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Mitochondrial microsatellite instability in patients with metastatic colorectal cancer.

ABSTRACT: Mitochondrial microsatellite instability (mtMSI), a change in length in mtDNA microsatellite sequences between normal and tumor tissue, has been described as a frequent occurrence in colorectal cancer (CRC). We evaluated the prevalence and prognostic value of mtMSI and its relation to nuclear microsatellite instability (MSI) in patients with metastatic CRC (mCRC). At six loci (D310, D514, D16184, ND1, ND5, and COX1), the mitochondrial DNA sequence was analyzed in normal and tumor tissue, and the mtMSI status was determined. We evaluated the prevalence and outcome in terms of overall survival (OS) in 83 CRC patients with a MSI tumor (including 39 patients with Lynch syndrome) and in 99 mCRC patients with a microsatellite stable (MSS) tumor. A meta-analysis was performed to compare our findings with existing data. mtMSI at the D-loop region was found in 54.4 % (99 out of 182) of all patients. Prevalence of mtMSI was most pronounced at the D310 locus (50.5 %). Prevalence of mtMSI at the D-loop region was not different among patients with MSI compared to MSS tumors. There was no effect of mtMSI on prognosis in patients with MSI or MSS tumors. Prevalence of mtMSI was high in mCRC patients with both MSI and MSS tumors, but there was no correlation with prognosis. mtMSI was particularly present at the D310 locus.

SUBMITTER: Venderbosch S

PROVIDER: S-EPMC4422840 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceOnly 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting.ObjectivesTo determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC.Design, setting, and participantsThe SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis.InterventionsPatients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal.Main outcome and measuresThe primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population).ResultsA total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months.ConclusionsThe SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile.Trial registrationClinicalTrials.gov Identifier: NCT03186326.

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Mitochondrial microsatellite instability in patients with metastatic colorectal cancer.

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