Efficacy of systemic treatment for metastatic renal cell carcinoma (mRCC) guided by comprehensive genomic profiling (CGP).

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 63-63
Author(s):  
Paulo Gustavo Bergerot ◽  
Cristiane Decat Bergerot ◽  
Nazli Dizman ◽  
Nicholas Salgia ◽  
Joann Hsu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

63 Background: Comprehensive genomic profiling (CGP) has been used to guide treatment selection in metastatic renal cell carcinoma (mRCC). This study sought to determine if genomic alterations guided treatment and contributed to improved outcomes. Methods: From a single institution, patients (pts) diagnosed with mRCC who had CGP in the course of clinical care were identified. Pts were tested on a CLIAA-certified platform (FoundationOne; Cambridge, MA). Pts who died/initiated hospice within the 30 days after the test was performed or who were lost to follow-up were excluded. Duration of therapy (DOT) was measured as months between first and last day of therapy following CGP test. The Kaplan-Meier method was undertaken to estimate the association of CGP-directed therapy with overall survival (OS). Cox regression was also performed and adjusted for histologic subgroup. Results: A total of 64 patients underwent CGP between February 2014 and August 2018. From this group, 15 patients were excluded due to death/hospice within 30 d (n = 10) and lack of follow-up (n = 5). Median age at diagnosis was 60 years (range, 24-84), and 79% were male. Most patients (69%) were diagnosed with clear cell RCC. The median identified genomic alterations (GAs) was 3 (range, 0-7). The most common GAs were VHL (54%), PBRM1 (28%), TERT (21%), TP53 (15%), BAP1 (13%), and SETD2 (13%). Of the 49 patients included in this analysis, 47% had actionable mutations based on their CGP results. Of those, 13 patients received directed-therapy of whom 57% had stable disease, 28% had partial response, and 14% had progressive disease. The median time from CGP test to treatment was 1 month (range, 0-17). The median duration of directed-therapy was 12 months (range, 1-28) and of non-directed therapy was 4 months (range, 1-40) (P = 0.04). Directed-therapy was significantly associated with better OS (adjusted HR, 0.32 [95% CI, 0.13 to 0.82]; P = 0.018) compared to non-directed therapy. Conclusions: This study provides preliminary evidence to justify CGP-guided therapy in mRCC. Forthcoming studies should prospectively explore the use of CGP in treatment allocation for mRCC to validate these findings.

Correlation between findings from comprehensive genomic profiling and targeted therapy response in metastatic renal cell carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 570-570 ◽  
Author(s):  
Thai Huu Ho ◽  
Toni K. Choueiri ◽  
Kai Wang ◽  
Jose A. Karam ◽  
Zachary Rockow Chalmers ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clinical Care ◽  
Predictive Biomarkers ◽  
Genomic Profiling ◽  
Duration Of Treatment ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

570 Background: Vascular endothelial growth factor- (VEGF-) and mammalian target of rapamycin- (mTOR-) directed therapies represent a standard of care in metastatic renal cell carcinoma (mRCC). However, these agents are not employed based on an assessment of predictive biomarkers such as genomic alterations (GA). We sought to determine if an association exists between GA detected by comprehensive genomic profiling (CGP) and the response to VEGFR and mTOR pathway targeted therapies in a cohort of mRCC treated in a clinical practice setting. Methods: The results of CGP performed in the course of clinical care on 31 consecutive mRCC obtained from patients who had received VEGFR- and/or mTOR-inhibitors were reviewed. Duration of treatment (DOT), extent and duration of clinical response was obtained from review of medical records. All classes of genomic alterations - base substitutions, short insertions, deletions, gene fusions, rearrangements and copy number - were assessed via CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents. Results: The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%) and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT > 21 months) were more frequent amongst patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1. Conclusions: Multiple GAs are more prevalent in exceptional responders to VEGF-directed therapy. Prospective validation of these findings may lead to use of CGP to optimize therapeutic selection.

Comprehensive genomic profiling of renal cell carcinoma with sarcomatoid dedifferentiation to pinpoint recurrent genomic alterations.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 537-537
Author(s):  
Gabriel G. Malouf ◽  
Siraj Mahamed Ali ◽  
Kai Wang ◽  
Sohail Balasubramanian ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Genomic Features ◽  
Routine Clinical Care ◽  
Comprehensive Genomic Profiling ◽  
Worse Prognosis

537 Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is found in five percent of all renal cell carcinoma (RCC) cases, and has a significantly worse prognosis relative to matched highgrade RCC with only epithelial elements. The genomic features underpinning sRCC are not well understood, and at present, there are no specific or effective therapies for sRCC. Methods: We conducted comprehensive genomic profiling (CGP) on paired epithelial and sarcomatoid areas of 3 sRCC cases. In the course of routine clinical care, CGP was performed on another 23 sRCC harboring diverse epithelial components. CGP was conducted using a hybrid capture next generation DNA sequencing assay(NGS) of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC devoid of sarcomatoid component, and with clear cell TCGA. Results: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Conclusions: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations.

Genomic alterations to refine prognostication of patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 626-626 ◽  
Author(s):  
Dominick Bosse ◽  
Wanling Xie ◽  
Aly-Khan A. Lalani ◽  
Guillermo de Velasco ◽  
Martin Henner Voss ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Value ◽  
Kinase Inhibitors ◽  
Cox Regression ◽  
Risk Groups ◽  
Genomic Alterations ◽  
Endothelial Growth Factor

626 Background: The IMDC risk score is a valid and simple tool to prognosticate patients (pts) with metastatic renal cell carcinoma (mRCC). Some non-VHL common genomic alterations may be associated with outcomes. We therefore assessed the prognostic value of most commonly mutated genes in mRCC beside VHL overall, and within IMDC risk groups. Methods: We identified patients treated at Dana-Farber Cancer Institute (n = 65) or part of TCGA (n = 33) who had genomic data available and were treated with first line vascular endothelial growth factor tyrosine kinase inhibitors. Information on genomic alterations (GA) focused on PBRM1, BAP1, SETD2, KDM5C and TP53 was extracted. Cox regression was performed to assess the association of each GA with overall survival (OS), adjusting for IMDC risk groups and age. Results: Overall, 98 pts were identified. 96/98 pts had clear-cell histology. Pts distribution by IMDC risk groups was: 7% good, 58% intermediate, 27% poor and 8% unknown. Mutation rates were 27% PBRM1, 17% BAP1, 29% SETD2, 9% KDM5C and 8% TP53. In multivariable models, there was an association between GA and worse OS for BAP1 and BAP1 or TP53 combined (Table). When stratified by IMDC risk groups, GA in BAP1 or TP53 was associated with shorter median OS in poor risk pts [12.1 mo (95%CI 8.3- 24.0) v. 27.6 mo (95%CI 18.9- 53.4), aHR 4.64 (95%CI 1.32-16.4), p = 0.017] and a trend toward worse median OS in intermediate risk pts [20.5 mo (95%CI 7.4-54.6) v. 36.3 mo (95%CI 21.1, NR), aHR 2.11 (95%CI 0.94-4.74)] compared to pts without GA in BAP1 or TP53. Too few death events were observed in good risk pts to assess the prognostic value of GA in BAP1 or TP53. Conclusions: GA in BAP1 or TP53 are prognostic in mRCC and further discriminate pts with distinct outcomes within IMDC risk groups. Validation in larger dataset is ongoing. [Table: see text]

Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling

2018 ◽  
Vol 73 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Sumanta K. Pal ◽  
Siraj M. Ali ◽  
Evgeny Yakirevich ◽  
Daniel M. Geynisman ◽  
Jose A. Karam ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Papillary Renal Cell Carcinoma ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Clinical Cases

scholarly journals Age at diagnosis is a determinant factor of renal cell carcinoma– specific survival in patients treated with nephrectomy

2008 ◽  
Vol 2 (6) ◽  
pp. 610 ◽  
Author(s):  
Pierre I. Karakiewicz ◽  
Claudio Jeldres ◽  
Nazareno Suardi ◽  
George C. Hutterer ◽  
Paul Perrotte ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Cubic Spline ◽  
Age At Diagnosis ◽  
Fuhrman Grade ◽  
Effect Of Age

Objective: Based on combined data for 4880 patients, 2 previous studies reported that advanced age is a predictor of increased renal cell carcinoma–specific mortality (RCC-SM). We explored the effect of age in cubic spline analyses to identify the age groups with the most elevated risk for renal cell carcinoma (RCC).Methods: Our study included 3595 patients from 14 European centres who had partial or radical nephrectomies. We used the Kaplan–Meier method to compile life tables, and we performed Cox regression analyses to assess RCC-SM. Covariates included age at diagnosis, sex, TNM (tumour, node, metastasis) stage, tumour size, Fuhrman grade, symptom classification and histological subtype.Results: Age ranged from 10 to 89 (mean 63, median 67) years. The median duration of follow-up was 2.9 years. The median survival for the cohort was 13.4 years. Stage distribution was as follows: 1915 patients (53.3%) had stage I disease, 388 (10.8%) had stage II, 895 (24.9%) had stage III and 397 (11.0%) had stage IV disease. In multivariate analyses, we coded age at diagnosis as a cubic spline, and it achieved independent predictor status (p < 0.001). The risk of RCC-SM was lowest among patients younger than 50 years. We observed an increase in RCC-SM until the age of 50, at which point the level of risk reached a plateau. We observed a second increase among patients aged 75–89 years. We found similar patterns when we stratified patients according to the 2002 American Joint Committee on Cancer (AJCC) stages.Conclusion: The effect of age shows prognostic significance and indicates that follow-up and possibly secondary treatments might need to be adjusted according to the age of the patient.

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