Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: A Mismatch?

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Approximately 15% of colorectal cancers are characterized by deficient DNA mismatch repair (MMR), leading to microsatellite instability (MSI) and mutations in critical genes involved in carcinogenesis, such as transforming growth factortype II receptor and BAX. It has long been recognized that MSI-high (MSI-H) tumors are pathologically distinct from colorectal tumors that arise from the traditional chromosomal instability pathway, with a predominantly proximal location in the right colon, poorer differentiation, mucinous histology, and peritumoral lymphocytic infiltration. Recent studies revealed that this pathologically unique subset of colorectal cancers also harbored significant differences in clinical behavior. Indeed, the seminal article by Ribic et al published in the New England Journal of Medicine in 2003 showed that among patients with stage II and III colon cancer pooled from five large, randomized clinical trials of adjuvant chemotherapy, 17% had MSI-H tumors. Patients with MSI-H tumors had a modestly better prognosis than those with microsatellite-stable (MSS) or MSIlow (MSI-L) cancers, yet also did not seem to benefit from adjuvant fluorouracil (FU) -based chemotherapy. This resistance to FU is presumably due to incorporation of FU metabolites into DNA rather than inhibition of its effective target, thymidylate synthase. In this issue of Journal of Clinical Oncology, Sargent et al have confirmed and extended these previous findings. They analyzed an additional 457 patients with stage II and III colon cancer from four of the five trials included in the Ribic study, as well as from another randomized trial of FU and leucovorin (LV) by the Gruppo Italiano di Valutazione Interventi in Oncologia (GIVIO). They found that deficient MMR status was associated with significantly improved 5-year disease-free survival (DFS) on univariate analysis (P .03), though not on multivariate analysis, in patients who were randomly assigned to surgery alone. Interestingly, in the subset of patients randomly assigned to adjuvant chemotherapy, MMR status did not seem to influence DFS, although the hazard ratios (HRs) do suggest a slight advantage for those with MMR deficiency. The authors then evaluated the impact of adjuvant chemotherapy according to MMR status, and, consistent with multiple large randomized trials, found a significant benefit for FU-based treatment on DFS, but only in patients with proficient MMR (multivariate HR 0.67; 95% CI, 0.48 to 0.93; P .02). Among stage II and III colon cancers characterized by MMR deficiency, absolutely no benefit was seen with adjuvant FU-based chemotherapy (multivariate HR for DFS 1.39; 95% CI, 0.46 to 4.15; P .56). For added power, the authors pooled data from these 457 patients with that of the 570 patients in Ribic et al’s original analysis and came to similar conclusions; namely, deficient MMR status was prognostic for a better outcome only in patients treated with surgery alone, and was not associated with a DFS or overall survival benefit from adjuvant FU-based chemotherapy (P interaction .04). The larger number of patients in this pooled analysis allowed an interesting exploration of treatment effect by MMR status and stage of cancer. Among stage III patients with intact MMR, adjuvant chemotherapy led to a statistically significant improvement in DFS (HR 0.64; 95% CI, 0.48 to 0.84; P .001), but no differences in outcome were seen in MMR-deficient stage III cancer (HR 1.01; 95% CI, 0.41 to 2.51; P .98). Among patients with stage II colon cancer, those with proficient MMR status had a nonsignificant 16% reduction in the relative risk of recurrence or death, whereas there was a trend toward worse outcome in tumors with MMR deficiency (P .09). These differential findings between deficient and intact MMR status, and between stage II and stage III colon cancer, are important and may have clinical implications for treatment. A strength of this pooled analysis by Sargent et al is its inclusion of large, international clinical trials that randomly assigned patients with colon cancer to both an adjuvant FU treatment arm and a nontreatment arm. This study design is critical for determining whether MSI-H is prognostic, predictive, or both. A prognostic biomarker is one that is associated with clinical outcome in the absence of therapy or with administration of standard therapy, and often reflects the natural history of the cancer. A control group from a randomized clinical trial is the ideal population to test the prognostic abilities of a marker, and indeed, Sargent et al demonstrate that deficient MMR status is a favorable prognostic marker for stage II and III colon cancer patients treated with surgery alone. In contrast, a predictive marker is one that is associated with differential response to a specific treatment (in this case, adjuvant FU), based on the status of the biomarker, and is statistically represented as a significant interaction between the biomarker and treatment response. With their large, pooled database, the authors were able to show that response to adjuvant FU-based chemotherapy is statistically dependent on MMR status. Thus, with these current data that tumors with MMR deficiency are both prognostic for better outcome and predictive for lack of benefit from adjuvant FU-based treatment, should such therapy be JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 20 JULY 1