Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study)

Abstract

Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. This prospective study enrolled consecutive patients with mCRC receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C), second (C) and/or third (C) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation () or hypermethylation (). CT scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity, and treatment line. Eighty-two patients with mCRC treated in first- (82.9%) or second- (17.1%) line chemotherapy were included. Patients with a high (>10 ng/mL) versus low (≤0.1 ng/mL) ctDNA concentration at C had a shorter overall survival (OS; 6.8 vs. 33.4 months: adjusted HR, 5.64; 95% CI, 2.5-12.6; < 0.0001). By analyzing the evolution of the ctDNA concentration between C and C or C (C), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" ( = 58) versus "bad ctDNA responder" () had a better objective response rate ( < 0.001), and a longer median progression-free survival (8.5 vs. 2.4 months: HR, 0.19; 95% CI, 0.09-0.40; < 0.0001) and OS (27.1 vs. 11.2 months: HR, 0.25; 95% CI, 0.11-0.57; < 0.001). This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in patients with mCRC. .

Monitoring the effect of first-line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.

“…Recent studies found a marked prognostic value of ctDNA in OS estimates [24,25]. Our result supports their conclusion, as patients with a plasma mutation were shown to have a significantly worse survival compared to the rest of the cohort (Fig.…”

Liquid Biopsy: Approaches to Dynamic Genotyping in Cancer

“…Later studies confirmed the predictive value of ctDNA levels for RFS and OS [20,21,48]. In addition, these studies indicated that the amount of ctDNA might be independent of established prognostic factors (age, ECOG performance status, and CEA) [20,21], and that the slope of ctDNA after initiation of treatment adds prognostic information [48]. In a prospective study with 230 stage II CRC patients, subjects with positive ctDNA at first follow-up had a 3-year RFS of 0% in contrast to 90% in the ctDNA-negative patients [83], suggesting that ctDNA might in the future be used to stratify for adjuvant treatment.…”

“…In patients with stage I-IV CRC, the detection of KRAS mutations in ctDNA predicted recurrence-free survival (RFS) and OS [82]. Later studies confirmed the predictive value of ctDNA levels for RFS and OS [20,21,48]. In addition, these studies indicated that the amount of ctDNA might be independent of established prognostic factors (age, ECOG performance status, and CEA) [20,21], and that the slope of ctDNA after initiation of treatment adds prognostic information [48].…”

“…The short half-life of ctDNA of less than 2 h represents a challenge for sample processing unless collection tubes including additives are used; however, on the other side, it allows real-time assessment of tumor activity and genotype. Studies in CRC, breast and ovarian cancer, melanoma, GIST, and lymphoma have shown that levels of ctDNA correlate with the clinical course of the disease in individual patients and can precede changes seen in imaging studies by weeks or months [21,28,29,[46][47][48]. Thus, ctDNA monitoring might allow early assessment of response and prediction of progression.…”

Molecular Diagnostics in Clinical Oncology

“…While informative serum markers are available for the minority of human tumors, the use of blood-based mutation tests for the immediate assessment of treatment efficacy can potentially be applied to every cancer patient, as all malignant neoplasms contain a spectrum of somatic mutations. The utility of circulating tumor DNA for the control of surgical tumor eradication as well as the response to systemic treatment has already been exemplified in a number of studies (Tie et al, 2016; Abbosh et al, 2017; Garlan et al, 2017; Jamal-Hanjani et al, 2017; Goldberg et al, 2018; Lee et al, 2018). A similar approach can be applied for the early detection of tumor relapse.…”