papagiannis, Isabelle Veys, Ahmad Awada, Christos Sotiriou, Ekaterina Kalashnikova, Alexey Aleshin, Denis Larsimont, David Venet, Michail Ignatiadis. Detection of circulating tumor DNA post neoadjuvant chemotherapy using a personalized assay is associated with disease relapse [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-06.