Abstract CT241: Gene expression profiling in the context of neoadjuvant chemotherapy with DDMVAC+B (dose dense methotrexate, vinblastine, doxorubicin, cisplatin, and bevacizumab) can predict clinical outcomes and tumor biology
Authors: Siefker-Radtke Arlene O. , Choi Woonyoung , Melquist John , Shen Yu , Kamat Ashish , Matin Surena , Millikan Randall , Dinney Colin P. , Czernial Bodgan A. , McConkey David J. 
Published: May 2015

Abstract
Background: Gene expression profiling (GEP) of bladder cancer at cystectomy suggests 3 main intrinsic subtypes of urothelial cancer: basal, which historically has the worst prognosis and is associated with high proliferation, increased EMT plasticity, TP63, and HIF-1 expression; p53-like/luminal A, a subtype with decreased proliferation and increased markers of extracellular matrix; and luminal B which has increased proliferation compared with luminal A tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict subtypes more likely to benefit from chemotherapy.
Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients.
Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 45%, respectively. GEP of TUR suggested the greatest downstaging with basal (n=11, pT0N0 = 45%, ≤pT1N0=55%) and luminal B tumors (n=16, pT0N0=31%, ≤pT1N0=56%), compared to luminal A (n=12, pT0N0=25%, ≤pT1N0=33%). The basal subtype had an improved survival as compared to the luminal subtypes (5 year OS 91% and 51%, respectively, log-rank p=0.047.) On multivariate analysis, pathologic stage and TUR subtype were independent predictors of outcome (pStage: HR 4.6, CI 2.0-10.3, p=0.0003, luminal B: HR 13.2, CI 1.4-120.9, p=0.02, luminal A:HR 5.7, CI 0.69-46.9, p=0.1). Development of bone metastases had a poor prognosis (OS 15 months, vs not reached, p≤ 0.00001), and were associated with luminal A subtype developing in 50% of the luminal A, 19% of luminal B, and none in the basal subtypes(p=0.015). All three of the luminal B tumors at TUR with bone metastases displayed a luminal A subtype at cystectomy. The luminal A subtype was the most frequent subtype remaining at cystectomy, and was observed in 19/33 (58%) of cases overall, with basal changing to luminal A subtype in 2/5 (40%) and luminal B to luminal A in 7/9 (77%) of cases, suggesting that luminal A is associated with chemotherapy-resistance.
Conclusions: In contrast to historical expectations, the basal subset had an improved survival in patients receiving neoadjuvant chemotherapy, potentially reflecting increased chemosensitivity observed in this group. Bone metastases were associated with the luminal A subtype on TUR and/or cystectomy, potentially related to the impact of stromal factors in patients with these tumors. The “shift” to luminal A at cystectomy in those who failed neoadjuvant chemotherapy, suggests this subtype may be associated with chemotherapy-resistance.
Citation Format: Arlene O. Siefker-Radtke, Woonyoung Choi, John Melquist, Yu Shen, Ashish Kamat, Surena Matin, Randall Millikan, Colin P. Dinney, Bodgan A. Czernial, David J. McConkey. Gene expression profiling in the context of neoadjuvant chemotherapy with DDMVAC+B (dose dense methotrexate, vinblastine, doxorubicin, cisplatin, and bevacizumab) can predict clinical outcomes and tumor biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT241. doi:10.1158/1538-7445.AM2014-CT241