Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma.
OBJECTIVE
The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.


METHODS
We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.


RESULTS
A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus.


CONCLUSIONS
In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Rana R
RR
McKay
Pfizer Oncology, Pfizer Inc., New York, New York.
Gustavo E
GE
Rodriguez
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Woman's Hospital, Boston, Massachusetts.
Xun
X
Lin
Department of Pharmacy and Clinical Support, Dana-Farber Cancer Institute, Boston, Massachusetts.
Marina D
MD
Kaymakcalan
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Woman's Hospital, Boston, Massachusetts.
Ole-Petter R
OP
Hamnvik
Department of Nephrology, Brigham and Woman's Hospital, Boston, Massachusetts.
Venkata S
VS
Sabbisetti
Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Rupal S
RS
Bhatt
Pfizer Oncology, Pfizer Inc., New York, New York.
Ronit
R
Simantov
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. toni_choueiri@DFCI.harvard.edu.
Toni K
TK
Choueiri
D000328:Adult; D000368:Aged; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077210:Sunitinib; D016896:Treatment Outcome
D000809:Angiotensins; D007211:Indoles; D011758:Pyrroles; C401859:temsirolimus; D000077210:Sunitinib; D020123:Sirolimus