Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy

Zaanan, Aziz; Shi, Qian; Taı̈eb, Julien; Alberts, Steven R.; Meyers, Jeffrey J.P.; Smyrk, Thomas C.; Julié, Catherine; Zawadi, Ayman; Tabernero, Josep; Mini, Enrico; Goldberg, Richard M.; Folprecht, Gunnar; Laethem, Jean‐Luc Van; Malicot, Karine Le; Sargent, Daniel; Laurent‐Puig, Pierre; Sinicrope, Frank

doi:10.1001/jamaoncol.2017.2899

Cited by 101 publications

(75 citation statements)

References 16 publications

(31 reference statements)

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“…Thus, most of the suggested genomic biomarkers have, at the best, a potential prognostic role in the early CRC, especially in stage III. Among them, the most relevant prognostic factor is the microsatellite instability (MSI) status of the tumor, reflecting a defect in DNA mismatch repair system . Other genetic alterations include BRAF and KRAS mutations, CpG island methylator phenotype (CIMP) and immune infiltrates …”

Section: Introductionmentioning

confidence: 99%

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Mini

Lapucci

Perrone

et al. 2019

Intl Journal of Cancer

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Five‐year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA‐sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease‐free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer‐related genes (n = 14) and cancer‐unrelated genes (n = 16). Three out of four down‐regulated genes were cancer‐related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

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Section: Introductionmentioning

confidence: 99%

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Mini

Lapucci

Perrone

et al. 2019

Intl Journal of Cancer

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“…The utility of adjuvant oxaliplatin in MSI high tumors has not been clarified, and therefore, major guidelines suggest not to change the indication for adjuvant FOLFOX/CAPOX based on MSI status. However, the favorable prognostic effect of MSI high status has been recently confirmed in a pooled analysis of 2 randomized phase III trials, the NCCTG N0147 and PETACC8 trials, where FOLFOX was the chemotherapy backbone for all patients (adjusted HR for DFS in favor of MSI high 0.73; 95% CI, 0.54–0.97; p 0.03) …”

Section: Discussionmentioning

confidence: 94%

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

Formica

Zaniboni

Loupakis

et al. 2018

Intl Journal of Cancer

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The eagerly awaited results of the multi-continental International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project have recently been presented at major oncological meetings. The 3-year disease-free survival (DFS) was presented for 12,834 Stage III colon cancer patients in a pooled analysis of 6 individual noninferiority phase III randomized trials, all investigating three versus six months of oxaliplatin-based adjuvant therapy. Noninferiority (NI) could not be demonstrated for the whole population as the DFS hazard ratio (HR) of 1.07 with its 95% CI of 1.00-1.15 crossed the postulated NI boundary of 1.12. However, there was an expected reduction in the incidence of specific side effects with the three months treatment. NI could be demonstrated for the T3N1 subgroup (∼60% of patients, HR for DFS 1.01, 95% CI 0.90-1.12). Moreover, NI was also declared for the subgroup treated with the CAPOX regimen (capecitabine plus oxaliplatin, ∼40% of patients), but the CAPOX choice was physician-based and not subject to randomization. Overall, the IDEA results indicate that three months of therapy might be adequate for most of Stage III tumors; however, a small subset of these patients still have high risk of recurrence and death with short treatment duration. Precise predictors of benefit need to be identified, nonetheless tumor-intrinsic factors, such as tumor stage, might currently be considered as useful tools to inform the decision-making process.

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“…Sample sizes of the selected studies ranged from 32 to 2693 (median, 266). Among these studies, 21 studies were conducted in Europe, 12 studies in Asia, 6 studies in America, 3 studies in Australia, and the remaining 9 studies were multicenter studies . Twenty‐seven studies were specifically restricted to patients with colon cancer, while other 24 studies investigated patients with colorectal cancer.…”

Section: Resultsmentioning

confidence: 99%

“…Among these studies, 21 studies were conducted in Europe, 6,17,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] 12 studies in Asia, [49][50][51][52][53][54][55][56][57][58][59][60] 6 studies in America, 16,[61][62][63][64][65] 3 studies in Australia, [66][67][68] and the remaining 9 studies were multicenter studies. [69][70][71][72][73][74][75][76][77] Twenty-seven studies were specifically...…”

Section: Study Characteristicsmentioning

confidence: 99%

Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis

et al. 2019

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DNA mismatch repair (MMR) status was considered to be a potential prognostic factor for colorectal cancer (CRC) but with conflicting reports, and varied in terms of TNM stages. Its relationship with prognosis in stage II-III CRC had not yet been systematically established. Therefore, we retrieved eligible studies published through May 2019, and screened out 51 studies that reported survival data (overall survival [OS] and/or disease-free survival [DFS]) in 28 331 CRC patients at stage II-III, totally 16.4% of whom were characterized as deficient MMR (dMMR). Significant associations of dMMR status were observed with longer OS (Hazard Ratio [HR] = 0.74, 95% CI: 0.68-0.82; P < .001), as well as DFS (HR = 0.67, 95% CI: 0.59-0.75, P < .001). However, dMMR patients received no statistically significant benefit from fluoropyrimidine-based treatment for either OS (HR = 0.84, 95%CI: 0.60-1.17; P = .31) or DFS (HR = 0.83, 95%CI: 0.60-1.15; P = .27), compared with that in proficient MMR (pMMR) patients for both OS (HR = 0.55, 95% CI: 0.43-0.71; P < .001)and DFS (HR = 0.60, 95% CI: 0.50-0.73; P < .001). Our analysis indicate that dMMR CRC patients at stage II-III had higher OS and DFS than pMMR ones, and fluoropyrimidine-based chemotherapy could improve survival in pMMR patients rather than dMMR ones.chemotherapy, colorectal cancer, DNA mismatch repair, prognosis † Zhujun Deng and Yun Qin contributed equally to this work

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Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy

Abstract: clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Cited by 101 publications

References 16 publications

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis

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