SAN FRANCISCO – African American patients with clear-cell renal cell carcinoma may have poorer survival in part because of genomic factors that render tumors more aggressive and less sensitive to anti-angiogenic therapy, suggests a study reported at the Genitourinary Cancers Symposium.
Dr. Tracy Lynn Rose
Genomic analysis in 438 patients with metastatic disease found that African Americans were about half as likely as Caucasians to have mutations of the von Hippel–Lindau (VHL) tumor suppressor gene, reported lead investigator Dr. Tracy Lynn Rose, a hematology-oncology fellow at the University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center. Mutational inactivation of this gene leads to increased signaling in the vascular endothelial growth factor (VEGF) pathway.
African Americans also were more likely to have the clear cell B molecular subtype and had less up-regulation of pathways associated with hypoxia-inducible factor (HIF), which collectively suggest a less angiogenic profile and activation of non-VEGF pathways.
A companion analysis of 35,152 patients treated during a 14-year period found that African American patients with metastatic renal cell carcinoma still had a higher risk of death than white peers in the contemporary era, after introduction of multiple agents that target the VEGF pathway and similar increases in receipt of systemic therapy.
“Our findings indicate clear differences in the biology of clear-cell renal cell carcinoma between African Americans and Caucasians. These differences could suggest a larger proportion of tumors from African Americans have a HIF- and VEGF-independent propensity for aggressiveness, and they also suggest perhaps increased resistance of African Americans to VEGF-targeted therapy,” Dr. Rose said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
“Overall, our data lend support to a role for tumor biology in the survival disparity observed between African American and Caucasian patients,” she said.
Dr. Guru Sonpavde
The study may be a step toward precision medicine, whereby race is used to guide treatment decisions, according to invited discussant Dr. Guru Sonpavde, director of the Genitourinary Malignancy Program at the University of Alabama at Birmingham. “That’s an exciting possibility,” he said.
“It is plausible that African American patients are less VEGF driven, less responsive to VEGF inhibitors, but I think the results right now are not ready for use in the clinic,” he further commented. “We need validation in a larger number of African American patients. But even more importantly, we need to focus more on molecular measures of VEGF-driven tumors, to select patients for VEGF inhibitors since we don’t have any biomarkers of this sort in the clinic today.”
“Finally, somatic differences may be driven by differences in the germline, and we may want to focus on integrating the germline and somatic alterations into a molecular panel which might be even better at predicting benefit from specific agents,” he concluded.
Previous studies have found a small but consistent elevation of the risk of death for African American patients with renal cell carcinoma, Dr. Rose noted when introducing the study. Initial hypotheses were that this disparity might be due to differences in comorbidities and use of nephrectomy.
She and her colleagues performed genomic analyses in a discovery cohort of 438 African American and Caucasian patients with metastatic clear-cell renal cell carcinoma from The Cancer Genome Atlas database.
Results indicated that African Americans in this discovery cohort were less likely to have a VHL mutation (17% vs. 50%, P = .036), a finding that was confirmed in a validation cohort of 135 similar patients (40% vs. 81%, P = .008).
African American patients were less likely to have several VEGF and HIF signatures relative to Caucasian counterparts. On the other hand, they were more likely to have the clear cell B molecular subtype (79% vs. 45%, P less than .01), which has been associated with decreased activation of angiogenic pathways and poorer prognosis.
The investigators next analyzed data from the National Cancer Database, assessing survival among 35,152 patients who received a diagnosis of metastatic clear-cell renal cell carcinoma between 1998 and 2011.
The proportion receiving systemic therapy over time was similar for African American and Caucasian patients, with both seeing a rise in 2006, corresponding to the introduction of VEGF-targeted therapies. The poorer median survival for African American versus Caucasian patients seen during 1998-2004 (6.0 vs. 7.6 months; adjusted hazard ratio, 1.07; P less than .01) was still evident in 2006-2011 (6.5 vs. 9.2 months; adjusted hazard ratio, 1.08; P less than .01).