ctDNA Successfully Detects Mutations With Treatment Implications in mCRC

In patients with metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) analysis successfully detected baseline mutations that would affect their response to EGFR-targeted treatment, according to a study published in Scientific Reports.

Analyzing ctDNA is a noninvasive procedure to look for tumor-specific genetic alterations, and it allows for tumor analysis even for patients who cannot provide tissue specimens.

“…ctDNA may be more comprehensive representation of the tumor mutations of an individual patient,” the authors explained. “Longitudinal ctDNA analysis can also provide a molecular profile of how a tumor evolves and changes over time in response to chemotherapy.”

They evaluated how the results of ctDNA analysis were associated with outcome in patients with metastatic cancer by collecting blood samples before, during, and after palliative first-line chemotherapy with cetuximab in patients with mCRC.

The study enrolled 93 patients. The majority (76.3%) of these patients had metastatic lesions in the liver, 22.6% in the lung, 21.5% in multiple organs, and 21.5% had peritoneal carcinomatosis. Because 1 patient discontinued study participation, only 92 patients had data for response evaluation. Of these patients, 75.0% had partial response, 20.7% had stable disease, and 4.3% had progressive disease. Overall, the median progression-free (PFS) survival was 10.5 months.

The researchers identified 230 mutations in 84 samples, and the remaining 9 patients had no mutations. “Patients with mutations had an average of 2.74 mutations,” they noted.

The tumor size was significantly smaller in patients without any ctDNA mutations (median, 17 mm vs 35 mm, respectively; P < .001). In addition, the researchers found some patients were more likely to have mutations based on the pattern of metastasis. Nearly all (95.8%) of patients with liver metastasis had mutations detected in ctDNA compared with 72.7% of patients without liver metastasis. In addition, ctDNA mutation was detected in 42.9% patients with peritoneal seeding without any other distant metastasis compared with 94.2% of patients with metastatic lesions anywhere other than peritoneal seeding.

Patients with KRAS or NRAS mutations in baseline ctDNA had significantly shorter PFS (median, 3.7 months) compared with patients with wild type KRAS or NRAS (10.8 months). KRAS and NRAS mutations are “the most important in predicting sensitivity to anti-EGFR treatment in mCRC patients,” the authors noted.

For the 84 patients with mutations, the mean of average variant allele frequency (VAF) at baseline was 23.34%, which decreased to less than 1% for 76.2% of patients after chemotherapy. Those patients with mean VAF below 1% after the first evaluation had a median PFS of 11.9 months compared with 5.5 months for patients above 1%. Among patients with a partial response, those with a higher VAF also had poorer PFS (median, 7.9 months vs 14.6 months).

The findings show that ctDNA, which only requires blood samples, may be an attractive alternative to obtaining tumor tissues, which is more invasive.

“ctDNA analysis was able to detect baseline mutations related to resistance to anti-EGFR treatment, and serial analysis have shown that changes in average VAF in ctDNA were associated with the response to treatment and have revealed a few emerging mutations at the time of resistance,” the authors wrote.

Reference

Lim Y, Kim S, Kang J-K, et al. Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR. Sci Rep. 2021;11(1):16333. doi:10.1038/s41598-021-95345-4