Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.

PURPOSE: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort. METHODS: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs. RESULTS: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC. CONCLUSION: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.

Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. Objective: To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. Design, Setting, and Participants: In this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. Exposures: Self-reported bilateral oophorectomy (with or without salpingectomy). Main Outcomes and Measures: All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. Results: There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy. Conclusions and Relevance: In this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures: Entrance into an MRI surveillance program. Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

Pharmacogenomics: An evolving clinical tool for precision medicine.

Pharmacogenomics, ie, the study of how an individual's genomic profile influences his or her response to drugs, has emerged as a clinical tool to optimize drug therapy. Certain variants in some genes increase the risk of severe, life-threatening adverse effects from certain drugs. Integrating pharmacogenomics into clinical practice to assist in drug selection and dosing has the potential to improve the outcomes of treatment, reduce the risk of drug-induced morbidity and death, and be cost-effective.

Assessment of clinical workload for general and specialty genetic counsellors at an academic medical center: a tool for evaluating genetic counselling practices.

With genomics influencing clinical decisions, genetics professionals are exponentially called upon as part of multidisciplinary care. Increasing demand for genetic counselling, a limited workforce, necessitates practices improve efficiency. We hypothesised that distinct differences in clinical workload exist between various disciplines of genetic counselling, complicating practice standardisation and patient volume expectations. We thus sought to objectively define and assess workload among various specialties of genetic counselling. Twelve genetic counsellors (GCs), representing 9.3 clinical FTE, in general or specialty (cancer, cardiovascular or prenatal) services at an academic health system developed a data collection tool for assessing time and complexity. Over a 6-week period, the data were recorded for 583 patient visits (136 general and 447 specialty) and analysed comparing general versus specialty GCs. Variables were compared with hierarchical linear models for ordinal or continuous data and hierarchical logistic models for binary data. General GCs completed more pre- and post-visit activities (P=0.011) and spent more time (P=0.009) per case. General GCs reported greater case discussion with other providers (P<0.001), literature review (P=0.026), exploring testing options (P=0.041), electronic medical record review (P=0.040), insurance preauthorization (P=0.05) and fielding patient inquiries (P=0.003). Lesser redundancy in referral indication was observed by general GCs. GCs in general practice carry a higher pre- and post-visit workload compared with GCs in specialty practices. General GCs may require lower patient volumes than specialty GCs to allow time for additional pre- and post-visit activities. Non-clinical activities should be transferred to support staff.

Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis.

PURPOSE: Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. One-quarter of patients who are diagnosed with CS have pathogenic germline PTEN mutations, which increase the risk of the development of breast, thyroid, uterine, renal, and other cancers. PTEN testing and regular, intensive cancer surveillance allow for early detection and treatment of these cancers for mutation-positive patients and their relatives. Individual CS-related features, however, occur commonly in the general population, making it challenging for clinicians to identify CS-like patients to offer PTEN testing. PATIENTS AND METHODS: We calculated the cost per mutation detected and analyzed the cost-effectiveness of performing selected PTEN testing among CS-like patients using a semi-quantitative score (the PTEN Cleveland Clinic [CC] score) compared with existing diagnostic criteria. In our model, first-degree relatives of the patients with detected PTEN mutations are offered PTEN testing. All individuals with detected PTEN mutations are offered cancer surveillance. RESULTS: CC score at a threshold of 15 (CC15) costs from $3,720 to $4,573 to detect one PTEN mutation, which is the most inexpensive among the different strategies. At base-case, CC10 is the most cost-effective strategy for female patients who are younger than 40 years, and CC15 is the most cost-effective strategy for female patients who are between 40 and 60 years of age and male patients of all ages. In sensitivity analyses, CC15 is robustly the most cost-effective strategy for probands who are younger than 60 years. CONCLUSION: Use of the CC score as a clinical risk calculator is a cost-effective prescreening method to identify CS-like patients for PTEN germline testing.

PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol.

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Clinically, deregulation of PTEN function resulting in reduced PTEN expression and activity is implicated in human diseases. Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. CS-related individual features occur commonly in the general population. Approximately 25% of patients diagnosed with CS have pathogenic germline PTEN mutations, which increase lifetime risks of breast, thyroid, uterine, renal and other cancers. PTEN testing and intensive cancer surveillance allow for early detection and treatment of these cancers for mutation positive patients and their relatives. In this review, we highlight our current knowledge of germline PTEN mutations in relation to human disease. We review current clinical diagnosis and management recommendations for PHTS including recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically.

PTEN germline mutations in patients initially tested for other hereditary cancer syndromes: would use of risk assessment tools reduce genetic testing?

PURPOSE: PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN. PATIENTS AND METHODS: Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were <18 years of age, or if they were diagnosed with Cowden syndrome before 1998. Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria, LS-relevant Amsterdam II/Bethesda 2004 criteria, or had adenomatous polyps. Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator. RESULTS: Of 137 PTEN mutation-positive adult probands, 59 (43.1%) met testing criteria for HBOC or LS. Of these, 45 (32.8%) were first offered HBOC, LS, or APS testing. Of those who underwent APS testing, none of the six patients met criteria. Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria. Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes, at a total cost of $66,080. CONCLUSION: PHTS is an important differential diagnosis for patients referred for HBOC, LS, or APS. Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing.

Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles.

This report is based on the Federation of American Societies for Experimental Biology's symposium, "Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles," held in Chevy Chase, MD, March 24-25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges.

Prospective comparison of family medical history with personal genome screening for risk assessment of common cancers.

Family history-based risk assessment (FHRA) is a genetic tool for identifying those at risk of disease. Genome-wide association studies have shown that single nucleotide polymorphisms (SNP) are statistically associated with low- to moderate-level risks of diseases. There has been limited study of complementarity for these two assessment methods. We sought to compare cancer risk categorizations from FHRA and from Navigenics Personal Genome Screening (PGS). We compared FHRA with PGS for breast (22 females), prostate (22 males), and colon cancer (44 males and females) assessed by kappa (κ) statistic. We also assessed each participant's hereditary risk based on clinical criteria and/or gene-test results. Both FHRA and PGS placed 59%, 68% and 44% of participants into the same risk categories for breast, prostate, and colon cancer, respectively. Overall, however, there was little concordance in FHRA versus PGS for all three cancer risks (κ<0.2). FHRA assigned 22 with hereditary risk compared with PGS, which identified one as high risk (P<0.0001). We assessed nine with hereditary colorectal cancer risk, five with germline mutations, but none were classified as PGS high risk (P=0.0001). FHRA and PGS may be complementary tools for cancer risk assessment. However, evaluation of family history remains the standard to evaluate an individual's cancer risk until further research.

A large health system's approach to utilization of the genetic counselor CPT® 96040 code.

PURPOSE: : In 2007, CPT® code 96040 was approved for genetic counseling services provided by nonphysician providers. Because of professional recognition and licensure limitations, experiences in direct billing by genetic counselors for these services are limited. A minority of genetics clinics report using this code because of limitations, including perceived denial of the code and confusion regarding compliant use of this code. We present results of our approach to 96040 billing for genetic counseling services under a supervising physicians National Provider ID number in a strategy for integration of genetics services within nongenetics specialty departments of a large academic medical center. METHODS: : The 96040 billing encounters were tracked for a 14-month period and analyzed for reimbursement by private payers. Association of denial by diagnosis code or specialty of genetics service was statistically analyzed. Descriptive data regarding appointment availability are also summarized. RESULTS: : Of 350 encounters January 2008 to February 2009, 289 (82%) were billed to private payers. Of these, 62.6% received some level of reimbursement. No association was seen for denial when analyzed by the diagnosis code or by genetics focus. Through this model, genetics appointment availability minimally doubled. CONCLUSION: : Using 96040 allowed for expanding access to genetics services, increased appointment availability, and was successful in obtaining reimbursement for more than half of encounters billed.

Bioethical and clinical dilemmas of direct-to-consumer personal genomic testing: the problem of misattributed equivalence.

A number of for-profit companies now provide personal genomic testing services to clients directly, without input from a physician or other health care provider, and the results of these tests include predictions about a broad spectrum of disease risks and traits. Validated clinical genetic testing and direct-to-consumer (DTC) genomic tests differ substantially in their reliability and usefulness, raising many clinical, ethical, and societal challenges, which are discussed in this Commentary. Of special concern is the problem of misattributed equivalence, which occurs when a patient or physician mistakenly views alternative methods of genetic evaluation as equivalent in their results and analytic rigor. Despite the many challenges raised by DTC genomic testing, we are reminded that commercial interests have sometimes acted as a disruptive force or technology that drives nonconventional approaches to difficult problems.

Autism spectrum disorders as a qualitatively distinct category from typical behavior in a large, clinically ascertained sample.

The present study evaluated the hypothesis that autism spectrum disorders (ASDs) are best represented as a discrete category distinct from typical behavior within autism-affected families. The latent structure, categorical versus dimensional, of ASDs informs future diagnostic revisions, clinical assessment, and the design of future research. Data were obtained from Interactive Autism Network, a registry that preferentially recruits families with at least one ASD-affected child. Caregivers reported autism symptoms for affected and unaffected children using the Social Responsiveness Scale and Social Communication Questionnaire. Taxometric and latent variable models examined whether dimensional or categorical models best fit the data. Taxometric and latent variable model comparisons consistently indicated two-group mixtures for all indicator sets, even in participants designated as unaffected by caregivers. The identified category was associated with external indicators of disability, supporting its validity. Results indicated that ASD is best characterized as a category, distinct from typical behavior within ASD-affected families.

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

PURPOSE: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are approximately $3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. EXPERIMENTAL DESIGN: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. RESULTS: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. CONCLUSIONS: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations.