Genomics May Explain Poor Survival of African Americans with Kidney Cancer

April 2016, Vol 7, No 3

Differences in 3 recently identified molecular factors in patients with metastatic renal-cell carcinoma (RCC) may explain the inferior survival rates in African-American ­patients versus in Caucasian patients, even in the age of targeted therapy. These factors are also associated with decreased responsiveness to vascular endothelial growth factor (VEGF) receptor (VEGFR)-directed therapy.

The factors include the presence of fewer VHL mutations; enrichment for the clear-cell B (ccB) subtype, which confers worse prognosis; and less upregulation of the HIF pathway in African-American patients compared with Caucasian patients, according to a study presented by Tracy Lynn Rose, MD, MPH, Hematology/Oncology Fellow, University of North Carolina at Chapel Hill, at the 2016 Genitourinary Cancers Symposium.

Historically, African-American patients have had worse survival compared with Caucasian patients. The investigators sought to determine if this survival gap has narrowed in the era of targeted therapy for metastatic RCC.

“Although survival for African-Americans and Caucasians with metastatic clear-cell renal-cell carcinoma has improved in the era post–targeted therapy [ie, 2006-2011], African-Americans continue to have inferior survival compared with Caucasians,” said Dr Rose.

“These molecular features predict for decreased responsiveness to VEGF-targeted therapies and inferior survival compared with Caucasians. Data from a national database confirm the inferior survival of African-Americans compared with Caucasians in the era of targeted therapy, and this is potentially related to underlying differences in tumor biology,” Dr Rose continued.

The genomic analysis included 438 patients (19 African Americans, 419 Caucasians) with clear-cell RCC from the Cancer Genome Atlas RCC data set. The investigators analyzed the differences between African-American patients and Caucasian patients in somatic mutation rate, molecular subtype, and RNA expression.

Inactivation of VHL tumor suppressor genes, which occurs in 90% of patients with clear-cell RCC, leads to the transcription of genes involved in cell growth and cell survival. Significantly fewer (17%) African-American patients with metastatic RCC had VHL mutations than Caucasian patients (50%; P = .04). There was no difference between the 2 patient groups in the frequency of other types of genetic mutations.

Clear-cell RCC is divided into 2 subtypes—(1) ccA tumors, which are associated with improved survival, and (2) ccB tumors, which are associated with worse survival. The African-American population with metastatic RCC was enriched for the ccB subtype (79% vs 45% for Caucasian patients; P <.01).

An analysis of RNA expression revealed the upregulation of several hypoxia-inducible factor–associated pathways (ie, the VEGFR axis) in Caucasian patients compared with African-American patients.

These findings were validated in a separate data set of 135 patients with clear-cell RCC that included 10 African Americans and 125 Caucasians.

Survival was analyzed in the pre–targeted therapy era (ie, 1998-2004) and in the post–targeted therapy era (ie, 2006-2011) in 35,152 African-American patients and Caucasian patients with stage IV clear-cell RCC from the National Cancer Data Base. Although the overall survival improved over time in both groups, African-American patients had inferior survival in both time periods.

The median overall survival in the post–targeted therapy era was 9.2 months for Caucasian patients versus 6.5 months for African-American patients. The 3-year survival rates were 20% and 141% for Caucasian patients and African-­American patients, respectively, and the 5-year survival rates were 11.8% and 9.1%, respectively.

Guru Sonpavde, MD, Associate Professor of Medicine, University of Alabama at Birmingham, who discussed this trial, noted that the data set from the Cancer Genome Atlas included only 19 African-American patients, and the validation set included only 10 African-American patients.

“These findings are based on a small number of African-American patients, and do not include mixed-race patients,” Dr Sonpavde noted.

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