Circulating tumor DNA and magnetic resonance imaging to predict neoadjuvant chemotherapy response and recurrence risk

Abstract

We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p < 0.05). Median FTV in ctDNA-positive patients was significantly higher compared to those who were ctDNA-negative (p < 0.05). FTV and ctDNA trajectories in individual patients showed a general decrease during NAC. Exploratory analysis showed that adding ctDNA information early during treatment to FTV-based predictors resulted in numerical but not statistically significant improvements in performance for pCR prediction (e.g., AUC 0.59 vs. 0.69, p = 0.25). In contrast, ctDNA-positivity after NAC provided significant additive value to FTV in identifying patients with increased risk of metastatic recurrence and death (p = 0.004). In this pilot study, we demonstrate that ctDNA and FTV were correlated measures of tumor burden. Our preliminary findings based on a limited cohort suggest that ctDNA at surgery improves FTV as a predictor of metastatic recurrence and death. Validation in larger studies is warranted.

Impact of Circulating Tumor DNA–Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors

“… 83 Interestingly, data from this trial also indicated ctDNA could serve as a complement to MRI functional tumor volume as a predictor of treatment response. 87 …”

“…83 Interestingly, data from this trial also indicated ctDNA could serve as a complement to MRI functional tumor volume as a predictor of treatment response. 87 Further evidence is needed before ctDNA dynamics or clearance can be approved as surrogate end points in trials. Approval by appropriate regulatory agencies depends on accumulation of evidence from observational studies and clinical trials.…”

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome

“…We additionally used an unpublished dataset that was obtained as part of a collaboration with Massachusetts General Hospital (MGH). Overall, we identified and set aside 21 datasets 20,24,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] the evaluation setsas unseen data for evaluation. See Table S1 and Supplementary Note 1 for full details.…”

Liquid Biopsy, ctDNA Diagnosis through NGS

“…The efficacy of neoadjuvant chemotherapy (NAC) can be evaluated by ctDNA profiling. Preliminary results of a study showed that combined profiling of ctDNA by NGS with functional tumor volume (FTV) by magnetic resonance imaging (MRI) improves the prediction of metastatic recurrence and death of patients treated with NAC [84]. They found that the levels of ctDNA (mean tumor molecules/mL plasma) were correlated with FTV at all time points, and patients with ctDNA-positivity after NAC showed an increased risk of metastatic recurrence and death.…”