Adjuvant fluoropyrimidine-based therapy in patients with stage III colon carcinoma is the standard of care worldwide; however, it remains controversial for patients with stage II disease. An American Society of Clinical Oncology (ASCO) panel in 2004 concluded that routine administration of adjuvant therapy in stage II colon cancers was not recommended.29
Pooled analyses have demonstrated a modest 2% to 4% benefit in 5-year DFS for FU-based adjuvant therapy in stage II colon cancer,29,30
findings which were verified in the recent QUASAR (Quick and Simple and Reliable) study (5-year OS, 80.3% for chemotherapy, 77.4% for observation; HR, 0.83; P
The QUASAR data, coupled with updated results from the MOSAIC (Multicenter International Study of Oxaliplation/5FU-LV in the Adjuvant Treatment of Colon Cancer) trial demonstrating no benefit for adding oxaliplatin to FU/leucovorin in unselected patients with stage II disease7
or even high-risk patients with stage II disease,32
support single-agent, fluoropyrimidine-based therapy as the preferred therapy for a patient with stage II disease in whom chemotherapy is deemed appropriate.
The modest therapeutic benefit of FU-based therapy in patients with stage II disease emphasizes the need for prognostic and predictive markers to risk-stratify patients. Fundamental principles of clinical trials require that predictive marker validation be from trials that randomly assigned patients between the treatments for which the marker is purported to predict differential efficacy. To our knowledge, only the previous report of Ribic et al20
and the current analysis meet this level of evidence.
Our findings in the independent data set assembled for this project are consistent and supportive of the findings of Ribic et al.20
MMR status was a significant prognostic factor in untreated patients in univariate analysis. Although the prognostic effect was not maintained in multivariate models, the estimated HRs suggest a strong protective effect. The prognostic importance of dMMR has been additionally confirmed recently in two large studies of patients with stage II disease.33,34
Regarding dMMR as a predictive factor, in multivariate models no benefit of treatment was observed in patients with dMMR tumors (HR, 1.39; P
The new data presented support MMR status as a clinically useful marker in patients being considered for fluoropyrimidine-based therapy, in particular in patients with sporadic stage II colon cancer. First, the favorable prognosis of patients with dMMR (v pMMR) colon cancers supports a no–adjuvant-treatment approach, a strategy already implemented in the ongoing US Intergroup trial E5202. Second, the lack of benefit from FU-based chemotherapy in patients with dMMR tumors indicates that such patients should not receive FU-based adjuvant chemotherapy. A recommendation for observation can spare such patients treatment-related toxicities, expense, and reduced quality of life during chemotherapy.
Our data do not support pMMR as a sole risk factor to recommend adjuvant treatment for patients with stage II disease. MSS and MSI-L tumors comprise the majority (80% to 85%) of colorectal cancers at all stages. In patients with pMMR tumors, decisions regarding adjuvant therapy should be based on other factors that indicate a high-risk patient, such as a T4 tumor, tumor perforation, bowel obstruction, poor differentiation, venous invasion, or fewer than 12 lymph nodes examined.5
Although the presence of dMMR appears to be an important predictive marker for stage II colon cancer, there are several cautionary notes. Patients in this analysis were drawn from multiple clinical trials conducted between 20 and 30 years ago in multiple countries. However, we felt the need to obtain data from the scarce trials that included a randomly assigned surgery-alone control arm outweighed this limitation. Second, although the current study and others35,36
provide substantial evidence that patients with dMMR colon cancers do not benefit from adjuvant FU/leucovorin, the current standard adjuvant therapy for stage III disease is infusional fluorouracil, leucovorin, and oxaliplatin. Preliminary data suggests that adding either oxaliplatin or irinotecan to FU/leucovorin may overcome the resistance observed to FU/leucovorin in patients with dMMR37,38
; however, this requires confirmation in samples from randomized trials. Thus available data do not justify excluding patients with stage III disease and dMMR tumors from infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy.
The molecular etiology of tumors involving dMMR is heterogeneous, involving several different genes and numerous mechanisms of gene inactivation, including epigenetic, somatic and germline alterations. Among sporadic colon cancer, the vast majority of occurrences with dMMR are due to inactivation of MLH1
(approximately 95%), and MSH2
account for a much smaller percentage (approximately 5% and less than 1%, respectively).39
, the most common mechanism (approximately 90%) of gene inactivation is promoter hypermethylation.40
In this series, tissue was inadequate to allow hypermethylation and/or BRAF
testing. However, as the vast majority of clinical trials represent unselected patients, the majority of dMMR occurrences will almost certainly be due to loss of MLH1
from promoter hypermethylation. Thus, the results derived from these trials primarily reflect the biology of sporadic MLH1
occurrences. Because dMMR tumors arising from other mechanisms represent a small subset of patients, we are not able to determine the prognostic and/or predictive value of MMR status in such patients. A final caution recognizes that, although greater than 1,000 occurrences were obtained for this pooled analysis, the absolute number of dMMR occurrences remains modest. To our knowledge, a single, large trial— the QUASAR study31
—remains possibly available to additionally confirm these findings30
; analyses of the predictive value of dMMR in that study are of interest.
Several hypotheses have been proposed to provide biologic mechanism(s) by which FU-based adjuvant chemotherapy does not benefit patients with dMMR. Possibilities include an antitumor immune response characterized by the lymphocytic infiltrate characteristic of dMMR tumors,41
which may be abrogated by the immunosuppressive effects of chemotherapy. In vitro studies have predicted differential efficacy of FU between dMMR versus pMMR tumors.42,43
A final hypothesis relates to the role of MMR systems in the removal of FU from DNA, whereby the absence of MMR may reduce repair DNA synthesis and thus attenuate the FU effect.44
The biologic question of whether FU-based adjuvant chemotherapy is of no benefit or is actually harmful in patients with dMMR tumors is not conclusively addressed by this study; however, neither possibility supports adjuvant treatment for such patients.
Extensive research is ongoing to identify multigene signature panels that are prognostic, predictive, or both in patients with stages II and III colon cancer.34,45–48
The relative utility of dMMR as a single test versus these multigene panels remains unknown; an initial report suggests that, for one panel, the two methods provide independent prognostic ability.34
It seems likely that MMR status may ultimately become integrated into a multigene panel.
In conclusion, this prospectively specified analysis of data from randomized, clinical trials provides independent, supportive evidence of the following: dMMR colon cancers have a favorable stage-adjusted prognosis compared with the majority of colon cancers; and patients with dMMR colon cancers do not benefit from FU-based adjuvant therapy. These findings support the conclusion that average-risk patients with colon cancer who are considered for FU-based adjuvant therapy should have the tumor MMR status assessed to inform the likelihood of patient benefit of chemotherapy. Our conclusions are restricted to patients being considered for single-agent, fluoropyrimidine-based therapy (ie, patients with stage II disease), and the conclusions provide guidance as to who should not be treated (ie, the dMMR subset). We believe that dMMR status in the setting of stage II disease should be considered a clinically useful marker of tumor biology and represents an additional step in individualized cancer therapy.