MRI Tumor Regression Grade and Circulating Tumor DNA as Complementary Tools to Assess Response and Guide Therapy Adaptation in Rectal Cancer

Abstract

Purpose: Response to preoperative chemo-radiotherapy (CRT) varies. We assessed whether circulating tumor DNA (ctDNA) might be an early indicator of tumor response or progression to guide therapy adaptation in rectal cancer.Experimental Design: A total of 243 serial plasma samples were analyzed from 47 patients with localized rectal cancer undergoing CRT. Up to three somatic variants were tracked in plasma using droplet digital PCR. RECIST and MRI tumor regression grade (mrTRG) evaluated response. Survival analyses applied Kaplan-Meier method and Cox regression.Results: ctDNA detection rates were: 74% (n ¼ 35/47) pretreatment, 21% (n ¼ 10/47) mid CRT, 21% (n ¼ 10/47) after completing CRT, and 13% (n ¼ 3/23) after surgery. ctDNA status after CRT was associated with primary tumor response by mrTRG (P ¼ 0.03). With a median follow-up of 26.4 months, metastases-free survival was shorter in patients with detectable ctDNA after completing CRT [HR 7.1; 95% confidence interval (CI), 2.4-21.5; P < 0.001], persistently detectable ctDNA pre and mid CRT (HR 3.8; 95% CI, 1.2-11.7; P ¼ 0.02), and pre, mid, and after CRT (HR 11.5; 95% CI, 3.3-40.4; P < 0.001) compared with patients with undetectable or nonpersistent ctDNA. In patients with detectable ctDNA, a fractional abundance threshold of !0.07% mid CRT or !0.13% after completing CRT predicted for metastases with 100% sensitivity and 83.3% specificity for mid CRT and 66.7% for CRT completion. All 3 patients with detectable ctDNA post-surgery relapsed compared with none of the 20 patients with undetectable ctDNA (P ¼ 0.001).Conclusions: ctDNA identified patients at risk of developing metastases during the neoadjuvant period and post-surgery, and could be used to tailor treatment.

Monitoring of Early Changes of Circulating Tumor DNA in the Plasma of Rectal Cancer Patients Receiving Neoadjuvant Concomitant Chemoradiotherapy: Evaluation for Prognosis and Prediction of Therapeutic Response

“…When performed during the initial phase of the NCRT, possibly within hours from receiving the first radiation fraction together with chemotherapy and continuing for the next several days, such approach could substantiate ctDNA dynamics underlying eventual transient changes in tumor morphology and its damage, including subsequent ctDNA uptake resulting from the administered multimodal therapy. Thus, understanding of the detailed timing of ctDNA release and clearance may be essential for the long-awaited applicability of the ctDNA-based therapy outcome prediction for NCRT treatment of LARC patients ( 58 ) and beyond.…”

How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement

“…In addition, we can measure the nuances of circulating tumour cells or cell free DNA [15][16][17]. Many attempts have been made to achieve concordance between the degree of response on imaging and the histopathological grading [18][19][20].…”

Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression

“…Although the authors provide a number of plausible biological reasons for this negative finding, including low rates of cell proliferation and ctDNA shedding in localised disease, as well as more restricted access to the vasculature compared to metastatic lesions, a further possibility is that the number of patients with truly high-risk disease within their cohort was too low to detect a positive signal. Certainly ctDNA measurement has proven feasible and clinically meaningful in detecting the presence of 'micrometastatic disease', and be prognostic for recurrence, in other tumour types in the localised setting [23,24].…”