Abstract P2-01-10: Detection of ctDNA following surgery predicts relapse in breast cancer patients receiving primary surgery
Authors: Garcia-Murillas Isaac , Cutts Rosalind J , Ulrich Lara , Beaney Matthew , Robert Marie , Coakley Maria , Bunce Catey , WalshCrestani Giselle , Hrebien Sarah , Kalashnikova Ekaterina , Wu Hsin-Ta , Dashner Scott , Sethi Himanshu , Aleshin Alexey , Ring Alistair , Okines Alicia , Smith Ian E , Dowsett Mitch , Barry Peter , Turner Nicholas C 
Published: March 2022

Abstract
Introduction: Identification of Molecular Residual Disease (MRD) by circulating tumour DNA (ctDNA) analysis has the potential to transform the clinical management of patients with early breast cancer. We present results from a proof-of-principle study to assess ctDNA analysis following primary surgery to identify MRD and anticipate which patients are at risk of relapse. Methods: Early breast cancer patients receiving primary surgery for breast cancer (48 total), enrolled in the PlasmaDNA/ITH sample collection studies were included in the analysis. Tumour DNA from FFPE samples was whole exome sequenced to identify patient specific mutations and design personalized Signatera ctDNA assays. Plasma samples were collected pre-surgery (n=31), 1-14 weeks post-surgery and prior to adjuvant therapy (n=48), and following adjuvant chemotherapy (n=36). Cell free DNA was extracted from a total of 144 plasma samples (median volume 3.6ml, range 1.8-4.7ml) and sequenced with Signatera ctDNA assays. Primary objective was to assess whether relapse free survival (RFS) and distant metastasis free survival (DMFS) are worse in patients with ctDNA detected at the post-surgery timepoint compared to those without ctDNA detected. Results: Median age was 50.5 years, 34 had hormone receptor positive HER2 negative (HR+HER2-), 5 HER2 positive and 9 triple negative breast cancer (TNBC), 32 were stage 1-2 and 16 were stage 3-4. At a median follow-up of 60 months post-surgery, 8 patients had relapsed. ctDNA was detected in the single post-surgery timepoint in 29% (14/48) of patients, and detected in 62.5% (5/8) of patients who relapsed. RFS in patients with ctDNA detected at a single post-surgery timepoint was worse than those with no detected ctDNA although it was not statistically significant (Hazard Ratio (HR): 3.7; 95% CI, 0.9-15.6; P=0.07), while ctDNA detection associated with worse DMFS (HR: 5.6; 95% CI, 1.1-29-3; P=0.04). DMFS at 4 years follow-up in those with MRD ctDNA detection was 0.78 (95% CI 0.47-0.92) and those without MRD detection was 0.97 (95% CI 0.80-0.99). In patients with a pre-surgical timepoint (n=31), 64.5% (20/31) had ctDNA detected. Detection of ctDNA at either pre-surgery or post-surgery was associated with worse outcomes compared to no ctDNA detection at both RFS (HR: 7.9; 95% CI, 0.9-64.7; P=0.05) and DMFS (HR: 6.7; 95% CI, 0.8-55.8; P=0.07). Conclusions: In this proof-of-principle study of early-stage breast cancer patients, ctDNA-detected MRD at a single post-surgical timepoint was associated with distant metastasis free survival. The majority of patients with ctDNA detected MRD did not relapse, during the period of follow-up, possibly suggesting activity of adjuvant therapy in these patients. Further assessment is warranted on the prognostic impact of ctDNA MRD detection, and its possible role in adjuvant chemotherapy selection.
Citation Format: Isaac Garcia-Murillas, Rosalind J Cutts, Lara Ulrich, Matthew Beaney, Marie Robert, Maria Coakley, Catey Bunce, Giselle WalshCrestani, Sarah Hrebien, Ekaterina Kalashnikova, Hsin-Ta Wu, Scott Dashner, Himanshu Sethi, Alexey Aleshin, Alistair Ring, Alicia Okines, Ian E Smith, Mitch Dowsett, Peter Barry, Nicholas C Turner. Detection of ctDNA following surgery predicts relapse in breast cancer patients receiving primary surgery [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 P2-01-10.