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A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naive 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.

ABSTRACT: 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. CONCLUSION: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. PATIENT SUMMARY: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.

SUBMITTER: McConkey DJ

PROVIDER: S-EPMC4775435 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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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.

McConkey David J DJ Choi Woonyoung W Shen Yu Y Lee I-Ling IL Porten Sima S Matin Surena F SF Kamat Ashish M AM Corn Paul P Millikan Randall E RE Dinney Colin C Czerniak Bogdan B Siefker-Radtke Arlene O AO

European urology 20150903 5

<h4>Background</h4>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.<h4>Objective</h4>To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B ...[more]

PMID: 26343003

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Project description:Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer.Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).The data from 205 patients were analyzed-59 patients were included in the discovery set and 146 in an independent replication cohort-from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate.Germline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.

Project description:Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis.The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

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A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naive 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.

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