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

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.

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Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17523 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17523-e17523

Author(s):

Yu Wei ◽

Yao Zhu ◽

Junlong Wu ◽

Dingwei Ye ◽

Hao Zeng ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Genetic Testing ◽

Family History ◽

High Risk ◽

Cancer Patients ◽

Germline Mutations ◽

Dna Repair Genes ◽

History Of ◽

Repair Genes

e17523 Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.

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Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.199 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 199-199

Author(s):

Ellen Jaeger ◽

Earle Frederick Burgess ◽

Jason Zhu ◽

Beth Dellinger ◽

Sara Elrefai ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

African American ◽

Metastatic Prostate Cancer ◽

Dna Repair Genes ◽

Variants Of Unknown Significance ◽

Brca Gene ◽

Brca1 Brca2 ◽

Gene Panels ◽

Repair Genes

199 Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.

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DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.245 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 245-245

Author(s):

James Vu ◽

Marcus Marie Moses ◽

Lahiru Ranasinghe ◽

Patrick Cotogno ◽

Charlotte Manogue ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Dna Repair ◽

Family History ◽

Treatment Outcomes ◽

Treatment Duration ◽

Pathogenic Mutation ◽

Germline Mutations ◽

Cancer Type ◽

History Of

245 Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients with a DNA repair pathogenic mutation were more likely to have > 2 family members affected by cancer, regardless of cancer type or degree of relationship (p = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.

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Genetic counseling processes and outcomes among prostate cancer patients (ProGen).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.tps343 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. TPS343-TPS343 ◽

Cited By ~ 1

Author(s):

Donna Rachel Vatnick ◽

Sandjida Aktar ◽

Jill E. Stopfer ◽

Lindsay Kipnis ◽

Samantha K. Culver ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Genetic Counseling ◽

Genetic Testing ◽

Cancer Risk ◽

Mismatch Repair ◽

Metastatic Prostate Cancer ◽

Germline Mutations ◽

Mismatch Repair Genes ◽

Repair Genes

TPS343 Background: Prostate cancer (PC) is among the leading causes of cancer mortality in males. Recent studies found 8-12% of advanced PC cases may be hereditary. Germline mutations have been reported in BRCA1/2, other DNA repair genes including ATM, CHEK2, PALB2 and DNA mismatch repair genes. Genetic testing can inform treatment decisions including drug targeting, such as PARP inhibitors for men with BRCA mutations, and checkpoint inhibitors for those with pathogenic mutations in mismatch repair genes2. Discovering a pathogenic mutation associated with increased cancer risk also prompts dissemination of this information to family, where subsequent testing can lead to risk stratification and impactful opportunities for cancer screening and prevention. It is critical that men with high risk and potentially lethal prostate cancer routinely be offered genetic testing as a component of their cancer care. Genetic counseling services are limited, and more efficient services are needed. Methods: We are investigating video education prior to genetic testing compared with in-person pretest counseling with a licensed genetic counselor (GC). ProGen is an ongoing randomized trial evaluating two distinct models of cancer genetics service delivery in 450 PC cases over a two-year period. The study is conducted in collaboration with Ambry Genetics utilizing a 67-gene cancer panel. The primary aim is analysis of the proportion and type of germline mutations identified. Secondary aims include testing uptake by arm, evaluation of distress, knowledge, satisfaction with testing services, family communication, and impact on cancer care. Results are communicated by telephone with a GC. Inclusion criteria are: potentially lethal PC (metastatic, localized with Gleason score ≥8, rising/persistent PSA after local therapy), early diagnosis (≤ 55 years), prior malignancy, and/or family history potentially indicating a hereditary cancer risk. Enrollment is 74% completed at a single institution. (NCT03328091). 1 Pritchard CC, et al. Inherited DNA‐repair gene mutations in men with metastatic prostate cancer. NEJM. 2016;375:443 2 Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEJM . 2015;373(18):1697-1708 Clinical trial information: NCT03328091.

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MP57-01 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE SIGNIFICANTLY ENRICHED IN LETHAL PROSTATE CANCER AND ARE ASSOCIATED WITH DISEASE SURVIVAL

The Journal of Urology ◽

10.1016/j.juro.2017.02.1775 ◽

2017 ◽

Vol 197 (4S) ◽

Author(s):

Rong Na ◽

S. Lilly S. Lilly ◽

Misop Han ◽

Hongjie Yu ◽

Deke Jiang ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Germline Mutations ◽

Dna Repair Genes ◽

Repair Genes ◽

Lethal Prostate Cancer

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PD20-04 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE INDEPENDENT PREDICTORS OF GRADE RECLASSIFICATION IN ACTIVE SURVEILLANCE FOR PROSTATE CANCER PATIENTS

The Journal of Urology ◽

10.1016/j.juro.2018.02.1008 ◽

2018 ◽

Vol 199 (4S) ◽

Author(s):

H. Ballentine Carter ◽

Mufaddal Mamawala ◽

Tricia Landis ◽

Kathleen Wiley ◽

Isaacs William B. ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Cancer Patients ◽

Active Surveillance ◽

Germline Mutations ◽

Dna Repair Genes ◽

Repair Genes

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Abstract A44: The identification of germline mutations in DNA repair genes in Brazilian individuals at-risk for hereditary breast cancer

10.1158/1557-3125.dnarepair16-a44 ◽

2017 ◽

Author(s):

Ana Rafaela de Souza Timoteo ◽

Jorge Estefano Santana de Souza ◽

Tirzah Braz Petta Lajus

Keyword(s):

Breast Cancer ◽

At Risk ◽

Dna Repair ◽

Hereditary Breast Cancer ◽

Germline Mutations ◽

Dna Repair Genes ◽

Repair Genes

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Clinical and genetic determinants of toxicity and quality-of-life (QOL) outcomes for SBRT in Asian prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.95 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 95-95

Author(s):

Janice Ser Huey Tan ◽

Sheena Xue Fei Tan ◽

Youquan Li ◽

Jeffrey Kit Loong Tuan ◽

Terence Wee Kiat Tan ◽

...

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Dna Repair ◽

Germline Mutations ◽

Dna Repair Genes ◽

Demographic Differences ◽

Patient Reported ◽

Asian Men ◽

Repair Genes

95 Background: There is limited data on clinical and patient-reported quality of life (PRO-QOL) outcomes after stereotactic body radiotherapy (SBRT) in Asian men with localised prostate cancer. Demographic differences with regard to PRO-QOL outcomes may be due to variation in germline genetics. We therefore conduct a single-institution prospective phase II trial of prostate SBRT in Asian men with intermediate-risk prostate cancers (IR-PCa). Additionally, we investigated association of dosimetric and genetic factors with outcomes. Methods: Patients with biopsy-proven NCCN-defined IR-PCa were recruited. SBRT was delivered at 36.25 Gy/5fr using a Linac-based RapidArc technique. Adverse events (AEs) were assessed with CTCAEv4.0 and IPSS; PRO-QOL assessed using the EPIC instrument at baseline, 1 and 2-year post-SBRT. Germline genetics were profiled by whole exome sequencing (30X). Results: 65 patients were recruited over the period of 2014-2016 (median follow-up = 30 mo). We observed 4 acute ≥G2 gastrointestinal (GI) events (3 fecal urgency, 1 diarrhea). Longitudinal assessment of acute genitourinary (GU) events by IPSS showed worsened symptoms that peaked at 1 wk post-SBRT (44.6% vs 6.2% at 1 mo for men reporting scale upgrade). There was no significant association between acute GU effects (by IPSS) and dosimetric parameters of the irradiated urethra and bladder. PRO-QOL scores demonstrated minimal change over time across all domains; however, sexual bother in the top 50th percentile subgroup at baseline indicated ≥20% worsening of scores for 10/32 (31%) at 12 mo and 5/12 (42%) at 24 mo; which was not associated with Dosemax to the penile bulb (P = 0.1). We observed a high frequency of germline mutations in DNA repair genes (N = 10; 15.4%), including two BRCA2 stop-gain and frameshift mutations. In particular, BRCA2 mutations were detected in 2 of 4 cases with ≥G2 GI effects, independent of rectal dose. Conclusions: While prostate SBRT is well tolerated in our Asian cohort, there appears to be demographic differences in sexual bother compared to Caucasian cohorts. Interestingly, we observed a higher than expected prevalence for germline mutations in DNA repair genes, which may predict treatment response. Clinical trial information: NCT02313298.

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