Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer

Abstract

Purpose Pathologic response after preoperative/neoadjuvant chemotherapy (NAC) is a continuum that can range from complete pathologic response (pCR) to extensive residual disease (RD). We hypothesized that post-NAC plasma circulating tumor DNA (ctDNA) fraction (TF) reflect pathologic response as continuum measured by the residual cancer burden (RCB) score. Methods ctDNA was assessed using the PredicineBEACON assay, that interrogates up to 50 personalized tumor variants and 500 hot-spot mutations, in 3 mL archived plasma isolated from EDTA tubes collected post-NAC but before surgery from 44 patients with stage I/III triple negative breast cancer (TNBC) who received durvalumab and weekly nab-paclitaxel followed by doxorubicin/cyclophosphamide on a clinical trial (NCT02489448). Circulating free tumor DNA methylation profiling was performed using PredicineEPIC assay in paired pre- and post-NAC plasma (N = 30). Youden's J-statistics was used to define optimal thresholds. Results We observed a significant positive correlation (r = 0.45, p = 0.004) between RCB scores and post-NAC TF. The median TF was significantly lower in pCR (RCB0) compared to RD patients (0.06 % vs. 0.3 %, p = 0.02). Using a TF positivity threshold of ≥0.05 %, PredicineBEACON had 58 % sensitivity at 83 % specificity for identifying RD. TF was higher in patients who experienced recurrence (n = 9) compared to those without recurrence (n = 35) (0.17 % vs. 0.05 % TF, p = 0.029). There was significant decrease in methylation signal in post-compared to pre-NAC samples, but post-treatment methylation signal was lower in cases with pCR vs RD. Conclusions Post-NAC plasma tumor fraction and change in tumor-derived methylation signal predict the extent of RD and recurrence in TNBC patients.

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