A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naïve Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer.
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.



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.



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.



Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests.



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.



GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease.



We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy.
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
David J
DJ
McConkey
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Woonyoung
W
Choi
Department of Statistics, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Yu
Y
Shen
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
I-Ling
IL
Lee
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Sima
S
Porten
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Surena F
SF
Matin
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Ashish M
AM
Kamat
Department of Genitourinary Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Paul
P
Corn
Essentia Health, Duluth, MN, USA.
Randall E
RE
Millikan
Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Colin
C
Dinney
Department of Pathology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA.
Bogdan
B
Czerniak
Department of Genitourinary Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address: asiefker@mdanderson.org.
Arlene O
AO
Siefker-Radtke
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage; D001859:Bone Neoplasms / Q000556:secondary*; D002295:Carcinoma, Transitional Cell / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D015653:Cystectomy; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D059467:Transcriptome; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage
D016159:Tumor Suppressor Protein p53; D000068258:Bevacizumab; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate
Basal; Bevacizumab; Dose-dense methotrexate cisplatin; Gene expression profiling; Luminal; Neoadjuvant; Subtype; Urothelial cancer; p53