Abstract P2-01-07: Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach

Abstract

Abstract BACKGROUNDDetection of minimal residual disease (MRD) using circulating tumor DNA (ctDNA) represents an attractive alternative to imaging, currently considered the gold standard in routine surveillance of early breast cancer (BrCa) following primary therapy. ctDNA has the potential to identify patients who may eventually develop distant metastatic disease and, as such, its implementation in the routine clinical follow-up setting may offer the means for earlier intervention for patients with oligometastatic disease and improved overall survival. However, due to the highly heterogeneous nature of the genomic alterations in BrCa, ultra-sensitive ctDNA assays are required for follow-up surveillance. Here we evaluate RaDaR™, a personalised liquid biopsy-based sequencing assay for the detection of residual disease and monitoring after standard treatment in early-stage BrCa. METHODS38 early-stage BrCa patients recruited through the BRandO BiO registry study were included (18% TNBC, 74% HR+/HER2-, 8% HER2+). 21 patients experienced clinical recurrence (13 distant and 8 local), with a median time to progression of 18.9 months. The remaining 17 case-control patients had no disease recurrence at the time of 3-year follow-up. Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissue from curative-intent surgery and selected variants were used to design personalised RaDaR panels (38-54 variants/panel: median 49). In total, 52 plasma samples were analyzed using RaDaR. This included samples taken at the time of recurrence and at 12-months post-diagnosis where available (33 samples from 21 patients), or in the case of no recurrence, samples taken at 3-year follow up, including one control case that had two additional samples analyzed at 12-months and 4-years of follow up (19 samples from 17 patients). RESULTSIn total, ctDNA was detected in 12/13 (92%) patients with distant recurrence and 3/8 (38%) patients with local recurrence at an estimated median variant allele frequency (VAF) of 0.827% (range: 0.0029% - 38%). The lowest levels were seen in the 3 patients with local recurrence (0.0029%, 0.0146% and 0.0248% VAF). Of the 6 patients negative for ctDNA, 5 had local and one distant recurrence of unusual histology, indicating a possible alternative origin or second primary tumor. Only one of the 17 control cases was positive for ctDNA (0.0085% VAF), from a patient with a Luminal A, stage I tumor, potentially indicating the presence of early molecular recurrence that precedes clinical progression. Two additional time points from this patient also showed positive ctDNA results, which could be indicative of residual disease remaining dormant. Of the 12 patients with disease recurrence for which an earlier plasma sample was available, 4 patients (3 with distant and one with local recurrence) had ctDNA detected at the earlier time point, a median of 92 days (range 42 – 308 days) prior to clinical recurrence. 3 patients had ctDNA detected only at the time of recurrence (one distant and 2 local). None of the 5 patients with ctDNA negative results at the time of recurrence had detectable ctDNA levels at the earlier timepoint. CONCLUSIONIn this real-world pilot study, the RaDaR assay detected the presence of ctDNA in plasma to levels as low as 0.0029% VAF. We found that ctDNA detection was strongly associated with distant recurrence in early-stage BrCa, with a sensitivity of 92% (12 of 13 cases detected). In a limited number of cases where samples were available prior to recurrence, ctDNA could be detected ahead of clinical progression, potentially offering the opportunity for earlier intervention. Citation Format: Wolfgang Janni, Jens Huober, Sophia Huesmann, Christodoulos Pipinikas, Tatjana Braun, Volkmar Müller, Giovanni Marsico, Angelina Fink, Paula Freire-Pritchett, Karin Koretz, Charlene Knape, Amelie deGregorio, Brigitte Rack, Thomas WP Friedl, Lisa Wiesmueller, Peter Möller, Karen Howarth, Klaus Pantel, Nitzan Rosenfeld. Detection of early-stage breast cancer recurrence using a personalised liquid biopsy-based sequencing approach [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 P2-01-07.