Study Explores Mutation Discordance Between Primary, Metastatic Sites in CRC

Mikhail Fedyanin, MD, PhD

Mutation discordance between primary and metastatic sites in colorectal cancer (CRC) may occur more often than previously understood, opening the door for potential new therapeutic approaches to treating the disease.

A recent study, presented in the poster session at the 2016 ESMO Congress, found that discordance was identified in almost 30% of patients across several different mutations. In some cases, mutational status changed, and the treatment timeline may have played a role, said lead study author Mikhail Fedyanin, MD, PhD, Russian Academy of Medical Science.

“The concordance of mutational status between primary tumor and metastases in colorectal cancer is between 80% and 95%,” said Fedyanin. “But in our study, we have found that we have high discordance status, and essentially the situation is connected to the time between primary tumor resection and metastasectomy.”

Using DNA melting analysis and sequencing techniques, researchers detected mutation hot-spots in KRAS exons 2 and 3, NRAS exons 2 and 3, BRAF exon 15, and PIK3CA exons 9 and 20 in 148 tumor tissues from 65 patients.

Patients ranged from 31 to 76 years of age, and 48% were male. The average number of metastasectomies per patient was 1.3 (range, 1-5). Primary tumors were located in the right colon in 10.8% of patients, in the left colon in 35.4%, and in the rectum in 53.8%. The median time between the resection of the primary tumor and metastasectomy was 13 months (range, 1-63). Most patients (88%) received chemotherapy before metastasectomy.

Among all patients, 43.1% were identified as having KRAS mutations, 13.8% had PIK3CA mutations, and 3.1% of patients had NRAS and BRAF mutations, respectively. The aim of the study was to find factors associated with the discordance of KRAS, NRAS, BRAF, and PIK3CA mutation status between the primary tumors and metastases in patients with CRC.

Discordance of mutation status of genes was identified in 29.2% of patients in total; 16.9% in KRAS, 3% in NRAS, 12.3% in PIK3CA and 3% in those with BRAF status. In all cases of metastases in the brain, discordance was identified in KRAS and PIK3CA mutation status (P = .08). Peritoneal metastases had discordance in KRAS status (P = 0.02).

One surprising finding was that patients with mutant RAS in the primary tumor had a higher chance of a changed RAS status in metastases than patients with wild-type RAS in primary tumors (OR, 4.5; 95% CI, 1.07-10.08, P = 0.04), said Fedyanin.

“This situation is strange because we have found that KRAS status was changing in patients that have mutation of KRAS in the primary tumor, and one of the metastases doesn’t have the mutation,” said Fedyanin. “Therefore if this is true, we can think about using JAK inhibitor antibodies.”

Age, sex, number of organs with metastases, tumor grade, mucinous component, adjuvant chemotherapy, radiotherapy, site of primary tumors, and other localization of metastases did not influence the discordance in mutation status.

Liquid biopsy, which extracts circulating tumor cells, cell-free DNA, or exosomes from blood and urine, was key to determining the study’s findings, said Fedyanin. It allowed researchers to understand how the mutational status changed throughout the study without additional invasive procedures.

“Our study is based on the use of liquid biopsy,” he said. “During the treatment, we see many changes in mutation. Therefore, we cannot biopsy each metastasis in our patients. When we use liquid biopsy, we can find the whole spectrum of mutations every time.”

Fedyanin M, Stroganova A, Senderovich A. Factors associated with disconcordance of KRAS, NRAS, BRAF, PIK3CA mutation status in the primary tumor and metastases in patients (pts) with colorectal cancer (CRC). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 529P.