Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Urologists' Current Practices in Screening and Treating Men With a Family History of Prostate Cancer.

OBJECTIVE: To assess urologists' knowledge and utilization of family history to determine prostate cancer (PC) screening and treatment recommendations. MATERIALS AND METHODS: Questionnaires that explored urologists' knowledge, frequency, and utilization of family history information for screening and treatment recommendations for PC were prospectively collected. Data were summarized and compared using descriptive statistics. RESULTS: A total of 87 responses were collected, for a response rate of 60% (87 of 145). The majority of urologists reported that they always collect family history when discussing risk (95%) or screening (87%), and recommended earlier screening for men with family history of PC in comparison with men with no family history. Although only 57% reported always collecting family history when discussing treatment, the majority of respondents reported that a positive family history influenced their treatment recommendations. Eight percent of urologists would recommend prostatectomy for men diagnosed with low-grade, low-risk PC and no family history of PC vs 52% who would recommend the same course of treatment when the patient had at least 1 first-degree relative who died of the disease. Conversely, 91% of urologists would recommend active surveillance for men with low-grade, low-risk PC and no family history vs 47% for those with at least 1 first-degree relative who died of the disease. CONCLUSION: The majority of urologists collect information on family history of PC. Despite the lack of literature to support that patients with familial PC require more aggressive treatment, urologists were more likely to recommend definitive therapies.

Primary care physician experiences with integrated pharmacogenomic testing in a community health system.

AIM: To explore primary care physicians' views of the utility and delivery of direct access to pharmacogenomics (PGx) testing in a community health system. METHODS: This descriptive study assessed the perspectives of 15 healthcare providers utilizing qualitative individual interviews. RESULTS: Three main themes emerged: perceived value and utility of PGx testing; challenges to implementation in practice; and provider as well as patient needs. CONCLUSION: While providers in this study viewed benefits of PGx testing as avoiding side effects, titrating doses more quickly, improving shared decision-making and providing psychological reassurance, challenges will need to be addressed such as privacy concerns, cost, insurance coverage and understanding the complexity of PGx test results.

Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease.

OBJECTIVE: To assess whether men with a family history of prostate cancer are more likely to fail active surveillance because of recategorization of their tumors on subsequent surveillance biopsies. METHODS: Men enrolled in an institutional review board-approved active surveillance program were studied, and data on first- and/or second-degree family history of prostate cancer was collected. Analyses were performed to compare the frequency of family history with recategorization (higher grade or volume disease) on surveillance biopsies. RESULTS: Men with and without family history were recategorized with higher grade disease at a similar frequency (30.9% vs 32.8%). There was no evidence that men with a family history with higher grade disease had more aggressive pathology at the time of radical prostatectomy than men without a family history. Although those with a family history tended to have a shorter time period to recategorization with more positive cores, the difference was not significant. CONCLUSION: Our results suggest that men with a family history of prostate cancer are not at an increased risk for recategorization on active surveillance. Men with a family history of prostate cancer should not be deterred from considering active surveillance as a treatment option.

Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice.

Next-generation sequencing genetic testing panels for cancer susceptibility (cancer panels) have recently become clinically available. At present, clinical utility is unknown and there are no set criteria or guidelines established for whom to offer such testing. Although it may be a cost-effective method to test multiple cancer susceptibility genes concurrently, the rate of finding variants of unknown significance (VUS) may be high and testing may yield mutations in genes with no established management recommendations. We describe our Center's experience over a 14-month period (April 2012-June 2013) for patient interest and uptake in cancer panel testing and whether there were predictors of pursuing testing or identifying mutations. Using a clinical ranking system, patients' family histories were ranked from 0 to 3 (low likelihood to high likelihood for underlying genetic susceptibility). The clinical ranking system was assessed to determine its predictability of finding mutations. Of the 689 patients who met inclusion criteria, the option of pursuing a cancer panel was discussed with 357 patients; 63 (17.6 %) patients pursued testing. Those who pursued testing were more likely to be older, male, affected with cancer, affected with multiple primary cancers, and had a higher clinical rank than non-pursuers. There were no significant predictors of finding a mutation on panel testing. Of the 61 patients who have received results, there was a 6.6 % mutation rate and 19.7 % VUS rate. The yield of cancer panels in clinical practice is low and the strength of family history alone may not predict likelihood of finding a mutation.

Physicians' preparedness for integration of genomic and pharmacogenetic testing into practice within a major healthcare system.

PURPOSE: Physicians will play a large role in the delivery of genomic medicine, given the limited number of trained genetics professionals. The objective of this study was to assess physician preparedness for incorporating genomic testing (GT) and pharmacogenetic testing (PT) into practice by determining knowledge, experience, comfort level, and barriers, as well as their expectations for practice and educational needs. METHODS: A 30-question survey was distributed to physicians spanning all disciplines within our healthcare system. RESULTS: Perceived knowledge was poor; 40%-72% reported "no to minimal knowledge" for all genomics topics. Recent graduates or those with no patients who had undergone GT or PT had lower comfort levels. Participating physicians anticipate usage to increase; however, most were uncertain when and how to incorporate genomics into practice. Physicians perceived lack of knowledge and time to keep updated as their greatest barriers to incorporating GT and PT into practice. CONCLUSION: Overall, physicians appear underprepared, perceiving they lack sufficient knowledge and confidence to incorporate GT and PT into practice. The majority of physicians expect their role in GT and PT to increase. The results underscore the importance of enhancing policies and initiatives to increase physician knowledge and comfort level.

Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers.

BACKGROUND: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. METHODS: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. RESULTS: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. CONCLUSION: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. IMPACT: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk.

Parents' perceptions of autism spectrum disorder etiology and recurrence risk and effects of their perceptions on family planning: Recommendations for genetic counselors.

Knowledge about the etiology of Autism Spectrum Disorders (ASDs) is increasing, but causes remain elusive for most cases. Genetic counselors are positioned to help families that have children with ASDs despite uncertainty regarding etiology. To determine how genetic counselors might best provide services, an anonymous survey was conducted with 255 parents whose children were diagnosed on the autism spectrum. Questions concerned: 1) their perceptions of ASD cause(s) and 2) recurrence risk, 3) whether perceived risk affected family planning decisions, 4) whether parents had received genetic services, and 5) how genetic counselors might assist families. The most prevalent perceived cause was genetic influences (72.6%). Most parents' recurrence risk perceptions were inaccurately high and significantly affected family planning. Only 10% had seen a genetic professional related to an ASD. Parents provided several suggestions for genetic counselor best practices. Findings indicate the importance of genetic counselor awareness of parent perceptions in order to best help families who have children with ASDs.

Fate of the initial follicle pool: empirical and mathematical evidence supporting its sufficiency for adult fertility.

The importance of the initial follicle pool in fertility in female adult mammals has recently been debated. Utilizing a mathematical model of the dynamics of follicle progression (primordial to primary to secondary), we examined whether the initial follicle pool is sufficient for adult fertility through reproductive senescence in CD1 mice. Follicles in each stage were counted from postnatal day 6 through 12 months and data were fit to a series of first-order differential equations representing two mechanisms: an initial pool of primordial follicles as the only follicle source (fixed pool model), or an initial primordial follicle pool supplemented by germline stem cells (stem cell model). The fixed pool model fit the experimental data, accurately representing the maximum observed primary follicle number reached by 4-6 months of age. Although no germline stem cells could be identified by SSEA-1 immunostaining, the stem cell model was tested using a range of de novo primordial follicle production rates. The stem cell model failed to describe the observed decreases in follicles over time and did not parallel the accumulation and subsequent reduction in primary follicles during the early fertile lifespan of the mouse. Our results agree with established dogma that the initial endowment of ovarian follicles is not supplemented by an appreciable number of stem cells; rather, it is sufficient to ensure the fertility needs of the adult mouse.

Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool.

Mammalian females enter puberty with follicular reserves that exceed the number needed for ovulation during a single lifetime. Follicular depletion occurs throughout reproductive life and ends in menopause, or reproductive senescence, when the follicle pool is exhausted. The mechanisms regulating the production of a species-specific initial follicle pool are not well understood. However, the establishment of a follicular reserve is critical to defining the length of reproductive cyclicity. Here we show that activin A (rh-ActA), a known regulator of follicle formation and growth in vitro, increased the number of postnatal mouse primordial follicles by 30% when administered to neonatal animals during the time of germline cyst breakdown and follicle assembly. This expansion in the initial follicle pool was characterized by a significant increase in both germ cell and granulosa cell proliferation. However, the excess follicles formed shortly after birth did not persist into puberty and both adult rh-ActA- and vehicle-treated animals demonstrated normal fertility. A follicle atresia kinetic constant (k(A)) was modeled for the two groups of animals, and consistent with the empirical data, the k(A) for rh-ActA-treated was twice that of vehicle-treated animals. Kinetic constants for follicle formation, follicle loss and follicle expansion from birth to postnatal day 19 were also derived for vehicle and rh-ActA treatment conditions. Importantly, introduction of exogenous rh-ActA revealed an intrinsic ovarian quorum sensing mechanism that controls the number of follicles available at puberty. We propose that there is an optimal number of oocytes present at puberty, and when the follicle number is exceeded, it occurs at the expense of oocyte quality. The proposed mechanism provides a means by which the ovary eliminates excess follicles containing oocytes of poor quality prior to puberty, thus maintaining fertility in the face of abnormal hormonal stimuli in the prepubertal period.