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Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma.

ABSTRACT: Majority of patients with clear-cell renal cell carcinoma (ccRCC) at first line (1L) treatment are classified in the intermediate-risk (IR) subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. As these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment. Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall survival (OS) was defined from start of 1L therapy to death or last follow-up. A multivariable Cox model with backward selection procedure (? = 0.01) and a Classification and Regression Tree (CART) analysis were performed to identify which prognostic factors were associated to OS in IR patients. From 2005 to 2017, 777 patients with ccRCC were treated with an anti-VEGF 1L therapy. Among 571 evaluable patients for IMDC score, 290 (51%) were classified as IR. With median follow-up 5.8 years (min: 0, max: 12.4) 212 deaths (73%) were observed and median OS was 25 months. Only platelet count was significantly associated to OS (hazard ratio 1.88 [95% CI 1.27-2.88] p = 0.0017). Median OS for patients with PLT > UNL was 18 months [95% CI 12-23] versus 29 months [95% CI 21.4-35.7] for patients with normal PLT count. The selection of PLT count was confirmed on bootstrap samples and was also selected for the first split of the CART-tree analysis. Patients in the IR group have a heterogeneous prognosis. Elevated PLT count seems identifies a subgroup of patients with poor outcome in the IMDC intermediate-risk population with ccRCC.

SUBMITTER: Guida A

PROVIDER: S-EPMC7733622 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma.

Guida Annalisa A Le Teuff Gwénaël G Alves Carolina C Colomba Emeline E Di Nunno Vincenzo V Derosa Lisa L Flippot Ronan R Escudier Bernard B Albiges Laurence L

Oncotarget 20201208 49

Majority of patients with clear-cell renal cell carcinoma (ccRCC) at first line (1L) treatment are classified in the intermediate-risk (IR) subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. As these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment. Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall ...[more]

PMID: 33346231

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Project description:IntroductionGene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77-84], and an 8-gene signature model [Eur Urol 2015;67:17-20], in the setting of systemic therapy for metastatic disease.Materials and methodsMetastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy.ResultsOverall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk-ccA (n = 17)-and the high-risk-ccB (n = 37)-subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51-0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47-0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49-0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor.ConclusionThe ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:286-292 IMPLICATIONS FOR PRACTICE: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.

Project description:BACKGROUND:International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. MATERIALS AND METHODS:Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. RESULTS:Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. CONCLUSION:This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. IMPLICATIONS FOR PRACTICE:This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.

Dataset Information

Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma.

Publications

Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma.

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