Article Dans Une Revue Clinical Cancer Research Année : 2023

Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma

1 University of Leeds
2 St James's University Hospital
3 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
4 McGill University = Université McGill [Montréal, Canada]
5 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
6 GIN - [GIN] Grenoble Institut des Neurosciences
7 Karolinska Institutet [Stockholm]
8 IMCS - Institute of Mathematics and Computer Science
9 CSIRO - Commonwealth Scientific and Industrial Research Organisation [Australia]
10 Cornell University [New York]
11 Leeds Teaching Hospitals NHS Trust
12 Newcastle Upon Tyne Hospitals NHS Foundation Trust
13 NHS Foundation Trust [London]
14 UON - University of Nottingham, UK
15 West Pomeranian University of Technology Szczecin
16 UK - Univerzita Karlova [Praha, Česká republika] = Charles University [Prague, Czech Republic]
17 University Hospital Motol [Prague]
18 Palacky University Olomouc
19 N.N. Blokhin Russian Cancer Research Center
20 N.N. Blokhin National Medical Research Center of Oncology
21 MMCI - Masaryk Memorial Cancer Institute
22 INSP - National Institute of Public Health [Romania]
23 UMPCD - University of Medicine and Pharmacy “Carol Davila”
24 University of Belgrade [Belgrade]
25 Military Medical Academy [Serbia]
26 Equipe BIOETHICS (CERPOP)
27 European Molecular Biology Laboratory [Hinxton]
28 CNRGH - Centre National de Recherche en Génomique Humaine
29 Department of Human Genetics [Montréal]
30 Department of Anthropology [McGill University]
Lars Egevad
Peter J Selby
Adebanji Adeyoju
Poulam M Patel
Antonin Brisuda
Vladimir Janout
Lenka Foretova
Marie Navratilova
Ljiljana Bogdanovic
Bozidar Kovacevic
Anne Cambon-Thomsen

Résumé

Purpose: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. Experimental Design: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. Results: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. Conclusions: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.
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cea-04342730 , version 1 (13-12-2023)

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Naveen S Vasudev, Ghislaine Scelo, Kate I Glennon, Michelle Wilson, Louis Letourneau, et al.. Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma. Clinical Cancer Research, 2023, 29 (7), pp.1220-1231. ⟨10.1158/1078-0432.ccr-22-1936⟩. ⟨cea-04342730⟩
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