Radical cystectomy is the standard therapeutic option for patients with muscle-invasive bladder cancer. However, 5-year overall survival for high-risk patients with pT3, pT4, pN-negative, and pN-positive M0 bladder cancer after radical cystectomy is only about 50% and ranges from 32% in patients with lymph node involvement to 75% in those without lymph node involvement. Optimal removal of adequate numbers of pelvic lymph nodes is fundamental.¹ Recurrence is mainly due to systemic occult disease that was present at the time of cystectomy. Neoadjuvant or adjuvant systemic chemotherapy has been recommended in this setting for patients at high risk of recurrence based mainly upon clinical and pathologic features.

There is more level 1 evidence from meta-analyses for the use of neoadjuvant than adjuvant chemotherapy, but in most countries, immediate cystectomy is usually the preferred option.² Identifying those patients who would derive the most benefit from these therapies is of utmost importance.

As reviewed in this issue of The ASCO Post, Mitra and colleagues have reported identification of a genomic signature that predicts postcystectomy recurrence in high-risk patients.³ This study was performed at the University of Southern California in collaboration with a molecular diagnostics company. Two-thirds of the patients were allocated to a discovery set, and one-third was placed in the validation set.

Patients underwent radical cystectomy and lymph node dissection at the same university hospital between 1998 and 2004, and all patients had a minimum of 2 years of follow-up. In the discovery set of 141 patients, 54 patients (41%) received adjuvant chemotherapy as per physician and patient preference, as did 34 (52%) of the 66 patients in the internal validation set. The clinical endpoint for discovery was recurrence-free survival, defined as the time from cystectomy to local recurrence or recurrence at distant soft-tissue sites.

Genomic Classifier Helps Predict Recurrence

Formalin-fixed paraffin-embedded cystectomy specimens were evaluated for histopathology, RNA extraction, and gene-expression profiling. The investigators identified a novel 15-marker gene-expression signature, a genomic classifier, which when added to clinical and pathologic prognostic features could help to predict high- and low-risk patients for recurrence following radical cystectomy. The genomic classifier is composed of biologically important RNA sequences that are involved in cell proliferation and differentiation, apoptosis, cell-cycle and transcriptional regulation, and signal transduction. All of these processes are associated with tumor development and progression. Four of the transcripts within the genomic classifier had been previously ­described.

The prognostic ability of the genomic classifier was compared with two clinical nomograms for predicting risk of recurrence: that of the International Bladder Cancer Nomogram Consortium (IBCNC) and the investigators’ own clinical classifier, which included age, gender, pathologic stage, and lymphovascular invasion. Their work suggested that combining the genomic classifier with the clinical and pathologic classifiers was best at predicting relapse-free survival, outperforming the clinical nomograms. Validation of the genomic classifier was also performed on 341 patients from 4 external datasets obtained through The Cancer Genome Atlas and the National Center for Biotechnology Information–Gene Expression Omnibus.

The patients received consistent surgical management at the same center, but adjuvant chemotherapy was given on an individual basis. Adjuvant chemotherapy trials have been fraught with difficulties in accrual, and results have been inconsistent as to which patients benefit. Recent meta-analyses seemed to suggest an advantage with adjuvant chemotherapy, but the patient population to benefit still requires further ­clarification.^4,5

The data from Mitra and colleagues are of great interest if they can differentiate those patients who are really at high risk and require treatment while avoiding chemotherapy for those patients at low risk for relapse. The fact that this test can be performed on paraffin-embedded tissue renders it practical. Since this signature was determined in a single institution, where surgical treatment was consistent, with many patients receiving adjuvant chemotherapy, further prospective validation on a multi-institutional basis is warranted. ■

Disclosure: Dr. Sternberg reported no potential conflicts of interest.

References

1. Yafi FA, Aprikian AG, Chin JL, et al: Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: A Canadian multicentre experience. BJU Int 108:539-545, 2010.

2. Sternberg CN, Bellmunt J, Sonpavde G, et al: ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol 63:58-66, 2013.

3. Mitra AP, Lam LL, Ghadessi M, et al: Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer.  J Natl Cancer Inst 106(11):dju290, 2014.

4. Leow JJ, Martin-Doyle W, Rajagopal PS, et al: Adjuvant chemotherapy for invasive bladder cancer: A 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66:42-54, 2014.

5. Sternberg CN, Skoneczna I, Kerst JM, et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, open-label, randomised phase 3 trial. Lancet Oncol. December 11, 2014 (early release online).