Published online Nov 15, 2019. doi: 10.4251/wjgo.v11.i11.1065
Peer-review started: May 9, 2019
First decision: July 31, 2019
Revised: August 10, 2019
Accepted: September 10, 2019
Article in press: September 10, 2019
Published online: November 15, 2019
Colorectal cancer (CRC) can arise through three distinct mutational pathways: Microsatellite instability, chromosomal instability, and CpG island methylator phenotype. We tested the hypothesis that CRC arising from the microsatellite-instability pathway through MLH1/MSH2-negative expression can lead a more favorable overall survival (OS) than MLH1/MSH2-positive patients. We also made an in-depth observation of the correlation between adjuvant chemotherapy and MLH1/MSH2 expression in different stages of CRC.
A larger sample size with a longer follow-up period was included to assess the effect of MLH1/MSH2 status on the prediction and prognosis of stage II-III CRC and its association with adjuvant chemotherapy. It is important for clinical doctors to choose optimal treatment regimen, especially adjuvant chemotherapy, for patients.
To evaluate the predictive and prognostic effects of MLH1/MSH2 status in stage II-III CRC patients and its significance in guiding adjuvant chemotherapy.
We analyzed 681 postoperative patients with CRC with a median follow-up period of 56 mo (range, 8.0–72.0 mo) between January 2013 and December 2016. The main outcome data included MLH1/MSH2-positive rate, MLH1/MSH2-negative rate, and long-term follow-up outcomes.
The outcomes showed that 550 patients were MLH1/MSH2-positive and 131 were MLH1/MSH2-negative. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and with poor differentiation and less mucin production (P < 0.05). Patients did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin. MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients (P < 0.001). In both stages II and III, MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95% confidence interval (CI): 2.241–7.369]. Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage III disease (P < 0.001, HR = 7.660, 95%CI: 2.974–15.883). Patients with stage II disease or MLH1/MSH2-positive stage III patients did not benefit from adjuvant chemotherapy.
MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC. MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage II-III CRC.
Our study demonstrated mismatch repair (MMR) is an important prognostic and predictive biomarker for stage II-III CRC, but we did not enroll the patients who used any PD-1/PD-L1 blocking therapy and had no data for survival improvement with different MMR statuses. In addition to detecting MMR status and tumor mutational burden, are there any indicators that are more sensitive to immunotherapy? The currently found immunologic drugs are only effective for high microsatellite instability (MSI-H)/dMMR population, but are ineffective for most patients with microsatellite stability (MSS). Would any new effective immune drugs be found for MSS patients? Is it possible to subdivide MSI-H (through the number of mutation sites) for enriching the dominant population in future? These issues will be the focal points and difficulty in our later research.