Biomarkers in Renal Cell Carcinoma: Evidence and Challenges

Renal cell carcinoma (RCC) is a urologic malignancy expected to be linked to 14,000 deaths in 2017.¹ RCC is significantly more common among men and between ages 50 and 70 years old and individuals who are obese, who smoke, or who have certain exposures (asbestos) and/or concurrent hypertension.

Patients diagnosed with RCC have a relatively good prognosis, with a mortality rate that continues to decline, and an approximate 5-year survival rate of 74%.² Most patients with RCC present in the localized stage (65%), while a smaller proportion of patients present in other stages: regional (16%, spread to regional lymph nodes only), distant (16%, metastases), and unknown (3%).

When RCC is diagnosed, it is typically classified by the pathology of the malignant cells: clear cell (75% to 85% of all cases) and non-clear cell (papillary, chromophobe, oncocytoma, collecting duct).³ It is unclear, however, whether the subtype of RCC has an impact on prognosis.

Despite the improving 5-year survival rates, clinicians and researchers are looking for ways to better guide therapy by improving outcomes and limiting toxicities. Advances in surgery and radiologic imaging will continue to lower RCC mortality, but some recent clinical trials focused on identifying biomarkers that may lead to better treatment outcomes. The role of biomarkers in RCC is controversial, due to uncertainty about which biomarker is the most beneficial. There is also debate about how often any biomarker should be monitored, how to quantify its effect, and how to determine which test results necessitate a therapeutic change.

A new biomarker being studied among patients with RCC is carbonic anhydrase-IX (CAIX). CAIX is an enzyme that undergoes increased expression in hypoxic environments created by tumor cells.⁴ Several studies showed that a CAIX expression of 85% or less (considered “low”) is associated with worse cancer-specific survival and lower response rates to high-dose interleukin (IL)-2.⁵

But not all studies supported these relationships, which could be explained by the heterogeneous patient population or difficulties interpreting and quantifying the expression of CAIX. One research group therefore attempted to formulate a “CAIX score” that would incorporate more sophisticated quantification, and evaluated this score among over 800 patients who were considered high risk for recurrence after nephrectomy. CAIX scores were prognostic biomarkers for overall survival, disease-free survival, and lymph node involvement when compared to the traditional CAIX expressions of above and below 85%.

Another group evaluated biomarkers in over 900 patients with advanced RCC receiving either placebo or sorafenib. The investigated biomarkers included vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), Ras p21, and tissue inhibitor of metalloproteinase 1 (TIMP-1).⁶ These biomarkers were prognostic for survival and helped to monitor response to sorafenib.

Plasma and urine glycosaminoglycan (GAG) levels were also used to develop scoring systems that can assist in predicting the prognosis of patients with RCC.⁷

The technicalities and high costs associated with some of the newer biomarkers such as VEGF, CAIX, and TIMP-1 led to research on more cost-effective options. Certain “ratios” or what could be considered “traditional labs” (eg liver function tests, complete blood count) and toxicities can also be used as biomarkers. The neutrophil-lymphocyte ratio (NLR, absolute neutrophil count/absolute lymphocyte count) was evaluated as a biomarker in patients with metastatic RCC undergoing treatment with high dose IL-2 (HD-IL2).⁸ An NLR score of 4 or lower was associated with improved overall and progression-free survival.