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

Alex, Alexandra Khichfy; Siqueira, Sílvia Regina Dowgan Tesseroli de; Coudry, Renata A.; Santos, Juliana Ferreira Lobo dos; Alves, Marcı́lio; Hoff, Paulo M.; Riechelmann, Rachel P.

doi:10.1016/j.clcc.2016.11.001

Cited by 50 publications

(38 citation statements)

References 32 publications

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“…The median OS observed in our study was higher than the median OS observed in smaller and older series on dMMR/MSI mCRC (11–14 months) . Some studies report a similar median OS of 16–21 months in dMMR/MSI mCRC . Interestingly, a study matched 75 cases of dMMR/MSI mCRC with 75 cases of pMMR/MSS mCRC (age, gender, disease sidedness and metachronous/synchronous) and no survival difference according to MMR status was identified .…”

Section: Discussioncontrasting

confidence: 76%

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Tougeron

Sueur

Zaanan

et al. 2020

Intl Journal of Cancer

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Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically Additional Supporting Information may be found in the online version of this article. ratio; ICI: immune checkpoint inhibitors; IHC: immunohistochemistry; IPTW: inverse of probability of treatment weighting; mCRC: metastatic CRC; MSI: microsatellite instability; OS: overall survival; PFS: progression-free survival; pMMR: proficient mismatch repair; RR: response rate Tumor Markers and Signatures significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00-3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.What's new? Some reports suggest short overall survival (OS) and chemoresistance of mismatch repair-deficient and/or microsatellite instability-high metastatic colorectal cancers (dMMR/MSI mCRC). In a large multicenter series of dMMR/MSI mCRC we observed a relatively long OS but short progression-free survival. Irinotecan-based chemotherapy was not associated with better OS than oxaliplatin-based chemotherapy but anti-VEGF, as compared to anti-EGFR, was associated with a trend to longer OS. These results could help clinicians to choose treatment in patients with dMMR/MSI mCRC.

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Section: Discussioncontrasting

confidence: 76%

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Tougeron

Sueur

Zaanan

et al. 2020

Intl Journal of Cancer

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“…The regimens in our study were mFOLFOX and CapeOx, which used higher doses of 5-FU than some previous studies. The dose of continuous 5-FU (2900 mg/m 2 , every 2 weeks) in our study was higher than the dose that Alex et al 19 used (500 mg/m 2 every week). des Guetz et al 18 have proved that patients with MSI colon cancer are sensitive to FOLFOX6 (5-FU 2800 mg/m 2 ) than mFOLFOX4 (5-FU 2200 mg/m 2 ).…”

Section: Discussioncontrasting

confidence: 70%

Microsatellite instability and sensitivity to fluoropyrimidine and oxaliplatin containing first-line chemotherapy in metastatic colorectal cancer

2018

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ObjectivesTo examine the effect of microsatellite instability (MSI) on the outcome of fluoropyrimidine and oxaliplatin containing first-line chemotherapy in metastatic colorectal cancer (mCRC).MethodsPatients with mCRC and treated with fluoropyrimidine/oxaliplatin first-line chemotherapy were included in our study. Demographic data, tumour characteristics, chemotherapy regimens, treatment responses and progression-free survival (PFS) were collected from medical records. The MSI analysis was performed using fluorescence-based PCR, and divided into MSI-high (MSI-H) and MSI-low (MSI-L)/microsatellite stable (MSS). Statistical analysis used Kaplan-Meier method, log-rank test and multivariate Cox model.ResultsFrom 1 January 2015 to 1 May 2016, a total of 192 patients with mCRC were included in our study. Among these, 14 (7.29%) exhibited MSI-H and 178 (92.71%) were MSI-L/MSS. The objective response rate (p=0.79), disease control rate (p=0.22) and PFS (p=0.22) of fluoropyrimidine/oxaliplatin first-line chemotherapy were not significantly different between MSI-H and MSI-L/MSS tumours. But MSI-H tumours had a trend to better disease control rate (71.43% vs 54.49%) and PFS (6.50 m vs 5.40 m) than MSI-L/MSS tumours. Multivariate analysis indicated that MSI was not a predictive factor for PFS (p=0.18).ConclusionThe effect of fluoropyrimidine/oxaliplatin first-line chemotherapy was not significantly different between MSI-H and MSI-L/MSS tumours. However, MSI-H tumours tended to have better disease control rate and PFS.

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“…High CpG island methylator phenotype and microsatellite instability as well as hypermutation within DNA mismatch repair (MMR), MAPK, TGF-β and insulin signalling pathways are prevalent in the right-sided disease compared with its counterpart 22 37–39. The MMR-deficient status impairs genomic stability, leading to carcinogenesis, chemoresistance and progression of the disease 40 41. Meanwhile, chromosome instability, mutations of APC , SMAD4 and P53 as well as EGFR amplification are frequently detected within the left-sided CRC,42 43 while the low instability of genome-wide copy number alterations within right-sided mCRC confers no additional benefit from bevacizumab, resulting in drug resistance 44.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials

et al. 2020

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BackgroundMonoclonal antibodies of anti-epidermal growth factor receptor (EGFR) have been recommended as first-line therapy for patients with left-sided metastatic colorectal cancer (mCRC) with wild-type RAS. The effect of tumour laterality on antivascular endothelial growth factor antibody and how to optimise targeted therapies for the right-sided cases remain controversial.Patients and methodsA comprehensive meta-analysis enrolling 16 first-line clinical trials was performed to evaluate the efficacy of chemotherapy alone and chemotherapy plus targeted therapies for patients with mCRC with right primary tumour site, and we validated the results in metastatic setting (14 trials containing 4306 patients with unresectable mCRC).ResultsHere, we found that progression-free survival (PFS) (combined HR 1.30, 95% CI 1.17 to 1.44) and overall survival (OS) (combined HR 1.46, 95% CI 1.32 to 1.62) of the right-sided patients were significantly inferior to the left-sided individuals receiving chemotherapy alone in overall population, regardless of race. Similar results were also observed in metastatic setting. OS of patients with left-sided mCRC receiving chemotherapy plus bevacizumab was superior to the right-sided individuals (combined median survival ratio (MSR)=1.23, 95% CI 1.08 to 1.39 for overall population; combined MSR=1.23, 95% CI 1.05 to 1.45 for metastatic setting), especially for wild-type RAS and mixed population. Moreover, the right-sided patients benefited more from chemotherapy plus bevacizumab comparing with chemotherapy alone in both overall population and metastatic setting. Importantly, the RAS-wild right-sided patients achieved longer PFS (combined HR 0.67, 95% CI 0.52 to 0.88) and OS (combined HR 0.74, 95% CI 0.56 to 0.98) from chemotherapy plus bevacizumab comparing with chemotherapy associated with anti-EGFR agents.ConclusionsPatients with right-sided mCRC show impaired chemosensitivity, and chemotherapy plus bevacizumab can be an optimal first-line therapeutic regimen for the RAS-wild patients with right-sided mCRC.

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

Cited by 50 publications

References 32 publications

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Microsatellite instability and sensitivity to fluoropyrimidine and oxaliplatin containing first-line chemotherapy in metastatic colorectal cancer

Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials

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