Release of reclassified VUS results of now deceased patients to family members: Practices and opinions.

Variants of uncertain significance (VUS) are commonly identified in genetic testing. The rate at which a VUS is reclassified depends on multiple factors. However, as the amount of time it might take for a VUS to be reclassified varies, some patients with a VUS genetic testing result might have passed away before the VUS is reclassified. A VUS that is reclassified after the patient's death has clinical implications for the deceased patient's family members. The disclosure of reclassified VUS results for a deceased patient has complex legal and ethical implications. There are no established guidelines on how the reclassified VUS result for a deceased patient should be disclosed to at-risk relatives. An online survey was sent to members of the National Society of Genetic Counselors (NSGCs) to elicit practices and opinions regarding this issue. A total of 153 (4%) NSGC members completed the survey. Thirty-seven (24.2%) respondents reported having received a reclassified VUS for a deceased patient. Respondents were more likely to attempt disclosure if the variant was reclassified as pathogenic (93.5%) versus benign (76.5%), although the difference did not reach statistical significance (p = 0.06). Respondents more often reported the impact on family members (85.5%) than the decedent's right to privacy (15.0%) as extremely important when considering disclosure to family members. A legal mechanism to allow disclosure to relatives was supported by 70.6% of respondents and 97.4% felt the issue was important enough to pursue if such a process was in place. Only 9.8% of respondents supported a legal requirement of consent before disclosing to family members when a VUS is reclassified after the patient has passed away. Our results indicate that there is no consensus for how these results should be handled and a mechanism for disclosure of reclassified results to family members is supported.

Timely cancer genetic counseling and testing for young women with breast cancer: impact on surgical decision-making for contralateral risk-reducing mastectomy.

PURPOSE: Genetic testing (GT) can identify individuals with pathogenic/likely pathogenic variants (PV/LPVs) in breast cancer (BC) predisposition genes, who may consider contralateral risk-reducing mastectomy (CRRM). We report on CRRM rates in young women newly diagnosed with BC who received GT through a multidisciplinary clinic. METHODS: Clinical data were reviewed for patients seen between November 2014 and June 2019. Patients with non-metastatic, unilateral BC diagnosed at age ≤ 45 and completed GT prior to surgery were included. Associations between surgical intervention and age, BC stage, family history, and GT results were evaluated. RESULTS: Of the 194 patients, 30 (15.5%) had a PV/LPV in a BC predisposition gene (ATM, BRCA1, BRCA2, CHEK2, NBN, NF1), with 66.7% in BRCA1 or BRCA2. Of 164 (84.5%) uninformative results, 132 (68%) were negative and 32 (16.5%) were variants of uncertain significance (VUS). Overall, 67 (34.5%) had CRRM, including 25/30 (83.3%) PV/LPV carriers and 42/164 (25.6%) non-carriers. A positive test result (p < 0.01) and significant family history were associated with CRRM (p = 0.02). For the 164 with uninformative results, multivariate analysis showed that CRRM was not associated with age (p = 0.23), a VUS, (p = 0.08), family history (p = 0.10), or BC stage (p = 0.11). CONCLUSION: In this cohort of young women with BC, the identification of a PV/LPV in a BC predisposition gene and a significant family history were associated with the decision to pursue CRRM. Thus, incorporation of genetic services in the initial evaluation of young patients with a new BC could contribute to the surgical decision-making process.

Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women.

Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers-specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients' lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.

Knowledge and opinions regarding BRCA1 and BRCA2 genetic testing among primary care physicians.

BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non-genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty-six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2-related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non-genetic professionals.

Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome.

Screening for DNA mismatch repair (MMR) deficiency in colorectal and endometrial carcinomas identifies patients at risk for Lynch syndrome. Some patients with MMR-deficient tumors have no evidence of a germline mutation and have been described as having Lynch-like syndrome. We compared the clinicopathological features of colorectal and endometrial carcinomas in patients with Lynch-like syndrome and Lynch syndrome. Universal screening identified 356 (10.6%) of 3352 patients with colorectal carcinoma and 72 (33%) of 215 patients with endometrial carcinoma with deficient DNA MMR. Sixty-six patients underwent germline mutation analysis with 45 patients (68%) having evidence of a germline MMR gene mutation confirming Lynch syndrome and 21 patients (32%) having Lynch-like syndrome with no evidence of a germline mutation. Most patients with Lynch-like syndrome had carcinoma involving the right colon compared to patients with Lynch syndrome (93% versus 45%; P < .002). All patients with colorectal carcinomas demonstrating isolated loss of MSH6 expression had Lynch syndrome confirmed by germline mutation analysis. Synchronous or metachronous Lynch syndrome-associated carcinoma was more frequently identified in patients with Lynch syndrome compared to Lynch-like syndrome (38% versus 7%; P = .04). There were no significant differences in clinicopathological variables between patients with Lynch-like syndrome and Lynch syndrome with endometrial carcinoma. In summary, 32% of patients with MMR deficiency concerning Lynch syndrome will have Lynch-like syndrome. Our results demonstrate that patients with Lynch-like syndrome are more likely to have right-sided colorectal carcinoma, less likely to have synchronous or metachronous Lynch syndrome-associated carcinoma, and less likely to demonstrate isolated loss of MSH6 expression within their tumor.

Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression.

Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression without a germline PMS2 mutation must have MLH1 mutation analysis performed.

A multidisciplinary clinic for individualizing management of patients at increased risk for breast and gynecologic cancer.

Increasing awareness of the hereditary component of breast and ovarian cancer has driven interest in creating clinics for the patient population at high risk for these cancers. Identifying adequate space and appropriate staff, coordinating multiple providers' schedules, establishing referral criteria, and addressing billing and reimbursement concerns are just some of the issues that are involved in the creation of a multidisciplinary high risk breast and ovarian cancer program. We provide an overview of the clinic structure at the Magee-Womens Hospital High Risk Breast and Ovarian Cancer Program (HRBOCP), which was created in 2002 due to recognition of a need for a more coordinated model of providing care for women at increased risk for breast and ovarian cancer. The goals of the HRBOCP are to evaluate women at high risk for breast and ovarian cancer and to organize their clinical care in a multidisciplinary setting staffed by experts in the field; to provide updates on new data regarding screening recommendations, prevention options, and risk factors pertinent to an individual's cancer risk; to provide ongoing support to patients and to coordinate family communication when appropriate; and to facilitate enrollment in appropriate research studies and registries.

Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A.

Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.

Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations.

Von Hippel-Lindau (VHL) disease type 2A is an inherited tumor syndrome characterized by predisposition to pheochromocytoma (pheo), retinal hemangioma (RA), and central nervous system hemangioblastoma (HB). Specific VHL subtypes display genotype-phenotype correlations but, unlike other familial syndromes such as MEN-2, the phenotype in VHL has not yet been stratified at the codon level. Over decades, we have managed two very large VHL type 2A regional kindreds with nearly adjacent but distinct VHL missense mutations. We determined the phenotype of Family 2 and compared the clinical and pathologic parameters of pheo between 30 members of Family 1 (Y112H mutation) and 33 members of Family 2 (Y98H mutation) with mean follow-up of 15.5 and 12.1 years, respectively (P = 0.24). In Family 2, pheo was the most frequent VHL manifestation (79%) and all pheo diagnoses occurred by age 50. Age at first diagnosis was younger in Family 2 than in Family 1 (mean 19.7 vs. 28.8 years; P = 0.02). Pheo expressivity differed by genotype: Family 1 pheo was more likely to be multifocal (P = 0.04), as well as malignant (P < 0.01) and lethal (P = 0.02). Family 1 pheo was also more likely to secrete vanillylmandelic acid (VMA) alone (P = 0.05). This analysis of 130 pheochromocytomas in 63 VHL type 2A patients demonstrates that mutation-specific malignancy and expression patterns exist within the VHL type 2A subtype, and provides information that may help tailor the screening and management algorithms of affected members and those at risk.

Comparison of Locoregional Recurrence with Mastectomy vs. Breast Conserving Surgery in Pregnancy Associated Breast Cancer (PABC).

We have compared outcomes, including the locoregional recurrence, between mastectomy and breast conserving therapy in PABC. Patients were divided into those who were treated with mastectomies (group 1) and those with breast conserving surgery (group 2). The groups were comparable except for lower mean age in group 2 and more patients with stage III disease and higher number of nodes positive in the group 1. Five-year actuarial LRR, distant metastases free survival and overall survival in group 1 vs. 2 were 10% vs. 37%, 73% vs. 81% and 57% vs. 59% respectively. The patients with PABC treated with breast conserving therapy, despite having lower stage disease, have a higher risk of local regional recurrence in comparison with those treated with mastectomy.

Identification of multiple endocrine neoplasia type 1 in patients with apparent sporadic primary hyperparathyroidism.

BACKGROUND: In the evaluation of patients with primary hyperparathyroidism (PHP), specific query for a personal or family history of MEN1 (Hx) is recommended widely, but responses are rarely positiv. We instituted a 6-question panel (6Q) to routinely screen for MEN1 preoperatively. METHODS: The clinical database entries of 939 patients explored for apparent sporadic PHP from June 1992 to November 2007 were examined for presenting diagnosis, demographics, anatomic findings, MEN1 analysis, and final diagnosis. To directly compare the results of 6Q and Hx, we also reviewed the charts of 654/939 PHP patients screened systematically from January 2000 to November 2007. RESULTS: MEN1 was undiagnosed until the preoperative evaluation in 1.6% of patients referred with apparent sporadic PHP. To date, MEN1 has been diagnosed in 42 of 939 (4.5%) PHP patients. Compared with those who have sporadic PHP, MEN1 patients were often male (38.1% vs 20.2%; P = .005) and young (mean, 38 +/- 17 years vs 60 +/- 13 years; P < .001). When hyperplasia was present at initial parathyroid exploration, the likelihood of MEN1 was 26% (32/123). For the 15 patients diagnosed by a surgeon to have MEN1, Hx was positive in 3 patients (20%) and 6Q in 13 (87%) (P = .0002). In a multivariate analysis of 635 patients with negative Hx, the likelihood of MEN1 increased with (1) younger age at initial parathyroid exploration and (2) number of positive 6Q responses. CONCLUSION: MEN1 occurs relatively often and can be missed. Systematic use of a simple 6-question panel helps to identify MEN1 prior to parathyroid exploration. Young male patients with parathyroid hyperplasia and positive 6Q results should be evaluated for MEN1.

Performance of the revised Bethesda guidelines for identification of colorectal carcinomas with a high level of microsatellite instability.

CONTEXT: Criteria for microsatellite instability (MSI) testing to rule out hereditary nonpolyposis colorectal cancer were recently revised and include parameters such as age and specific histologic features that can be identified by the pathologist, triggering reflex MSI testing. OBJECTIVE: To review the performance of the revised Bethesda guidelines to identify MSI-positive colorectal cancers. DESIGN: Seventy-five patients with colorectal cancer were included; 68 patients younger than 50 years and 7 patients between 50 and 60 years were selected based on histopathologic criteria. Microsatellite instability testing with the National Cancer Institute--recommended panel and immunohistochemistry for hMLH1 and hMSH2 were performed. Tumors were classified into microsatellite instability high (MSI-H), low (MSI-L), or stable (MSS) categories. RESULTS: Overall, 17 (23%) of 75 colorectal cancer cases were classified as MSI-H, including 13 patients younger than 50 years and 4 patients between 50 and 60 years. Among the MSI-H tumors, 10 (59%) were characterized by loss of hMLH1 and 6 (35%) were hMSH2 negative. Histologic features suggestive of MSI-H phenotype were present in 80% of MSI-H and 35% of MSS/MSI-L tumors. The number of positive lymph nodes was higher in MSS/MSI-L adenocarcinomas (P = .04). CONCLUSIONS: By selecting for age and histologic features, we detected MSI-H tumors in approximately one quarter of colorectal cancer cases meeting the revised Bethesda guidelines and identified 17 MSI-H cases, whereas only 8 would have been recognized by the prior guidelines. These data indicate that reflex testing requested by pathologists based on the revised Bethesda guidelines increases the detection of MSI-H and potential hereditary nonpolyposis colorectal cancer cases.

Recognition and management of hereditary breast cancer syndromes.

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.