Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark.

BACKGROUND: An estimated 5-10% of breast and ovarian cancers are due to hereditary causes such as hereditary breast and ovarian cancer (HBOC) syndrome. Medicare, the third-party payer that covers 44 million patients in the United States, has implemented a set of clinical criteria to determine coverage for the testing of the BRCA1 and BRCA2 genes. These criteria, developed to identify carriers of BRCA1/2 variants, have not been evaluated in the panel testing era. This study investigated a series of Medicare patients undergoing genetic testing for HBOC to determine the efficacy of genetic testing criteria in identifying patients with hereditary risk. METHODS: This study retrospectively examined de-identified data from a consecutive series of Medicare patients undergoing genetic testing based on personal and family history of breast and gynecologic cancer. Ordering clinicians indicated whether patients did or did not meet established criteria for BRCA1/2 genetic testing. The genetic test results were compared between the group that met the criteria and the group that did not. Patients in families with known pathogenic (P) or likely pathogenic (LP) variants were excluded from the primary analysis. RESULTS: Among 4196 unique Medicare patients, the rate of P/LP variants for the patients who met the criteria for genetic testing was 10.5%, and for those who did not, the rate was 9% (p = 0.26). CONCLUSIONS: The results of this study indicate that a substantial number of Medicare patients with clinically actionable genetic variants are being missed by current testing criteria and suggest the need for significant expansion and simplification of the testing criteria for HBOC.

Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

Risk of Colorectal and Other Cancers in Patients With Serrated Polyposis.

Patients with serrated polyposis develop multiple colorectal hyperplastic and/or serrated sessile adenomas/polyps. We investigated the risk of colorectal and other cancers by analyzing data from 64 patients with serrated polyposis (mean age at diagnosis, 54 y; 41% men; 92% white) listed in the Johns Hopkins Polyposis Registry. Medical, endoscopic, and histopathology reports were evaluated. Six patients (9.4%) had a history of colorectal cancer, diagnosed at a mean age of 56 years; 6 additional patients (9.4%) had at least 1 advanced colorectal adenoma. Extracolonic cancers were found in 16% of the study population. The standard incidence ratio for colorectal cancer in patients with serrated polyposis was 18.72 (95% confidence interval, 6.87-40.74) and for extracolonic cancer was 31.20 (95% confidence interval, 14.96-57.37), compared with the Surveillance, Epidemiology, and End Results population. Patients with serrated polyposis therefore have a high risk for colorectal cancer and require vigilant colorectal surveillance, starting at the time of diagnosis of serrated polyposis. The risk of extracolonic cancer also appears to be increased, but this requires further evaluation.

Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.

During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome.

Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; -6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; provides guidelines for screening at-risk and affected persons with Lynch syndrome; and lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

Serrated polyposis: rapid and relentless development of colorectal neoplasia.

OBJECTIVE: Serrated (hyperplastic) polyposis (SP) is a rare disorder with multiple colorectal hyperplastic polyps and often sessile serrated adenomas/polyps (SSA/P) or adenomas. Although associated with colorectal cancer, the course of SP is not well described. DESIGN: 44 patients with SP were studied. The results of 146 colonoscopies with median follow-up of 2.0 years (range 0-30) and a median of 1.0 years (range 0.5-6) between surveillance colonoscopies were evaluated. Findings from oesophogastroduodenoscopy examinations were analysed. RESULTS: The mean age at diagnosis of SP was 52.5 ± 11.9 years (range 22-78). In two pedigrees (5%) another family member had SP. None of 22 patients had gastroduodenal polyps. All patients had additional colorectal polyps at surveillance colonoscopy. SSA/P or adenomas were found in 25 patients (61%) at first colonoscopy and 83% at last colonoscopy. Recurrent SSA/P or adenomas occurred in 68% of patients at surveillance colonoscopy. Three patients had colorectal cancer. Eleven patients (25%) underwent surgery (mean time from diagnosis of SP 2.0 ± 0.9 years). After surgery all seven surveyed patients developed recurrent polyps in the retained colorectum (4/7 had SSA/P or adenomas). No association was found between colorectal neoplasia and sex, age at diagnosis of SP or initial number of colorectal polyps. CONCLUSIONS: In SP, rapid and unrelenting colorectal neoplasia development continues in the intact colorectum and retained segment after surgery. These findings support the possibility of annual colonoscopic surveillance, consideration for colectomy when SSA/P or adenomas are encountered and frequent postoperative endoscopic surveillance of the retained colorectum.

Patient preferences regarding recontact by cancer genetics clinicians.

BACKGROUND: Ongoing advances in cancer genetics lead to new opportunities for early disease detection, predictive genetic testing and potential interventions. Limited information exists on patient preferences concerning recontact to provide updated information. We evaluated colon cancer genetics patient preferences concerning recontact about advances in medical genetics. METHODS: Information was mailed to 851 individuals seen at the Colon Cancer Risk Assessment Clinic at the Johns Hopkins Hospital and to participants in a colon cancer gene testing study seen during an 8-year period. Information provided included description of advances in gene testing technology, discovery of MSH6 and MYH genes, detailed fact sheets and a survey of patient preferences for notification and potential uses of new information. RESULTS: Most patients wanted an ongoing relationship with genetics providers (63%), reinitiated by genetics providers (65%) and contact only with information specifically relevant to them (51%). Most preferred personalized letters as the means of contact (55%). Reasons for and against recontact and circumstances in which individuals would pursue additional genetic testing were also tabulated. There were few statistically significant differences in the responses between clinic and study participants. CONCLUSION: Patients evaluated in a colon cancer risk assessment clinic want updated information at a rate similar to those who participated in a colon cancer gene testing study. These findings have implications for the consultative nonlongitudinal nature of such clinics and suggest patient preferences for personally-tailored information could be labor intensive.

Weight change in breast cancer survivors compared to cancer-free women: a prospective study in women at familial risk of breast cancer.

BACKGROUND: This study prospectively examines weight gain in breast cancer survivors compared with cancer-free women from a familial risk cohort. METHODS: Absolute and percent weight change over 4 years was compared among 303 breast cancer survivors and 307 cancer-free women matched on age and menopausal status, from the same familial risk cohort. Linear and logistic regression was used to estimate the association between survivor status and weight gain. RESULTS: Overall, breast cancer survivors gained significantly more weight [ß = 3.06 pounds; 95% confidence intervals (CI), 0.94-5.17] than cancer-free women. Significant weight gain was observed in survivors diagnosed less than 5 years prior to baseline (ß = 3.81 pounds; 95% CI, 1.22-6.29) and women with estrogen receptor (ER)-negative tumors (ß = 7.26 pounds; 95% CI, 2.23-12.30). Furthermore, survivors treated with chemotherapy were 2.1 times more likely to gain at least 11 pounds during follow-up compared with cancer-free women (OR, 2.10; 95% CI, 1.21-3.63). Weight gain was even greater among survivors who took statins while undergoing chemotherapy treatment (Pinteraction = 0.01). CONCLUSION: This is the first study to demonstrate that weight gain is an important issue in breast cancer survivors with a familial risk. In the first five years posttreatment, breast cancer survivors gain weight at a faster rate than cancer-free women, particularly after chemotherapy and statin use but not after hormone therapy alone. IMPACT: Our findings provide support for the development of weight gain interventions for young breast cancer survivors with a familial risk.

Genetic testing by cancer site: pancreas.

It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.

A new phenotypic manifestation of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant disease with hundreds of colorectal adenomas in teenagers and progression to colorectal cancer if colectomy is not performed. We investigated the association of two phenotypic manifestations-oral mucosal vascular density (OMVD) and oral mucosal reflectance (OMR)--with FAP and patients with multiple colorectal adenomas. Thirty-three patients with FAP from 29 unrelated pedigrees with APC gene mutation, 5 with multiple adenomas and no known gene mutations, and 50 population controls were evaluated for the two different manifestations utilizing a photographic/spectrophotometric system capturing images and reflectance at various wavelengths. Statistical analysis was performed with student t test and test performance characteristics were calculated. There were no significant differences in demographic variables between the FAP and control group. A significant difference in OMVD between FAP patients and controls was noted, P < 0.001. The sensitivity and specificity of oral mucosal vascular density for FAP was 91 and 90%, respectively. No association between this phenotypic manifestation and age or gender was found. All 5 patient with multiple polyps were positive for OMVD and the value was significantly higher than controls, P = 0.002. No significant difference was noted in OMR between the two patient groups and controls. OMVD is a new phenotypic manifestation in patients with FAP and also may identify those with multiple adenomas without known gene mutation.

Absence of germline BRCA1 mutations in familial pancreatic cancer patients.

Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing pancreatic cancer. To determine if BRCA1 mutations explain a significant proportion of familial pancreatic cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial pancreatic cancer and we evaluated the pathology of breast neoplasms that developed in relatives of pancreatic cancer patients. The BRCA1 gene was fully sequenced in 66 pancreatic cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with pancreatic cancer. None of the 66 (0/66: 97.5% one-side CI 0-0.054%) familial pancreatic cancer patients were found to have a deleterious mutation in the BRCA1 gene. While patients were not selected based upon their family history of breast and ovarian cancer, over half of the patients whose samples were sequenced reported a family history of breast and/or ovarian cancer. Our findings suggest that mutations in the BRCA1 gene are not highly, or even moderately, prevalent in families with a clustering of pancreatic cancer, including pancreatic cancer families who report a family history of breast and/or ovarian cancer.

Familial pancreatic cancer: from genes to improved patient care.

Pancreatic cancer is essentially a disease caused by inherited and acquired mutations in cancer-causing genes. A number of the genes responsible for the aggregation of pancreatic cancer in families have been discovered, including BRCA2, p16/CDKN2A, STK11 and PRSS1. Individuals can be tested for germline mutations in these genes; however, until recently, little could be done about the risk of pancreatic cancer if a patient was found to carry a mutation. Currently, new approaches are being developed to screen at-risk individuals for curable precancerous pancreatic lesions and laboratory studies have led to novel therapies that specifically target some of these genetic defects. This review focuses on the genetic basis for the familial aggregation of pancreatic cancer, with emphasis placed on the implications of the genetic alterations on clinical patient care.

Patient perspective on the value of genetic counselling for familial pancreas cancer.

PURPOSE: To assess patient views regarding the value of genetic counselling for familial pancreas cancer in the absence of predictive genetic testing. PATIENTS AND METHODS: At-risk adults with three or more relatives with pancreas cancer received genetic counselling prior to research screening via endoscopic ultrasound. Questionnaires were mailed after the visit to assess perceived value of the counselling session. RESULTS: Ninety-three percent of respondents felt genetic counselling for pancreas cancer was helpful despite the lack of a causative gene, while only 7% felt that it should not be offered until such a gene is discovered. Over half of respondents believed the pancreas cancer in their family was caused by a gene mutation, and 42% thought they had inherited the mutation. The average perceived lifetime risk of developing pancreas cancer was 51%, and 87% of respondents would ultimately seek predictive genetic testing. When more information is gained, 89% would be interested in another genetic counselling session, and 82% would recommend current genetic counselling for pancreas cancer to a friend or relative with a family history of the disease. CONCLUSION: Despite the lack of an identified major causative gene for pancreas cancer, respondents found genetic counselling for this malignancy to be helpful. These patients perceive their personal cancer risk to be high, and would seek predictive genetic testing if it were available. Referral for genetic counselling should be offered to appropriate individuals.

Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach.

BACKGROUND & AIMS: Relatives of patients with pancreatic cancer and persons with certain inherited syndromes are at increased risk for developing pancreatic cancer. We prospectively evaluated the feasibility of screening for pancreatic neoplasia in high-risk individuals. METHODS: Individuals from familial pancreatic cancer kindreds and a patient with Peutz-Jeghers syndrome underwent screening endoscopic ultrasound (EUS). If the EUS was abnormal, EUS-guided fine-needle aspiration, endoscopic retrograde cholangiopancreatography (ERCP), and spiral computed tomography (CT) were performed. Patients with abnormalities suggesting neoplasia had surgery. RESULTS: Thirty-eight patients were studied; 31 (mean age, 58 yr; 42% men) from kindreds with > or =3 affected with pancreatic cancer; 6 from kindreds with 2 affected relatives, 1 was a patient with Peutz-Jeghers syndrome. None had symptoms referable to the pancreas or suggestive of malignancy. Six pancreatic masses were found by EUS: 1 invasive ductal adenocarcinoma, 1 benign intraductal papillary mucinous neoplasm, 2 serous cystadenomas, and 2 nonneoplastic masses. Hence, the diagnostic yield for detecting clinically significant pancreatic neoplasms was 5.3% (2 of 38). The 1 patient with pancreatic cancer was treated and still is alive and disease-free >5 years after surgery. EUS changes similar to those associated with chronic pancreatitis were found, which were more common in patients with a history of regular alcohol intake (P = 0.02), but also occurred in patients who did not consume alcohol. Screening also led to a new diagnosis and treatment of symptomatic upper-gastrointestinal conditions in 18.4% of patients. CONCLUSIONS: EUS-based screening of asymptomatic high-risk individuals can detect prevalent resectable pancreatic neoplasia but false-positive diagnoses also occur.