Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma Journal Article

Authors: Hsieh, J. J.; Chen, D.; Wang, P. I.; Marker, M.; Redzematovic, A.; Chen, Y. B.; Selcuklu, S. D.; Weinhold, N.; Bouvier, N.; Huberman, K. H.; Bhanot, U.; Chevinsky, M. S.; Patel, P.; Pinciroli, P.; Won, H. H.; You, D.; Viale, A.; Lee, W.; Hakimi, A. A.; Berger, M. F.; Socci, N. D.; Cheng, E. H.; Knox, J.; Voss, M. H.; Voi, M.; Motzer, R. J.
Article Title: Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma
Abstract: Background Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. Objective To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participants Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysis Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitations Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. Conclusions PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summary Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies. © 2016 European Association of Urology
Keywords: sunitinib; tumor suppressor gene; targeted therapy; kidney cancer; everolimus; bap1; setd2; pbrm1; genomic biomarker; kdm5c
Journal Title: European Urology
Volume: 71
Issue: 3
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2017-03-01
Start Page: 405
End Page: 414
Language: English
DOI: 10.1016/j.eururo.2016.10.007
PROVIDER: scopus
PUBMED: 27751729
PMCID: PMC5431298
Notes: Article -- Export Date: 2 February 2017 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Robert Motzer
    744 Motzer
  2. Martin Henner Voss
    126 Voss
  3. Yingbei Chen
    221 Chen
  4. Agnes Viale
    205 Viale
  5. James J Hsieh
    114 Hsieh
  6. Nancy Bouvier
    30 Bouvier
  7. Umeshkumar Kapaldev Bhanot
    37 Bhanot
  8. Nicholas D Socci
    182 Socci
  9. Emily H Cheng
    55 Cheng
  10. Michael Forman Berger
    380 Berger
  11. Helen Hyeong-Eun Won
    79 Won
  12. William Lee
    38 Lee
  13. Abraham Ari Hakimi
    129 Hakimi
  14. Daoqi You
    20 You
  15. Patricia Ibai Wang
    12 Wang