Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC).

Abstract

102 Background: Numerous studies have shown the clinical utility of ctDNA, a non-invasive biomarker to detect MRD and stratify CRC patients who are more likely to relapse. We present an analysis of MRD detection in CRC patients from a prospective multicentre UK study, who were monitored pre- and post-surgery before adjuvant chemotherapy (ACT). Methods: The study recruited patients diagnosed with stage II-III CRC (n=122), including a subset of rectal patients who underwent tri-modality treatment (TMT). All patients had their primary tumor resected and 56% (68/122) received ACT. Paired plasma samples (n=244) were collected before surgery/neaodjuvant chemoradiotherapy and after surgery; median follow-up for survival was 15.48 months (0.16 - 42.1 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) identified. Multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in plasma samples. The study evaluated ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by post-op ctDNA status. Patients were also stratified into low and high-risk groups based on the clinicopathological features. Multivariate analysis was performed with covariates: ctDNA, age, gender, laterality, stage, number of lymph node resected, MSI & TMB. Results: Pre-treatment ctDNA was detected in 93.4% (100/107) of patients. Post-operative ctDNA status prior to ACT was assessed in 107 patients, of whom, 13% (14/107) were MRD-positive (MRDpos). Of the MRDpos patients 42.9% (6/14) eventually relapsed. In contrast, only 8.6% (8/93) of MRD-negative (MRDneg) cases relapsed (HR: 10; 95% CI: 3.3-30; p<0.001). MRD rates stratified by risk features in each of the stages with respective recurrence rates are shown in Table. In stage III patients (n=64), 45.4% (5/11) of the MRDpos patients relapsed, whilst only 17% (9/53) of the MRDneg cases relapsed (HR: 9; 95% CI:2.6-32; p<0.0001). In the multivariate analysis, ctDNA status was the most significant prognostic factor associated with RFS (HR: 28.8, 95% CI: 3.5-234.1; p<0.001). Conclusions: Postoperative ctDNA analysis with tumor informed assay enables detection of CRC patients at high-risk of recurrence. Early detection of MRD could guide ACT decisions in intervention trials and is currently underway in TRACC. Clinical trial information: NCT04050345. [Table: see text]

Signed in Blood: Circulating Tumor DNA in Cancer Diagnosis, Treatment and Screening

“…Of the positive patients, 42.9% (6/14) eventually relapsed while only 8.6% (8/93) of the negative patients relapsed (HR: 10; 95% CI: 3.3-30; p < 0.001). In multivariate analysis, ctDNA status was the most significant prognostic factor associated with relapse-free survival (HR: 28.8, 95% CI: 3.5-234.1; p < 0.001) [79]. Similarly, in patients undergoing surgery for peritoneal metastases, high levels of pre-operative ctDNA and new postoperative ctDNA alterations in the context of preoperative alterations predicted worse outcomes [59].…”

Liquid Biopsy-Based Biosensors for MRD Detection and Treatment Monitoring in Non-Small Cell Lung Cancer (NSCLC)

“…Reliable MRD diagnosis is employed to predict relapse, risk classification, treatment selection and guide risk-adapted adjuvant immune therapy. Data from multicentre prospective studies in other tumours such as colon [9] and breast cancer [123] have shown that precision medicine largely relies on MRD. An appropriate drug dose is administered to patients through MRD detection, therefore preventing the drug's adverse effects.…”

“…MRD refers to the cells that persist after therapy and are resistant to conventional therapy. Several studies have proven that MRD can be a prognostic factor for relapse in these patients [9]. MRD is well established in malignancies of the haematological and lymphoid organs.…”

Plasma-Based Genotyping in Advanced Solid Tumors: A Comprehensive Review

“…In metastatic colorectal cancer (mCRC), KRAS , NRAS , and BRAF assessment is mandatory for treatment selection and prognostication, as RAS mutations confer resistance to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. NGS testing for extended RAS and BRAF gene mutations is currently standard practice, and ctDNA testing using single gene assays (PCR-based) has been shown to be an effective alternative to tissue-based genotyping and is approved by the European Medicines Agency (Idylla TM ctKRAS, Idylla TM ctNRAS-BRAF, OncoBEAM TM RAS) but remains to be incorporated into clinical guidelines [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Although tumor tissue in patients with metastatic CRC is often easier to obtain than in lung cancer patients, the benefits of fast turnaround time with plasma ctDNA ddPCR testing may confer a benefit to patients needing to start treatment sooner.…”

“…Moving forward, in early-stage colorectal cancer (CRC), there is compelling evidence demonstrating the role of ctDNA detection after curative-intent therapy as an important prognostic factor [ 73 ]. This approach, known as minimal residual disease (MRD) detection, represents an opportunity to better select patients that may benefit from more intense adjuvant therapy, or those that do not need further chemotherapy, with the aim of improving survival rates and minimizing toxicity and unneeded therapy [ 74 ].…”