We adjusted for standard clinical variables and found the cell-cycle proliferation score was an independent prognosticator of key outcomes.— Todd M. Morgan, MD
A prognostic model proved able to accurately predict long-term outcomes for patients with stage I to III renal cell carcinoma, the developers of the instrument reported at the 2017 National Comprehensive Cancer Network Annual Conference.1
The model was derived from molecular tissue analysis and clinical evaluation of more than 500 patients with localized disease from the University of Michigan and Massachusetts General Hospital. It incorporated the multigene cell-cycle proliferation score (CCP), known as Polaris (Myriad Genetics), which is used in prostate cancer to predict the risk for recurrence and death. The cell-cycle proliferation creates a molecular signature based on proliferation genes.
In renal cell cancer, there are essentially no biomarkers or prognostic tools for use following nephrectomy. There is clearly a need to improve prognostic assessment, ideally via a tissue-based marker, so patients could be optimally selected for either adjuvant therapy or active surveillance, according to lead investigator Todd M. Morgan, MD, a urologic oncologist at the University of Michigan Comprehensive Cancer Center, Ann Arbor.
“We hypothesized that proliferation would be a significant prognostic indicator in renal cell carcinoma as well,” he said.
The RNA-based cell-cycle proliferation score (based on genes related to proliferation) was derived after radical nephrectomy in 565 patients treated between 2000 and 2009. Patients had clear cell, papillary, or chromophobe renal cell carcinoma and no nodal or distant metastases.
“We extracted RNA, looked for proliferation signatures, and found broad distribution of proliferation scores. Patients with lower-stage disease tended to have lower cell-cycle proliferation scores, but there was a lot of overlap. Some patients with high-stage disease, for example, could have lower scores,” he added.
“We adjusted for standard clinical variables and found the cell-cycle proliferation score was an independent prognosticator of outcomes,” Dr. Morgan reported. The study correlated scores with recurrence and disease-specific mortality.
The researchers also adjusted for baseline clinical variables using the Karakiewicz predictive nomogram. The resulting Karakiewicz score carried a hazard ratio of 10.15 (P < .001) as a predictor of disease-specific mortality in this analysis. “When we adjusted for this, the molecular signature was still prognostic, suggesting that the cell-cycle proliferation score is, in fact, an independent predictor of outcome in patients with renal cell carcinoma,” he revealed.
Cell-cycle proliferation scores were only moderately correlated with Karakiewicz nomogram scores, however; the greatest risk of disease-specific mortality was among patients with high cell-cycle proliferation score and high Karakiewicz score. “You see a large drop-off in survival as you get to higher scores,” he said.
The fact that correlation was poor between the cell-cycle proliferation and the clinical Karakiewicz score is “a good thing,” he explained. “If it correlates with what we know clinically, we don’t need it. They are both informative, but they give separate information. Our goal was to use them together.”
Combining Both Scores
The ultimate model combined the molecular signatures and the clinical nomogram scores, and it proved to be robust. Using the prespecified cut-point corresponding to 5-year recurrence rate of 12.7% and mortality rate of 3.8%, the researchers grouped patients into low-risk (n = 338) and high-risk (n = 202) categories.
Patients meeting low-risk criteria had a 99% disease-specific survival at 5 years, compared with 84% for patients in the high-risk group (P < .001), Dr. Morgan reported. “There was a big spread according to risk. This suggests that by combining these factors, we can more accurately predict outcomes,” he commented.
Some patients with stage III disease actually fared as well as those with stage I disease. “Even in higher-stage, higher-risk patients, some can be reclassified into lower-risk groups based on the combined score,” he said.
“We are trying to develop a clinically useful test in renal cell cancer. We have a lot of signs suggesting this is feasible,” Dr. Morgan concluded. ■
Disclosure: Dr. Morgan has received research funding from and served on an advisory board for Myriad Genetics.
1. Morgan TM, Mehra R, Tiemeny P, et al: Prognostic utility of a multi-gene signature (the cell cycle proliferation score) in patients with renal cell carcinoma after radical nephrectomy. 2017 National Comprehensive Cancer Network Annual Conference. Poster 46.