What Impact Does Microsatellite Instability Have on Survival in Stage III Colon Cancer?

In a study conducted prior to the immunotherapy era, microsatellite instability and mismatch repair deficiency (MSI/dMMR) were associated with improved survival after recurrence compared with microsatellite stable/mismatch repair proficient disease (MSI/pMMR) in patients with resected stage III colon cancer.

However, BRAF^V600E  mutation was associated with worse outcomes regardless of microsatellite or mismatch repair status.

“As both MSI and BRAF status influence recurring colon cancer patients’ outcome, these factors should be used to stratify patients in future clinical trials dedicated to MSI or BRAF mutant metastatic CRC,” researchers led by Julien Taieb, of Universite Paris Descartes, France, and colleagues wrote in the study published in Annals of Oncology.

The retrospective study included data from 2,630 patients from seven adjuvant studies that included information on MMR and BRAF^V600E  status. The primary endpoint was survival after recurrence.

BRAF^V600Emutation was harbored in 11.7% of tumors, and 10.3% were MSI/dMMR. Among the MSI/dMMR tumors, about one-third harbored BRAF^V600E.

At a median follow-up of 77.3 months, the median survival after recurrence was 23.1 months.

Multivariable analysis showed that patients with MSI/dMMR tumors had significantly better survival after recurrence than those patients with MSS/pMMR tumors (adjusted hazard ratio [aHR]=0.82; 95% CI, 0.69–0.98; P=.029). When looking at only those patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens, this advantage remained (aHR=0.76; 95% CI, 0.58–1.00; P=.048). Finally, similar trends were observed in patients with BRAF^v600e mutations (aHR=0.88; P=.43) and in those without (aHR=0.84; P=.10).

Among patients with BRAF^V600E, survival after recurrence was significantly shorter for all patients (aHR=2.06; 95% CI, 1.73–2.46; P<.0001), even among those patients with MSI/dMMR (aHR=2.65; 95% CI, 1.67–4.21; P<.0001).

“Having a clearer picture of the prognosis of each of these molecular subgroups is important given that approaches to their treatment is rapidly changing,” the researchers wrote.

In an analysis adjusted for MSI/dMMR and BRAF^V600E status, other factors associated with poor survival after recurrence included older age, male sex, T4/N2, proximal primary tumor, poor differentiation, and early recurrence.

The researchers discussed several limitations to the study including the fact that only about one-half of the patients in the seven studies were included due to missing data on BRAF and MMR testing.

“Moreover, in contrast to prior reports, all patients had subsequent recurrent disease and were treated with previous adjuvant therapy,” the researchers wrote. “This may explain why our results differ compared to studies of patients with non-resectable mCRC eligible for a first-line trial.”

Commenting on these results, Frederico Innocenti, MD, PhD, of University of North Carolina's Eshelman School of Pharmacy, told Cancer Network that the results further highlight the importance of molecular stratification of patients with metastatic CRC.

"In this scenario, the demonstration of different prognosis and response to treatment of subgroups of patients is limited by the requirement of adequate sample sizes to detect statistically significant differences, as shown in this paper when the prognosis of a two-way subgrouping (by BRAF and MSI) is difficult to detect, even in this large analysis," Innocenti said. "This study supports the notion of investigating the tumor molecular features to inform treatment selection and the design of new trials. I would expect that even the MSI classification will be replaced by more advanced signatures, for example by immune profiling of tumors."