Genetic counseling and testing for females at elevated risk for breast cancer: Protocol for the randomized controlled trial of the Know Your Risk intervention.

BACKGROUND: Genetic counseling and testing have an important role in the care of patients at elevated risk for breast cancer. However, conventional pre- and post-test genetic counseling is labor and time intensive, less accessible for patients living outside major urban centers, and impractical on a large scale. A patient-driven approach to genetic counseling and testing may increase access, improve patients' experiences, affect efficiency of clinical practice, and help meet workforce demand. The objective of this 2-arm randomized controlled trial is to determine the efficacy of Know Your Risk (KYR), a genetic counseling patient preference intervention. METHODS: Females (n = 1000) at elevated risk (>20% lifetime) for breast cancer will be randomized to the KYR intervention or conventional genetic counseling. The study will provide comprehensive assessment of breast cancer risk by multigene panel testing and validated polygenic risk score. Primary outcome is adherence to National Comprehensive Cancer Network guidelines for a clinical encounter every 6-12 months and an annual mammogram (breast MRI if recommended) determined by medical record review. Secondary outcomes include adherence to other recommended cancer screening tests determined by medical record review and changes in breast cancer knowledge, perception of risk, post-test/counseling distress, and satisfaction with counseling by completion of three surveys during the study. Study aims will be evaluated for non-inferiority of the KYR intervention compared to conventional genetic counseling. CONCLUSION: If efficacious, the KYR intervention has the potential to improve patients' experience and may change how genetic counseling is delivered, inform best practices, and reduce workforce burden. TRIAL REGISTRATION: ClinicalTrials.govNCT05325151.

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

CONTEXT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. OBJECTIVE: To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. DESIGN, SETTING, AND PATIENTS: Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. MAIN OUTCOME MEASURES: Molecular, clinical, and histopathological findings in patients with unexplained polyposis. RESULTS: Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. CONCLUSIONS: Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

Identification and referral of families at high risk for cancer susceptibility.

PURPOSE: Obtainment of family history and accurate assessment is essential for the identification of families at risk for hereditary cancer. Our study compared the extent to which the family cancer history in the physician medical record reflected that entered by patients directly into a touch-screen family history computer program. PATIENTS AND METHODS: The study cohort consisted of 362 patients seen at a comprehensive cancer center ambulatory clinic over a 1-year period who voluntarily used the computer program and were a mixture of new and return patients. The computer entry was assessed by genetics staff and then compared with the medical record for corroboration of family history information and appropriate physician risk assessment. RESULTS: Family history information from the medical record was available for comparison to the computer entry in 69%. It was most often completed on new patients only and not routinely updated. Of the 362 computer entries, 101 were assigned to a high-risk category. Evidence in the records confirmed 69 high-risk individuals. Documentation of physician risk assessment (ie, notation of significant family cancer history or hereditary risk) was found in only 14 of the high-risk charts. Only seven high-risk individuals (6.9%) had evidence of referral for genetic consultation. CONCLUSION: This study demonstrates the need to collect family history information on all new and established patients in order to perform adequate cancer risk assessment. The lack of identification of patients at highest risk seems to be directly correlated with insufficient data collection, risk assessment, and documentation by medical staff.