Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival

Abstract

The aim of the study was to compare ctDNA response rate and objective response rate as surrogate markers for overall survival (OS) in patients with metastatic cancer treated with chemotherapy. Methods: The study included 420 patients distributed in five cohorts with colorectal, ovarian, and nonesmall cell lung cancer. It represents a retrospective analysis of patients enrolled in prospective biomarker studies and clinical trials. All patients had ctDNA measured before start of treatment and at the first evaluation of objective response. ctDNA response rate was defined as the fraction of patients converting from a measurable level at baseline to an unmeasurable level at the first evaluation of objective response.Aberrant, tumour specific, methylated DNA was measured in plasma. The method involves DNA isolation, bisulphite conversion and droplet digital PCR.The primary outcome measure was the correlation between ctDNA response rate, overall response rate (ORR) and median survival. Results: There was moderate correlation between ctDNA response rate and objective response at first evaluation (R 2 Z 0.68). The same applied to ctDNA response rate and ORR (R 2 Z 0.57). ctDNA held prognostic information in all the investigated tumour types (p < 0.05). There was a high correlation between ctDNA response and median survival across the included tumour types and treatments (R 2 Z 0.99) clearly outperforming both response at first evaluation and ORR (R 2 Z 0.70 and 0.57, respectively).

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…An emerging interest in plasma ctDNA assays lies in their ability to be used as an early marker of response to systemic therapy in mCRC. Here, several groups have shown that reductions in ctDNA following initiation of chemotherapy (as early as after 1 cycle) was prognostic for improved survival and predictive of tumor response when correlated to CT responses as early as 8-10 weeks after chemotherapy initiation [125][126][127][128][129][130][131]. These findings have been concordant in the prospective PLACOL study where mCRC patients treated after cycle 1 of chemotherapy having low (≤0.1 ng/mL) plasma concentrations of methylated ctDNA experienced improved OS and higher objective response rates [132].…”

The Clinical Impact of Methylated Homeobox A9 ctDNA in Patients with Non-Resectable Biliary Tract Cancer Treated with Erlotinib and Bevacizumab

“…However, the cohort sizes of the two above phase II studies [ 26 , 36 ] were rather small ( n = 32 and n = 23, respectively) as in the present study. Jakobsen et al [ 37 ] found a prognostic impact of meth-HOXA9 in ovarian cancer and late-stage NSCLC patients. This was supported by Wen et al [ 24 ] reporting a prognostic impact at baseline and after one treatment cycle analysing 231 late-stage NSCLC patients.…”

Reporting on circulating tumor DNA monitoring in metastatic cancer—From clinical validity to clinical utility

“…The majority of studies across cancer types define early dynamics to occur within the first 3 months. 15,19,22 A recent study on metastatic breast cancer analyzing blood sampled at baseline and once during treatment (between 4 and 12 weeks) found that the one ctDNA analysis after treatment initiation held significant prognostic information and correlated with the later radiologic assessment. 23 In advanced melanoma, Syeda et al 9 reported an independent prognostic value of ctDNA.…”

“…The effect of early changes in the level of ctDNA was also found in a study by Thomsen et al 37 Colorectal cancer patients treated with chemotherapy who had an undetectable level of ctDNA after the first treatment cycle had a median survival of 25.4 months compared to 13.5 months in the group with detectable ctDNA. Another study 22 investigated the correlation between ctDNA level at the first evaluation of objective response and prognosis. An undetectable level or a level with a lower confidence interval (CI) including zero correlated with OS in all 4 cohorts (ie, colorectal, ovarian, and lung cancer).…”