Promising biomarker may not be reliable for bladder cancer treatment

Researchers from the University of Pennsylvania (Philadelphia, PA, USA) have demonstrated that a previously reported biomarker candidate that had the potential to be utilized in predicting cancer progression and identify effective treatment methods, may not be effective at predicting the overall survival of patients with muscle-invasive bladder cancer or help determine which patients may benefit from chemotherapy before surgery.

The study, recently published in Cancer, investigated the utility of neutrophil-to-lymphocyte ratio (NLR) by performing a category B biomarker study, to identify whether NLR is prognostic for overall survival after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy.

Previous studies have distinguished an elevated NLR with worse overall survival after radical cystectomy and correlation with the amount of cancer detected during surgery, suggesting that a blood based test to confirm the presence of the biomarker may serve to predict which patients will benefit from pre-surgery chemotherapy to shrink their tumors.

“Dozens of earlier studies reported NLR as a biomarker for bladder cancer, and we hoped that this would be true,” lead author Eric Ojerholm (University of Pennsylvania) commented. “Yet extraordinary claims require extraordinary evidence. And all prior studies relied on observational datasets. Many also used statistical methods that can lead to false positive results. So we decided to rigorously put NLR to the test.”

The team analyzed data collected in real-time during a prospective clinical trial, distinguishing this as the first study of NLR in bladder cancer not to rely on observational data. The trial, termed SWOG 8710, was a randomized phase III trial that assessed cystectomy with or without neoadjuvant chemotherapy in 317 patients with muscle-invasive bladder cancer.

“The trial we used has a few big advantages to study NLR,” Ojerholm elaborated. “First, baseline blood samples were collected as part of the trial protocol. Second, the study’s long-term follow-up gave us adequate ‘statistical power,’ meaning that if NLR really was a biomarker, then we should be able to detect it. Third, the trial randomly assigned some patients to receive pre-surgery chemotherapy. This allowed us to test NLR both as a prognostic and predictive biomarker.”

For the prognostic analysis, 230 patients were identified to determine if NLR could serve as a predictor for life expectancy after curative treatment and 263 were identified for the predictive analysis to establish if NLR could tell which patients would respond to chemotherapy.

The results of the study indicated that NLR was not prognostic for overall survival, suggesting that age and whether the patient received pre-surgery chemotherapy are the important factors. Nor did the findings indicate that NLR can be utilized to predict the overall survival benefit from neoadjuvant chemotherapy.

When asked why most previous publications supported NLR as a biomarker Ojerholm explained “There’s also the problem of publication bias. Sometimes authors won’t submit negative results, and sometimes journals won’t accept them. That could be a real issue as NLR research continues.”

Despite the results of the study contrasting previous findings and suggesting that NLR is neither a prognostic or predictive biomarker for overall survival in muscle-invasive bladder cancer, Ojerholm stressed that no single study is definitive, and doctors must weigh results from the entire literature.

“Yet this study does raise questions about NLR for bladder cancer,” Ojerholm added, “and we need more evidence before using this biomarker in clinical practice.”

Sources: Ojerholm E, Smith A, Hwang W et al. Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710. Cancer doi: 10.1002/cncr.30422 (2016) (Epub ahead of print);
www.uphs.upenn.edu/news/news_releases/2016/10/ojerholm/