Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

Abstract

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p < 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with >1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with >2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of >2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.

Germline genetics of prostate cancer

“…A study of 867 patients with metastatic prostate cancer evaluated the rates of pathogenic variants, likely pathogenic variants, and variants of unknown signficance (VUS) in cancer genes among patients that identified as Caucasian and African American. They showed that the pathogenic and likely pathogenic variants of known cancer genes did not vary by race, however, the rates of VUS were higher in the African American group 57 …”

Germline Variant Spectrum Among African American Men Undergoing Prostate Cancer Germline Testing: Need for Equity in Genetic Testing

“…Although no differences were noted overall in P/LPV rates between AA and White men, this study also reported lower rates of P/LPVs specifically in non- BRCA genes among AA men than White men. 15 Limitations of this study noted that patients had GT from various laboratories and had a modest sample size. 15 Another study sequenced BRCA1/2 to define the pathogenic spectrum among AA and White men in a cohort of 1,240 patients with PCA, of whom 30% were AA.…”

“…14 A multi-institutional study also reported on differences in P/LPVs between AA and White men undergoing GT for PCA. 15 This report included 867 patients, of whom 22% were AA. Although no differences were noted overall in P/LPV rates between AA and White men, this study also reported lower rates of P/LPVs specifically in non- BRCA genes among AA men than White men.…”

“…13 To address this gap, multiple previous studies have specifically focused on characterizing the germline variant spectrum associated with PCA with attention to AA men. [14][15][16][17] One study reported that among men engaged in PCA GT from a large commercial data set, AA men represented 8% of men tested and AA men had lower rates of P/LPVs in non-BRCA genes compared with White men. 14 The report noted limitations such as lack of data to assess association of P/LPV rates with clinical features and family history.…”

Nature versus Nurture: Investigating Racial Disparity in Advanced Prostate Cancer

“…Although specific mutations were differentially prevalent between the two groups (MYC amplification, PTEN mutations, and TMPRSS2‐ERG rearrangement), targetable genomic alterations such as the presence of high tumor mutation burden, microsatellite instability, and mutations in DNA damage repair and androgen receptor were not significantly different between the two groups. Although AA men were more likely to harbor germline BRCA alterations, the overall prevalence of germline mutations was similar between AA and White men [14]. With the approval of poly (ADP‐ribose) polymerase (PARP) inhibitors in patients with DNA damage repair mutations [15] and the several molecularly targeted agents in development, these findings suggest the AA men are as likely to harbor these targetable genomic alterations and could benefit from biomarker selected therapy similar to White patients.…”