16P Trastuzumab deruxtecan (T-Dxd) in metastatic HER2-positive breast cancer: Early circulating tumor DNA (ctDNA) responses detected by comprehensive genomic profiling

Background: Early hormone receptor positive breast cancer is treated with surgery followed by adjuvant systemic therapy, including chemotherapy and endocrine therapy.There is a need for a better method to determine more precisely the prognosis of these high risk ER+ breast cancer patients.Tumor bespoke circulating tumor DNA (ctDNA) assays have been shown to accurately predict tumor relapse.In our Q-CROC-03 and TRICIA trials we identified a ctDNA negative (ctDNA-) group in triple-negative breast cancer patients with excellent prognosis.We now present our results of serial ctDNA testing in patients with early ER+ breast cancer in the adjuvant setting.Methods: Plasma samples were collected post-operatively in patients with 34 mostly stage II/III ER+ breast cancer every 3-12 months 5 years after surgery.We performed a case-control study in which 14 patients with relapse were compared with 20 patients without relapse.Serial plasma samples were analysed in the 2 years prior to relapse in relapsed patients and up to 5 years post-operatively in non-relapsed patients.Patient-specific digital PCR assays (5/patient) were designed in-house using somatic mutations identified by whole exome sequencing. Results:The median time to relapse was 35 months.We were able to detect relapses in ER+ breast cancer patients at a median of 21.6 months (range 4.9-53.3)prior to clinical relapse.12 of 14 (86%) relapsed patients were ctDNA+ compared to 7 of 20 non-relapsed patients in at least one time point.Patients with negative ctDNA (ctDNA-) had a relapse-free survival (RFS) of 87% compared to 21% in ctDNA+ patients (p = 0.01, HR = 0.19 (95% CI = 0.07 to 0.54)), a negative predictive value (NPV) of 87%, sensitivity of 86% and specificity of 65%.When examining only samples collected no more than 6 months after surgery, ctDNA-patients reached an RFS of 79% compared to 0% in ctDNA+ patients (p<0.0001,HR = 0.06 (95% CI = 0.007 to 0.57)), reaching a NPV of 81%, sensitivity of 60% and specificity of 100%.Moreover, the mean cFA of tested variants in relapsed patients was over 10-fold higher than that of non-relapsed patients.Conclusions: Personalized ctDNA monitoring of serial plasma samples in the adjuvant setting can accurately stratify relapse risk in early ER+ breast cancer patients.