ASCO GU 2020: Assessment of Inherited DNA Repair Defects in African-American and Caucasian Men with Prostate Cancer

San Francisco, CA (UroToday.com) Pathogenic loss-of-function alterations in DNA damage repair (DDR) genes, especially BRCA2, are associated with more aggressive disease and are associated with response to PARP inhibitors in men with prostate cancer. Numerous studies have reported rates of inherited germline DDR (gDDR) alterations in men with prostate cancer, however, these studies are comprised mostly of men of European descent. Comparative data in men of African ancestry is lacking. In this study, investigators utilized germline data from Invitae (a company that provides commercially-available genetic testing services) to compare rates of gDDR (pathogenic and likely pathogenic) alterations in African-American (AA; n = 213) men and Caucasian American (CA; n = 2,488) men. 14 well-annotated DDR genes were evaluated, although not all men were assessed for each of the 14 genes.

The rate of gDDR alterations was significantly lower (p = 0.008) in AA men (7.5%) than CA men (13.9%). gDDR alterations in AA men were observed in ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, and RAD51C. BRCA2 was the most frequently altered gene in AA men (2.8%) and although the rate was lower than that observed in CA men (4.8%), this difference was not statistically significant (p = 0.18). On gene-by-gene analysis, the only one that reached statistical significance for a difference in the rate between AA and CA men was CHEK2 (0.48% versus 3.11%; p = 0.03).

ASCOGU_gDDR_alterations.png

Shown below is a bar graph of the gene-by-gene alteration rates in CA men and AA men compared to a landmark paper by Pritchard, et al in the New England Journal of Medicine that first defined rates of gDDR alterations in men with metastatic prostate cancer.1 Rates in the Invitae CA cohort are similar to the Pritchard cohort.

ASCOGU_BRCA.png

The investigators also evaluated whether the frequency of germline BRCA1/2 alterations and non-BRCA1/2 alterations differed between the AA and CA cohorts. Lower frequency of germline non-BRCA1/2 alterations was observed in AA men compared to CA men, however, there was no difference in the frequency of germline BRCA1/2 alterations.

ASCOGU_germline_BRCA.png

A strength of this study is that it represents “real-world” data as providers at both academic medical centers as well as private practices and community providers utilize Invitae for genetic testing. An important limitation of this study is that reliable clinical data and other important information, such as family history, were not available. Therefore, it is not known whether the AA and CA populations were balanced for factors known to be associated with higher rates of germline alterations, such as metastatic disease. Nevertheless, this study is an important step towards defining rates of germline DDR alterations in populations other than white men of European descent.

Presented by: A. Oliver Sartor, MD Medical Oncologist, Professor of Cancer Research, and Medical Director of the Tulane Cancer Center

Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2020 ASCO Genitourinary Cancers Symposium (#GU20), February 13th to 15th, 2020, San Francisco, CA.

References:

  1. Pritchard CC, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53.
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