Genome-wide DNA methylation status as a biomarker for clinical outcomes of first-line treatment in patients with RAS wild-type metastatic colorectal cancer: JACCRO CC-13AR.

BACKGROUND

Several retrospective studies have demonstrated an association between genome-wide DNA methylation status (GWMS) and clinical outcomes after treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (mCRC). This biomarker study evaluated the association of GWMS with clinical outcomes in mCRC patients who were enrolled in a randomized phase II DEEPER trial of comparing modified (m)-FOLFOXIRI plus bevacizumab (Bev) and m-FOLFOXIRI plus cetuximab (Cet) as first-line treatment.

PATIENTS AND METHODS

GWMS was measured using tumor tissues which were collected from patients with tissue samples available in the DEEPER trial. In addition, tumor tissues were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) groups. The correlation between GWMS and survival was analyzed by comparing progression-free survival (PFS) and overall survival (OS) between the two different groups of GWMS.

RESULTS

Of the 137 patients, 15 were classified into the HMCC group, and 122 were classified into the LMCC group; 71 patients were treated with Bev, and 66 were treated with Cet. In the Bev arm, OS was significantly shorter in the HMCC group than in the LMCC group (median 24.2 versus 48.9 months, P = 0.03). In the Cet arm, both PFS and OS were significantly shorter in the HMCC group than in the LMCC group (median 4.0 versus 14.3 months, P < 0.01 and median 13.6 versus 42.7 months, P < 0.01). The interaction tests revealed that GWMS was a significant predictor of PFS and OS in the Cet arm.

CONCLUSIONS

GWMS was associated with survival in RAS wild-type mCRC patients treated with initial chemotherapy. Also, it may serve as a predictor for selection of molecular-targeted antibodies in first-line treatment.