Initial Findings from a High Genetic Risk Prostate Cancer Clinic

Sessine, Michael; Das, Sanjay; Park, Bumsoo; Salami, Simpa S.; Kaffenberger, Samuel D.; Kasputis, Amy; Solorzano, Marissa A.; Luke, Mallory; Vince, Randy; Kaye, Deborah R.; Borza, Tudor; Stoffel, Elena M.; Cobain, Erin F.; Merajver, Sofía D.; Jacobs, Michelle F.; Milliron, Kara J.; Caba, Laura; Neste, Leander Van; Mondul, Alison M.; Morgan, Todd M.

doi:10.1016/j.urology.2021.05.078

Cited by 6 publications

(6 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in the PLCO trial, a family history of PCa was predictive of higher PCa mortality in the non-screening arm (hazard ratio 1.89, 95% CI 1.15-3.10) [24]. According to different guidelines, individual screening for early diagnosis of PCa is suggested for men between the ages of 50 and 70-75 years or if they are clearly likely to live >10 years longer [25]. Men, exposed to a genetic factor increasing the risk of early onset PCa, have a decrease in the risk of developing late-onset PCa, which is often associated with a more aggressive disease and a worse outcome, if they did not declare the disease early.…”

Section: Discussionmentioning

confidence: 99%

Clinical performance of magnetic resonance imaging and biomarkers for prostate cancer diagnosis in men at high genetic risk

et al. 2023

View full text Add to dashboard Cite

Objectives To evaluate different scenarios for the management of early diagnosis of cancer (PCa) in men at high genetic risk, using recently developed blood and urinary molecular biomarkers in combination with clinical information alongside multiparametric magnetic resonance imaging (mpMRI). Patients and Methods A total of 322 patients with a high genetic risk (familial or personal history of cancers or a predisposing germline variant) were included in this study. The primary outcome was the detection rates of PCa (positive biopsy) or clinically significant PCa (biopsy with International Society of Urological Pathology [ISUP] grade >1). Clinical parameters included age, body mass index, ancestry, and germline mutational status, mpMRI, prostate‐specific antigen density (PSAD), Prostate Health Index and urinary markers (Prostate Cancer Associated 3, SelectMdx™ and T2:ERG score) were assessed. Sensitivity (Se) and specificity (Sp) for each marker at their recommended cut‐off for clinical practice were calculated. Comparison between diagnoses accuracy of each procedure and scenario was computed using mutual information based and direct effect contribution using a supervised Bayesian network approach. Results A mpMRI Prostate Imaging‐Reporting and Data System (PI‐RADS) score ≥3 showed higher Se than mpMRI PI‐RADS score ≥4 for detection of PCa (82% vs 61%) and for the detection of ISUP grade >1 lesions (96% vs 80%). mpMRI PI‐RADS score ≥3 performed better than a PSA level of ≥3 ng/mL (Se 96%, Sp 53% vs Se 91%, Sp 8%) for detection of clinically significant PCa. In case of negative mpMRI results, the supervised Bayesian network approach showed that urinary markers (with the same accuracy for all) and PSAD of ≥0.10 ng/mL/mL were the most useful indicators of decision to biopsy. Conclusions We found that screening men at high genetic risk of PCa must be based on mpMRI without pre‐screening based on a PSA level of >3 ng/mL, to avoid missing too many ISUP grade >1 tumours and to significantly reduce the number of unnecessary biopsies. However, urinary markers or a PSAD of ≥0.10 ng/mL/mL when mpMRI was negative increased the detection of ISUP grade >1 cancers. We suggest that a baseline mpMRI be discussed for men at high genetic risk from the age of 40 years.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical performance of magnetic resonance imaging and biomarkers for prostate cancer diagnosis in men at high genetic risk

et al. 2023

View full text Add to dashboard Cite

show abstract

“…About 40–50% of PCs are hereditary, frequently showing earlier onset, familial clustering, and multifocality; mutations and polymorphisms of several tumor suppressor genes and proto-oncogenes play a key role in PC onset and progression [ 10 , 169 ]. The impairment of MMR genes has been linked not only to sporadic PC cases (usually harboring MSH2 or MSH6 gene defects), but also to some hereditary forms of PC [ 4 , 10 , 169 , 178 , 179 ]. Lynch syndrome is an autosomal-dominant genetic disorder driven by germline mutations in MMR genes (such as MLH1 , MSH2 , MSH6 , and PMS2 ), harboring greater cancer risk (especially for colorectal adenocarcinoma, but also for PC) through MSI [ 4 , 10 , 169 , 178 , 179 ].…”

Section: Discussionmentioning

confidence: 99%

“…The impairment of MMR genes has been linked not only to sporadic PC cases (usually harboring MSH2 or MSH6 gene defects), but also to some hereditary forms of PC [ 4 , 10 , 169 , 178 , 179 ]. Lynch syndrome is an autosomal-dominant genetic disorder driven by germline mutations in MMR genes (such as MLH1 , MSH2 , MSH6 , and PMS2 ), harboring greater cancer risk (especially for colorectal adenocarcinoma, but also for PC) through MSI [ 4 , 10 , 169 , 178 , 179 ]. NGS may identify germline MMR mutations, and genetic counselling for Lynch syndrome is advised for MSI-H/dMMR patients by the NCCN guidelines [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

et al. 2022

View full text Add to dashboard Cite

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.

show abstract

“…These advances are likely to reduce the burden on health systems and individuals compared with managing disease at advanced stages [ 4 , 5 ]. Recent studies have highlighted the benefits and feasibility of dedicated clinics to serve high-risk prostate cancer patients with pathogenic mutations in PC susceptibility genes, and clinics dedicated to identifying these high-risk individuals in a streamlined fashion [ 6 , 7 ]. Modified protocols for BRCA2 mutation carriers have resulted in improved clinical outcomes [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

Mondschein

Bolton

Clouston

et al. 2022

Cancers

View full text Add to dashboard Cite

Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

show abstract

Initial Findings from a High Genetic Risk Prostate Cancer Clinic

Cited by 6 publications

References 29 publications

Clinical performance of magnetic resonance imaging and biomarkers for prostate cancer diagnosis in men at high genetic risk

Clinical performance of magnetic resonance imaging and biomarkers for prostate cancer diagnosis in men at high genetic risk

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

Contact Info

Product

Resources

About