Molecular markers tied to survival after colon cancer recurrence

Last Updated: 2016-12-28

By David Douglas

NEW YORK (Reuters Health) - DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (BRAF) are among prognostic indicators after recurrence in patients with stage III colon carcinoma, according to a secondary analysis of two clinical trials.

Dr. Frank A. Sinicrope told Reuters Health by email, "We focused on how molecular markers relate to survival after a patient has experienced a recurrence of their colon cancer. We and others have observed that BRAF mutations are more strongly associated with overall survival than disease-free survival in stage III colon cancer, suggesting that BRAF-mutated tumors might behave more aggressively once relapsed."

"Indeed," he added, "our data demonstrate significantly poorer survival after recurrence for BRAF mutated tumors compared to those lacking this mutation, and this occurred irrespective of DNA mismatch repair status."

As reported December 22 online in JAMA Oncology, Dr. Sinicrope of the Mayo Clinic, Rochester, Minnesota and colleagues studied 1,395 patients with recurrence being treated with adjuvant chemotherapy.

Multivariable analysis showed that patients whose tumors had deficient versus proficient MMR had significantly better survival after recurrence (adjusted hazard ratio, 0.70). Patients whose tumors harbored mutant BRAF had worse survival after recurrence compared with those whose tumors had wild-type copies (aHR, 2.45).

This was also the case in those with somatic mutation or exon 2 of the KRAS proto-oncogene (KRAS), although the difference did not reach significance (aHR, 1.21).

Significant interactions were found for MMR and KRAS by primary tumor site for survival after recurrence, with improved survival in patients with deficient MMR tumors of the proximal versus distal colon (aHR, 0.57), and worse survival with tumors of the distal colon with mutant KRAS in codon 12 (aHR, 1.76) and codon 13 (aHR, 1.76).

"Together," concluded Dr. Sinicrope, "these findings may inform patient management at the time of tumor recurrence and underscore the need for more effective therapy in patients with BRAF mutant colon cancers."

In an editorial, Dr. Andrea Sartore-Bianchi observes that "the presence of a BRAF mutation should discourage an aggressive upfront surgical approach in favor of medical treatment, with allowance for the test of time. On the other hand, in patients without BRAF mutation, a longer time to relapse is paralleled by better survival after relapse and should integrate the decision concerning surgery for metastases."

Dr. Sartore-Bianchi, of Grande Ospedale Metropolitano Niguarda, Milan, Italy, concluded, "Future large-scale comprehensive studies will elucidate the interplay among immunevariables and oncogene alterations for capturing the multifaceted biology and thus prognosis of individual CRCs."

SOURCE: http://bit.ly/2hNORjL and http://bit.ly/2hoOhrs

JAMA Oncol 2016.