Genetic Testing For Men Research Articles

Genetic Testing in Men With Metastatic Castration-Resistant Prostate Cancer

This cross-sectional study assesses homologous recombination repair mutation genetic testing and associated characteristics among men with metastatic castration-resistant prostate cancer (mCRPC).

Utilization of genetic testing in men with advanced prostate cancer.

Genetic evaluation of men with advanced prostate cancer is recognized as imperative both to guide treatment decisions and to trigger cascade genetic testing of family members. Here we investigate utilization patterns of genetic testing among a contemporary cohort of men with advanced prostate cancer at our institution. We queried the Northwestern Electronic Data Warehouse from January 2021 to present for all men diagnosed with National Comprehensive Cancer Network high-risk/very high-risk, regional, or metastatic prostate cancer. Patients were excluded from analyses if treated at an outside institution and/or presented for a second opinion evaluation. Statistics were performed using t-test, Chi-squared test, and univariable and multivariable logistic regression with significance defined as p < 0.05. Atotal of 320 men (52.5%) had local/regional disease and 290 (47.5%) had metastatic disease, 53 (18.3%) of whom had castrate resistant prostate cancer. Rates of germline genetic testing rate were low in patients with localized disease (9.4%) and metastatic disease (34.1%). Only 19 (35.8%) men diagnosed with metastatic castrate resistant prostate cancer underwent germline genetic evaluation. Germline testing was most frequently discussed or ordered by medical oncologists (52%) followed by urologists (20%). Men who underwent germline testing were younger (p < 0.001), more likely to have Medicaid or private insurance (p = 0.002), and more likely to have metastatic disease (p < 0.001). There were no statistically significant differences in baseline PSA, ethnicity, race, or castration sensitivity status. Age (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.97, p < 0.001) and metastatic disease (OR: 5.71, 95% CI: 3.63-9.22, p < 0.001) were significant independent predictors of genetic testing on multivariable logistic regression. Here we report that utilization of genetic testing is associated with metastatic disease and inversely associated with age. Overall, utilization rates of genetic testing remain low in all patient groups, including in the metastatic castrate resistant setting, where genetic testing can identify patients with homologous recombination repair deficiency who may benefit from use of targeted therapeutics such as PARP inhibitors. Genetic testing in men with aggressive prostate cancer is critical and barriers to routine implementation of testing require further study to develop strategies to improve utilization rates.

Mainstream germline genetic testing in men with metastatic prostate cancer: design and protocol for a multicenter observational study

BackgroundIn international guidelines, germline genetic testing is recommended for patients with metastatic prostate cancer. Before undergoing germline genetic testing, these patients should receive pre-test counseling. In the standard genetic care pathway, pre-test counseling is provided by a healthcare professional of a genetics department. Because the number of patients with metastatic prostate cancer is large, the capacity in the genetics departments might be insufficient. Therefore, we aim to implement so-called mainstream genetic testing in the Netherlands for patients with metastatic prostate cancer. In a mainstream genetic testing pathway, non-genetic healthcare professionals discuss and order germline genetic testing. In our DISCOVER study, we will assess the experiences among patients and non-genetic healthcare professionals with this new pathway.MethodsA multicenter prospective observational cohort study will be conducted in 15 hospitals, in different regions of the Netherlands. We developed an online training module on genetics in prostate cancer and the counseling of patients. After completion of this module, non-genetic healthcare professionals will provide pre-test counseling and order germline genetic testing in metastatic prostate cancer patients. Both non-genetic healthcare professionals and patients receive three questionnaires. We will determine the experience with mainstream genetic testing, based on satisfaction and acceptability. Patients with a pathogenic germline variant will also be interviewed. We will determine the efficacy of the mainstreaming pathway, based on time investment for non-genetic healthcare professionals and the prevalence of pathogenic germline variants.DiscussionThis study is intended to be one of the largest studies on mainstream genetic testing in prostate cancer. The results of this study can improve the mainstream genetic testing pathway in patients with prostate cancer.Trial registrationThe study is registered in the WHO’s International Clinical Trials Registry Platform (ICTRP) under number NL9617.

Rates of germline genetic testing and DNA damage response mutations found through population-based recruitment of men with incident metastatic prostate cancer.

10501 Background: Approximately 10% of men with metastatic prostate cancer (mPC) have germline DNA damage response gene mutations (gDDRm), indicating candidacy for precision treatment. Consequently, national guidelines recommend germline genetic testing be offered to all men with mPC. It is currently unclear what the rates of testing are in the community, and barriers to testing are not well understood. We conducted a population-based study to better understand current rates of germline genetic testing in men with newly diagnosed mPC, and to determine whether removing major barriers of cost and access could expand uptake of germline genetic testing. Methods: This is a prospective observational study that identifies men ages 35-79y with mPC residing in a 13-county area of Washington State through the Surveillance, Epidemiology, and End Results (SEER) program (NCT04254133). Men with new diagnoses of mPC are contacted by mailed invitation and follow-up phone inquiry. Interested men are then invited to provide informed consent and complete a questionnaire about personal and family health history. A saliva collection kit for a 30-gene targeted panel of cancer predisposition genes (Color Genomics) is mailed to participants’ homes free of charge. Results are issued by phone and/or email with genetic counseling support, including discussion about cascade genetic testing if relevant. Results: As of Feb 9, 2022, 484 men with incident mPC diagnosed 1/2018-6/2021 were identified through SEER. 430 men were reached via a letter to their home address sent &gt; 3 months after diagnosis. 175 of 430 (40.6%) men expressed interest and completed the questionnaire, the majority preferring to complete testing through mail after a phone-initiated introduction to the study. 164 of 175 men completed the consent process and were eligible. Of these 164 men, 45 (27.4%) reported prior genetic testing, and reports were requested and reviewed to ensure adequate testing. Ultimately, 121 of 164 (73.8%) participants initiated and 101/121 (83.5%) have completed genetic testing through the study. Nine percent (9/101) of participants completing testing as part of the study were found to have gDDRm. Conclusions: We used a population-based approach to understand the proportion of men with mPC undergoing germline genetic testing through clinical care, and the subsequent uptake of genetic testing when access and cost barriers are removed. The uptake of guideline-based germline genetic testing among men with mPC in the community prior to study enrollment is only 27.4%. With study interventions in the form of free testing through mail, and phone-based support, 83.5% of men in this community successfully completed testing. Further work in this study will aim to elucidate and attempt to eliminate other barriers in germline genetic testing to further improve testing rates in this community.

Genetics in prostate cancer: implications for clinical practice.

Recent advances in our understanding of prostate cancer genetics have transformed the field. However, challenges in implementation and clinical application remain. The aim of this review is to discuss recent noteworthy publications in prostate cancer germline testing, genetically informed treatment, and polygenetic risk. The recent U.S. Food and Drug Administration approval of two poly adenosine diphosphate-ribose inhibitors (olaparib and rucaparib) for the treatment of men with metastatic castration-resistant prostate cancer with mutations in DNA damage repair genes and updates to the National Cancer Center Network testing guidelines that expand the eligibility criteria for germline and somatic genetic testing in men with prostate cancer provide an opportunity for a larger portion of the prostate cancer population to access genetic testing and targeted therapies. Due to this, clinicians have needed to rapidly adapt their clinical workflows. Further, the field has renewed efforts to evaluate polygenetic risk profiles to better understand the complex genetic landscape beyond single genes. This review highlights advances in the understanding of prostate cancer genetics, and areas that remain less well defined. Collaboration between multidisciplinary team members is necessary to move this field forward and provide quality, optimal care.

Genetic testing for men with infertility: techniques and indications.

Genetic testing is an integral component in the workup of male infertility as genetic conditions may be responsible for up to 15% of all cases. Currently, three genetic tests are commonly performed and recommended by major urologic associations: karyotype analysis (KA), Y-chromosome microdeletion testing, and CFTR mutation testing. Despite widespread adoption of these tests, an etiology for infertility remains elusive in up to 80% of cases. Recent work has identified intriguing new targets for genetic testing which may soon see clinical relevance. This review will discuss the indications and techniques for currently offered genetic tests and briefly explore ongoing research directions within this field.

Evaluation of a mainstream model of genetic testing for men with prostate cancer.

1521 Background: In order to identify the ∼12% with inherited cancer predisposition, it is recommended that all men with metastatic prostate cancer (mPC) be offered testing. This has implications for treatment choices and cancer prevention in family. Limited geneticists/genetic counsellors globally present a major barrier to testing. We tested a potential solution, mainstreaming, where testing is performed by the patient’s oncologist. Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53) was performed on saliva/blood (Invitae). Primary outcomes were clinician and patient acceptability (modified Royal Marsden Satisfaction Questionnaires). Secondary outcomes included mutation rates and cost-effectiveness. A sample size of 44 provided 90% power, with a one-sided alpha of 5%, to distinguish a proportion of men happy with mainstreaming of 80% vs. 60% or less. Allowing for 25% drop-out, we aimed to recruit 60 men. Results: Of 66 men offered testing from April to November 2019, 63 (95%) accepted. Four pathogenic variants were identified (2 BRCA2, 1 NBN, 1 MSH6). 48 patients and eight clinicians completed questionnaires. Acceptability was high. All (48/48) patients were happy to have been tested, and 45/48 (94%) were happy to have been tested at their oncology appointment. All were happy to receive their results from their oncologist. All clinicians were satisfied mainstreaming and 88% (7/8) felt confident doing so. Mainstreaming was cost-effective, requiring 87% fewer genetic consultations than traditional genetic counselling. Conclusions: This study shows that mainstreaming of men with mPC is feasible, resource efficient and acceptable to both clinicians and patients. Widespread implementation as a new standard of care would facilitate timely access to genetic testing for men with mPC.

Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer

BackgroundRare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa). ObjectiveTo compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease. Design, setting, and participantsA retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics. Outcome measurements and statistical analysisCarrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher’s exact test. Results and limitationsOverall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10–6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10–5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10–6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10–9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10–13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02). ConclusionsIn men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment. Patient summaryProstate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.

Metastatic Prostate Cancer: Effects of Genetic Testing on Care.

The National Comprehensive Cancer Network now recommends BRCA1/2 genetic testing in men with metastatic prostate cancer. The purpose of this article is to provide a review of principles of genetic testing in prostate cancer and highlight the significance of clinical genetic testing of BRCA1/2 and other genes (CHEK2, HOXB13, PALB2), including Lynch syndrome genes (MLH1, MSH2, MSH6, and PMS2) in men with metastatic prostate cancer. The potential impact of genetic testing on systemic treatments and the significance of the pathogenic results for at-risk family members is discussed.

An analysis of the frequency of Y-chromosome microdeletions and the determination of a threshold sperm concentration for genetic testing in infertile men.

To describe the prevalence of Y-chromosome microdeletions in a multi-ethnic urban population in London, UK. To also determine predictive factors and a clinical threshold for genetic testing in men with Y chromosome microdeletions. A retrospective cohort study of 1473 men that were referred to a tertiary Andrology centre with male factor infertility between July 2004 and December 2016. All had a genetic evaluation, hormonal profile and 2 abnormal semen analyses. Those with abnormal examination findings also had targeted imaging performed. The prevalence of microdeletions was 4% (n = 58) in this study. These microdeletions were partitioned into the following regions: Azoospermia factors (AZF); AZFc (75%), AZFb+c (13.8%), AZFb (6.9%), AZFa (1.7%), and partial AZFa (1.7%). A high follicle-stimulating hormone level (P < 0.001) and a low sperm concentration (P < 0.05) were both found to be significant predictors for the identification of a microdeletion. Testosterone level, luteinising hormone level and testicular volume did not predict the presence of a microdeletion. None of the men with an AZF microdeletion had a sperm concentration of >0.5 million/mL. Lowering the sperm concentration threshold to this level retained the high sensitivity (100%) and increased the specificity (31%). This would produce significant cost savings when compared to the European Academy of Andrology/European Molecular Genetics Quality Network and European Association of Urology guidelines. The surgical sperm retrieval (SSR) rate after microdissection testicular sperm extraction was 33.2% in men with AZFc microdeletion. The prevalence of Y-chromosome microdeletions in infertile men appears to vary between populations and countries. A low sperm concentration was a predictive factor (P < 0.05) for identifying microdeletions in infertile males. A threshold for genetic testing of 0.5 million/mL would increase the specificity and lower the relative cost without adversely affecting the sensitivity. The rate of SSR was lower than that previously described in the literature.

The GENTleMEN study: Genetic testing for men with metastatic prostate cancer in Washington state and beyond.

TPS5098Background: Germline DNA repair gene mutations are present in ~10% of patients with metastatic prostate cancer (mPC) irrespective of age at diagnosis or family history, and have potential pr...

Interest in genetic testing among affected men from hereditary prostate cancer families and their unaffected male relatives

PurposeThe objective of this study was to evaluate potential sociodemographic, medical, psychosocial, and behavioral correlates of interest in genetic testing in men from hereditary prostate cancer families. MethodsFamily members affected with prostate cancer (n = 559) and their unaffected male relatives (n = 370) completed a mailed survey. Multivariable logistic regression models were used to examine the association between potential correlates and interest in genetic testing for prostate cancer. ResultsForty-five percent of affected and 56% of unaffected men reported that they definitely would take a genetic test for prostate cancer. More affected men reported high levels of familiarity with genetic testing than unaffected men (46 vs. 25%). There were several variables that were significantly correlated with interest in either affected or unaffected men, but only age and familiarity with genetics were significant in both groups. After controlling for confounding variables, only familiarity remained a significant correlate in both groups. ConclusionsThe contrast between low levels of familiarity with genetics and high test interest among unaffected men highlights the need for increased educational efforts targeting hereditary prostate cancer families. Overall, results illuminated several novel characteristics of men from hereditary prostate cancer families that should be considered when developing future informed consent procedures or educational materials for prostate cancer genetic testing.