Clinical utility of circulating cell-free DNA in advanced colorectal cancer

Abstract

BackgroundCirculating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described.MethodsPatients were prospectively consented to a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]), with collection of blood for cfDNA extraction and sequencing of a 54-gene panel in a CLIA-certified lab. Formalin-fixed, paraffin-embedded (FFPE) tissue from prior resections or biopsies underwent 50-gene sequencing. Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow-up surveys of treating physicians and chart reviews assessed clinical utility.Results128 mCRC pts were enrolled between 6/2014 and 1/2015. Results were returned in median of 13 and 26 days for cfDNA and FFPE sequencing, respectively. With cfDNA sequencing, 78% (100/128) of samples had a detectable somatic genomic alteration. 50% of cfDNA cases had potentially actionable alterations, and 60% of these could be genomically matched to at least one clinical trial in our institution. 50% (15/30) of these pts enrolled onto an identified matched trial. Physicians reported that the cfDNA testing improved the quality of care they could provide in 73% of the cases, and that 89% of pts reported greater satisfaction with the efforts to personalize experimental therapeutic agents.ConclusionscfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

“…Evidence of ctDNA in the blood, as estimated by MSAF > 0, was detected in 82% of cases, similar to recent studies in colon cancer (21, 22). Among cases with evidence of ctDNA, at least one reportable GA was detected in 89% of cases with an average of 2.28 reportable alterations per case.…”

“…In contrast, the spectrum and incidence of genes with short variant alterations was similar to that observed in tissue samples from patients with gastrointestinal cancers, supporting the ability of ctDNA profiling to reflect tissue-based characterization. In recent studies comparing ctDNA and tissue samples in colorectal carcinoma patients, similar rates of short variant alterations to those seen here were also observed for frequently altered genes (21, 22). However, in one study (21), reported frequencies of EGFR and MET amplification in ctDNA samples were notably enriched compared with ctDNA results observed here and relative to published tissue studies of colorectal carcinoma (21).…”

“…In recent studies comparing ctDNA and tissue samples in colorectal carcinoma patients, similar rates of short variant alterations to those seen here were also observed for frequently altered genes (21, 22). However, in one study (21), reported frequencies of EGFR and MET amplification in ctDNA samples were notably enriched compared with ctDNA results observed here and relative to published tissue studies of colorectal carcinoma (21). In another study (22), although short variant alteration frequencies were reported, the prevalence of gene amplifications and fusions detected in cell-free DNA samples were not included for the majority of cases (22).…”

“…Other studies of ctDNA profiling in gastrointestinal cancers have focused on colon cancer, and most have been limited in size, and in some cases restricted to hotspot alterations in a limited set of genes (21, 28, 34). Strickler and colleagues recently reported cell-free DNA genomic profiling results for over 1,000 colorectal carcinoma patients, but analysis was largely focused on short variant alterations, and no comparison with paired tissue samples was available (22).…”

Circulating tumor DNA (ctDNA) in the era of personalized cancer therapy

“…Use of RAS mutations in cfDNA of patients with metastatic colorectal cancer brought a promising personalized dashboard for this cancer [108,109]. Clinical utility of ctDNA sequencing in advanced CRC can provide appropriate information on potential mutations, in that way to ease clinical trial enrollment and enlightening the supposed value of care [110]. The quantitative relationship of cfDNA with tumor specific mutations in plasma from metastatic colorectal cancer (mCRC) patients was related to the efficacy of third line treatment with cetuximab and irinotecan [111].…”