Circulating DNA Offers Real-Time Genotype Information in CRC

The use of BEAMing technology on circulating DNA to identify multiple mutations in real time could help guide treatment in colorectal cancer (CRC) patients, according to a retrospective analysis of the CORRECT trial published in the Lancet Oncology. The analysis also showed that regorafenib provides benefit over placebo across mutational subgroups.

“Genotyping of tumor tissue can help with the selection of patients with tumors amenable to treatment,” wrote study authors led by Josep Tabernero, MD, of Vall d’Hebron University Hospital and Institute of Oncology in Barcelona. “However, the value of testing a tumor sample is limited by intertumor and intratumor heterogeneity. Moreover, archival tissue will not show genotypic changes that have occurred since the sample was obtained.”

The CORRECT trial was a phase III study of patients with metastatic adenocarcinoma of the colon or rectum, all of whom had received standard therapies and progressed during or soon afterward. Regorafenib was compared with placebo in these patients. The new study used results of a BEAMing analysis of mutational status in 503 patients enrolled in CORRECT.

The researchers found that tumor-associated mutations were “readily detected with BEAMing of plasma DNA.” They found KRAS mutations in 69% of patients, PIK3CA mutations in 17% of patients, and BRAF mutations in 3% of patients. Notably, of the 86 patients who had received anti–epidermal growth factor receptor (EGFR) therapy and whose archival tumor tissue DNA was KRAS wild-type, 48% (41 patients) had KRAS mutations when fresh plasma DNA was analyzed.

Regorafenib provided clinical benefit across mutational status. In KRAS wild-type patients, regorafenib yielded a hazard ratio (HR) for progression-free survival vs placebo of 0.52 (95% confidence interval [CI], 0.35–0.76); in KRAS-mutant patients, the HR was 0.51 (95% CI, 0.40–0.65) in favor of regorafenib.

The findings were similar in PIK3CA wild-type patients, with an HR of 0.50 (95% CI, 0.40–0.63), and in PIK3CA-mutant patients, with an HR of 0.54 (95% CI, 0.32–0.89). There was no statistically significant difference between those mutant and wild-type groups in either case. Regorafenib was also clinically superior in subgroups based on a number of protein biomarkers.

“Our analysis shows that regorafenib provides a consistent overall and progression-free survival benefit in a range of subgroups of patients with metastatic colorectal cancer based on tumor mutation status and plasma protein biomarker concentrations,” concluded the study authors. “The findings from this biomarker study also support BEAMing analysis of circulating DNA as a viable approach to obtain real-time tumor-associated genotypic information in a non-invasive way.”