Abstract PS06-08: Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort
Authors: Elliott Mitchell , Antras Jesus Fuentes , Echelard Philippe , Dou Aaron , Veitch Zachary , Bedard Philippe , Amir Eitan , Nadler Michelle , Meti Nicholas , Gregorio Nancy , Shah Elizabeth , Yu Celeste , Campbell Nathan , Pipinikas Christodoulos , Howarth Karen , Siu Lillian , Berman Hal , Cescon David 
Published: May 2024

Background:

ctDNA is detectable in early breast cancer (EBC) using sensitive assays and treatment-related changes in ctDNA are associated with clinical response. RaDaR® (NeoGenomics), a tumor-informed assay, has been shown to detect circulating tumor DNA (ctDNA) prior to clinical recurrence. We retrospectively quantified ctDNA using RaDaR in serial samples from a large cohort of patients with EBC receiving standard neoadjuvant therapy (NAT).

Methods:

Unselected patients with EBC were enrolled prior to NAT in the TRACER cohort from 2015 onwards. Plasma samples were collected at baseline, during treatment, perioperatively, and in follow-up. For patients with available tissue for assay generation, RaDaR was performed on all available plasma timepoints. Clinical and pathologic characteristics (assessed on core biopsy), treatment, and outcomes were recorded.

Results:

Of 128 patients evaluated, 9 (7.0%) were excluded from this analysis due to panel quality control metrics, leaving 119 patients (41 ER+, 32 TNBC, 46 HER2+) with 681 individual timepoints (median=6, range: 1-12). 103/119 patients (86%) received neoadjuvant anthracycline- and taxane-based chemotherapy. Median followup from diagnosis was 3.8 years (range: 0.6-6.3 years) and 16 recurrences have occurred (9 ER+, 6 TN, 1 HER2+). 114 patients had a baseline plasma sample collected prior to NAT, in which the detection rate was 77% (70% ER+, 90% TNBC, 76% HER2+), with a median estimated variant allele frequency (eVAF) of 0.0823% (range: 2.90E-5 - 7.5%). All patients with clinical recurrence had ctDNA detected at baseline. Baseline detection was associated with tumor grade (p=0.050) but not size (p=0.65) or clinical nodal status (p=0.36). There were non-significant associations between eVAF and grade (p=0.097) and eVAF and tumor size (p=0.086). Persistent ctDNA detection midway through neoadjuvant therapy (pre-cycle 5) was associated with an increased risk of recurrence in patients with ER+ (HR: 10.27, 95%CI: 1.61-65.4; p=0.014) and TNBC (HR: 20.17, 95%CI: 1.97-206.4; p=0.011). Residual cancer burden (RCB) status further stratified the risk of recurrence; those with RCB-2/3 disease and ctDNA detected pre-cycle 5 were at the highest risk. Few patients had detectable ctDNA in pre- or initial post-operative specimens, all of which had residual disease (non-pCR). 9/16 patients with clinical recurrence had evaluable post-operative and follow-up samples for lead time calculation; ctDNA was detected prior to recurrence in 7/9 (78 %), with a median lead time of 152 days (range: 13-699 days). Of the 2 patients without a positive test, one had an ipsilateral local recurrence (grade 2, 1.8 mm), the other had a negative, but borderline, test 72 days prior to recurrence (solitary 8 mm lung nodule on PET). Follow up is ongoing for two patients with ctDNA detected but no recurrence at data cutoff (time since last positive test: 0.60 and 1.78 years). Any ctDNA detection postoperatively or in follow-up was strongly associated with disease recurrence (HR: 37.35, 95%CI: 2.7-520.7; p&lt; 0.0001).

Conclusion:

RaDaR detects ctDNA in most patients prior to the initiation of NAT for EBC. Changes in ctDNA levels during treatment and its presence are associated with clinical outcomes. Prospective evaluation and integration of RaDaR testing into clinical trials are warranted. Further analysis of ctDNA detection, clinical outcomes, and genomic data will be presented at the meeting.

Citation Format: Mitchell Elliott, Jesus Fuentes Antras, Philippe Echelard, Aaron Dou, Zachary Veitch, Philippe Bedard, Eitan Amir, Michelle Nadler, Nicholas Meti, Nancy Gregorio, Elizabeth Shah, Celeste Yu, Nathan Campbell, Christodoulos Pipinikas, Karen Howarth, Lillian Siu, Hal Berman, David Cescon. Longitudinal Neoadjuvant and Post-operative Evaluation of Circulating Tumor DNA in Early Breast Cancer using a Tumor-Informed Assay: Updated Analysis of the TRACER Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-08.