Response to Chemotherapy and Prognosis in Metastatic Colorectal Cancer With DNA Deficient Mismatch Repair

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Abstract

Background:

DNA deficient mismatch repair (dMMR) genes are associated with microsatellite instability and good prognosis in early-stage colorectal cancer (CRC). However dMMR is rare in metastatic CRC (mCRC) and little is known about its influence on treatment response rate (RR). The primary objective of this study was to compare the RR of patients with mCRC according to dMMR status.

Methods:

This was a retrospective study that compared the RR by Response Evaluation Criteria In Solid Tumors 1.1 criteria in patients with mCRC treated with chemotherapy according to dMMR status. All digital images were retrieved for RR evaluation by a single radiologist blinded to dMMR results. dMMR was defined as loss of immunohistochemistry expression of at least 1 of the MMR genes (MLH1, MSH2, MSH6, or PMS2). Cases were dMMR patients, and controls were proficient MMR (pMMR) patients (1:2 fashion). Based on clinical and molecular features, dMMR patients were classified as probable Lynch or sporadic.

Results:

From January 2009 to January 2013, 762 out of 1270 patients were eligible and screened for dMMR: n = 27 (3.5%) had dMMR mCRC and n = 735 (96.5%) had pMMR mCRC. Given the rarity, 14 dMMR cases outside the inclusion period were included (total 41 dMMR cases) and 84 controls (pMMR). By intention-to-treat analysis, considering all patients who received at least 1 dose of oxaliplatin-based chemotherapy (N dMMR = 34), those with dMMR had lower RR compared with those with pMMR (RR, 11.7% vs. 28.6%; odds ratio, 0.33; 95% confidence interval, 0.08-1.40; P = .088); patients with probable Lynch-related mCRC presented higher RR than subjects with probable sporadic dMMR (22.2% vs. 0%). dMMR was associated with BRAF mutations and poor prognosis, particularly in the sporadic subgroup (median survival, 29.8 vs. 5.9 months; P = .025).

Conclusion:

This study suggests that the dMMR phenotype is predictive of resistance to oxaliplatin-based chemotherapy. Apparently, such resistance is more pronounced in the sporadic dMMR phenotype, suggesting biological heterogeneity within the dMMR mCRC subgroup.

This study suggests that the DNA deficient mismatch repair (dMMR) phenotype is predictive of resistance to oxaliplatin-based chemotherapy in metastatic colorectal cancer. Patients with dMMR had numerically lower response rate compared with patients with proficient MMR (11.7% vs. 28.6%;P= .088). Furthermore, dMMR was associated with BRAF mutations and was factor of poor prognostic, particularly in sporadic versus Lynch-related tumors.

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