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

<div><p>Background</p><p>Circulating 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.</p><p>Methods</p><p>Patients 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.</p><p>Results</p><p>128 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.</p><p>Conclusions</p><p>cfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.</p></div

Patient demographic characteristics.

<p>Patient demographic characteristics.</p

Clinical utility of cfDNA sequencing results.

<p><b>(A)</b> Detectable mutations and/or amplification were present in 78% of patients. <b>(B)</b> 50% of these patients (N = 50) had “potentially actionable” mutations and/or amplifications. <b>(C)</b> Among these, 60% (N = 30) patients had a clinical trial identified based on the matched biomarker detected from the cfDNA (D) 15 patients ultimately enrolled on a biomarker-based clinical trial. Pt = patient; MDACC = MD Anderson Cancer Center.</p

Number of patients with genomic alterations detected by both FFPE and cfDNA analysis.

<p>FFPE = formalin-fixed, paraffin-embedded tissue; cfDNA = cell-free DNA; Amplif = amplification.</p

Provider survery results.

<p>Physician preference for convenience (A) and clinical utility (B) according to the sample detection method and a stated desire to incorporate sequencing results into clinical decisions. FFPE = formalin-fixed, paraffin-embedded tissue; cfDNA = cell-free DNA.</p

Additional findings noted in sequencing of historic FFPE specimens compared to cfDNA sequencing.

<p>FFPE = formalin-fixed, paraffin-embedded tissue; cfDNA = cell-free DNA.</p

The impact of the use of cfDNA in (A) quality of care and (B) patient satisfaction.

<p>The impact of the use of cfDNA in (A) quality of care and (B) patient satisfaction.</p

Demographic and tumor characteristics of CRC patients according to SMAD4 mutation status.

<p>Demographic and tumor characteristics of CRC patients according to SMAD4 mutation status.</p

Comparison of survival curves in patients with metastatic CRC according to SMAD4 mutation status.

<p>Median OS durations of 29 months (95% CI, 20–48 months) and 56 months (95% CI, 51–63 months) were observed in patients with mutated and wild-type SMAD4, respectively.</p

OncoPrint of genomic alterations in TCGA CRC cases (n = 220) showing mutations of SMAD4, KRAS, NRAS, and BRAF.

<p>OncoPrint of genomic alterations in TCGA CRC cases (n = 220) showing mutations of SMAD4, KRAS, NRAS, and BRAF.</p