TY - JOUR
T1 - A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naïve Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy
T2 - A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer
AU - McConkey, David J.
AU - Choi, Woonyoung
AU - Shen, Yu
AU - Lee, I. Ling
AU - Porten, Sima
AU - Matin, Surena F.
AU - Kamat, Ashish M.
AU - Corn, Paul
AU - Millikan, Randall E.
AU - Dinney, Colin
AU - Czerniak, Bogdan
AU - Siefker-Radtke, Arlene O.
N1 - Publisher Copyright:
© 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p = 0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p = 0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP.
AB - Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p = 0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p = 0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP.
KW - Basal
KW - Bevacizumab
KW - Dose-dense methotrexate cisplatin
KW - Gene expression profiling
KW - Luminal
KW - Neoadjuvant
KW - Subtype
KW - Urothelial cancer
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=84940703220&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940703220&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2015.08.034
DO - 10.1016/j.eururo.2015.08.034
M3 - Article
C2 - 26343003
AN - SCOPUS:84940703220
SN - 0302-2838
VL - 69
SP - 855
EP - 862
JO - European Urology
JF - European Urology
IS - 5
ER -