IMProving care After inherited Cancer Testing (IMPACT) study: protocol of a randomized trial evaluating the efficacy of two interventions designed to improve cancer risk management and family communication of genetic test results.

BACKGROUND: Implementing genetic testing for inherited cancer predisposition into routine clinical care offers a tremendous opportunity for cancer prevention and early detection. However, genetic testing itself does not improve outcomes; rather, outcomes depend on implemented follow-up care. The IMPACT study is a hybrid type I randomized effectiveness-implementation trial to simultaneously evaluate the effectiveness of two interventions for individuals with inherited cancer predisposition focused on: 1) increasing family communication (FC) of genetic test results; and 2) improving engagement with guideline-based cancer risk management (CRM). METHODS: This prospective study will recruit a racially, geographically, and socioeconomically diverse population of individuals with a documented pathogenic/likely pathogenic (P/LP) variant in an inherited cancer gene. Eligible participants will be asked to complete an initial trial survey and randomly assigned to one of three arms: A) GeneSHARE, a website designed to increase FC of genetic test results; B) My Gene Counsel's Living Lab Report, a digital tool designed to improve understanding of genetic test results and next steps, including CRM guidelines; or C) a control arm in which participants continue receiving standard care. Follow-up surveys will be conducted at 1, 3, and 12 months following randomization. These surveys include single-item measures, scales, and indices related to: 1) FC and CRM behaviors and behavioral factors following the COM-B theoretical framework (i.e., capability, opportunity, and motivation); 2) implementation outcomes (i.e., acceptability, appropriateness, exposure, and reach); and 3) other contextual factors (i.e., sociodemographic and clinical factors, and uncertainty, distress, and positive aspects of genetic test results). The primary outcomes are an increase in FC of genetic test results (Arm A) and improved engagement with guideline-based CRM without overtreatment or undertreatment (Arm B) by the 12-month follow-up survey. DISCUSSION: Our interventions are designed to shift the paradigm by which individuals with P/LP variants in inherited cancer genes are provided with information to enhance FC of genetic test results and engagement with guideline-based CRM. The information gathered through evaluating the effectiveness and implementation of these real-world approaches is needed to modify and scale up adaptive, stepped interventions that have the potential to maximize FC and CRM. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov (NCT04763915, date registered: February 21, 2021). PROTOCOL VERSION: September 17th, 2021 Amendment Number 04.

The duty to warn at-risk relatives-The experience of genetic counselors and medical geneticists.

Studies published over 15 years ago surveyed genetic counselors (GC) and medical geneticists (MG) to examine their clinical experiences with the conflict of "duty to warn" versus patient confidentiality. Federal and state laws pertaining to medical professionals' duty to warn have since been implemented following the publications of these studies. Using a merged version of surveys employed in the prior studies, this study seeks to understand clinicians' current decision-making process when faced with patient refusal to inform at-risk relatives, as well as their familiarity with and opinions of laws and guidelines covering this issue. Consistent with the previous studies, the majority of MG and almost half of GC experience patient refusal. Significantly, fewer MG and GC believe they had a duty to warn their patients' relatives of genetic risk. Only 8% of participants believe current guidelines effectively address the issue of duty to warn. Participant awareness of federal or state laws regulating the disclosure of genetic information remains low. The conflict of duty to warn remains a shared experience among genetics professionals, and resources are needed to facilitate informed decision-making. Participants' opinions of current policies and clinical decisions may guide professional actions regarding duty to warn.

Differences in referral patterns based on race for women at high-risk for ovarian cancer in the southeast: Results from a Gynecologic Cancer Risk Assessment Clinic.

OBJECTIVE: To compare referral patterns, genetic testing and pathogenic variant rates in Black women (BW) and White women (WW) in a large academic Gynecologic Cancer Risk Assessment Clinic (GCRAC). METHODS: Cross sectional study of an IRB-approved prospective, cohort study from a GCRAC. Data evaluated included: age, race, referral provider specialty and indication, genetic testing frequency, as well as frequency and types of pathogenic variants. RESULTS: 588 WW and 57 BW were evaluated from 1/2010-12/2015. Although approximately one-third of BW and WW were referred for family history alone, referral indications varied. BW were more likely referred for a known pathogenic variant (20.0% vs. 6.2%) although less likely referred for a personal history of ovarian cancer (24.0% vs. 46.8%; p = 0.0023). While gynecologic oncologists referred most patients (BW 43.6% vs. WW 63.0%), BW were more likely to be referred by surgical oncologist (23.0% vs. 12.8%) or genetic counselor (12.8% vs. 5.9%) than WW (p = 0.0234). Referral from non-OBGYN primary care providers was <3% in both groups. Genetic testing rates were similar in both races (82.4% vs. 85.5%). Rates of BRCA1 mutations (12.7% vs. 11.5%) were similar; however, BW had more BRCA2 mutations (21.3% vs. 9.5%; p = 0.0194). CONCLUSIONS: Since BW are more likely to be referred by surgical oncology or genetics counselor, breast clinics might be an entry point to ensure genetic counseling and testing. Continued efforts to increase awareness regarding the importance of patient referral at the primary care level may help identify the subset of women not currently undergoing counseling and testing.

Characteristics of African American women at high-risk for ovarian cancer in the southeast: Results from a Gynecologic Cancer Risk Assessment Clinic.

OBJECTIVES: Describe patient characteristics in African American (AA) women seen for gynecologic cancer related genetic counseling at a large southeastern comprehensive cancer center. METHODS: We reviewed an IRB approved, prospective observational cohort of patients from a Gynecologic Cancer Risk Assessment Clinic. Data evaluated included personal cancer history, family history, frequency of genetic testing, frequency/type of genetic mutations, and frequency of surgical intervention. Standard statistical statistics were utilized. RESULTS: 1227 patients were evaluated from 2003 to 2015, of which 95 (7.7%) were AA. Sixteen patients had a personal history of ovarian cancer. 21 women (22%) underwent genetic counseling only; subsequent genetic testing was not recommended based on absence of risk factors. Of the seventy-four AA patients in whom genetic testing was recommended, sixty-six (69.5%) completed testing. Of women tested, 37 (56%) had abnormal results. Eight and 14 patients had pathogenic variants in BRCA1 and BRCA2, respectively. Two were found to have pathogenic PALB2 variants; one had a pathogenic ATM variant and one constitutional MLH1 epimutation case was identified. Eleven had BRCA variants of uncertain significance. Of the patients with abnormal testing, six of 22 women with pathogenic BRCA variants underwent risk-reducing salpingo-oophorectomy (RRSO). CONCLUSIONS: Our study demonstrates that in a region where AAs represent 27% of the population, the proportion of AA patients referred to a Gynecologic Cancer Risk Assessment Clinic remains low. Pathogenic variant and variant of uncertain significance rates were high in patients tested, likely representing a selection bias of high-risk patients. Endeavors should continue to identify minorities at risk for ovarian cancer and institute measures to provide thorough genetic counseling and testing.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.

Pediatric cancer genetics.

PURPOSE OF REVIEW: The current review will focus on the current knowledge of the contribution of both germline and somatic mutations to the development and management of cancer in pediatric patients. RECENT FINDINGS: It has long been thought that genetic mutations in both germline and somatic cells can contribute to the development of cancer in pediatric patients. With the recent advances in genomic technologies, there are now over 500 known cancer predisposition genes. Recent studies have confirmed an 8.5-14% germline mutation rate in cancer predisposition genes in pediatric cancer patients. SUMMARY: The discovery of both germline and somatic cells mutation(s) in pediatric cancer patients not only aids in the management of current disease, but can also have direct implications for future management as well as the medical management of family members.

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.

Incidental detection of cancer predisposition gene copy number variations by array comparative genomic hybridization.

We describe 2 pediatric patients who presented to medical genetics clinic for evaluation and were incidentally found via array comparative genomic hybridization to have pathogenic copy number variations of cancer predisposition genes. We subsequently reviewed 3554 previous array comparative genomic hybridization results to estimate the frequency of similar incidental findings.

Breast Cancer Genomics: Primary and Most Common Metastases.

Specific genomic alterations have been found in primary breast cancer involving driver mutations that result in tumorigenesis. Metastatic breast cancer, which is uncommon at the time of disease onset, variably impacts patients throughout the course of their disease. Both the molecular profiles and diverse genomic pathways vary in the development and progression of metastatic breast cancer. From the most common metastatic site (bone), to the rare sites such as orbital, gynecologic, or pancreatic metastases, different levels of gene expression indicate the potential involvement of numerous genes in the development and spread of breast cancer. Knowledge of these alterations can, not only help predict future disease, but also lead to advancement in breast cancer treatments. This review discusses the somatic landscape of breast primary and metastatic tumors.

Challenges and Errors in Genetic Testing: The Fifth Case Series.

PURPOSE: In this ongoing case series, 33 genetic testing cases are documented in which tests were recommended, ordered, interpreted, or used incorrectly and/or in which clinicians faced challenges related to history/reports provided by patients or laboratories. METHODS: An invitation to submit cases of challenges or errors in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, as part of a case series with Precision Oncology News, and via social media (i.e., Facebook, Twitter, LinkedIn). Deidentified clinical documentation was requested and reviewed when available. Thirty-three cases were submitted, reviewed, and accepted. A thematic analysis was performed. Submitters were asked to approve cases before submission. RESULTS: All cases took place in the United States, involved hereditary cancer testing and/or findings in cancer predisposition genes, and involved medical-grade genetic testing, direct-to-consumer testing, or research genetic testing. In 9 cases, test results were misinterpreted, leading to incorrect screening or risk-reducing procedures being performed/recommended. In 5 cases, incorrect or unnecessary testing was ordered/recommended. In 3 cases, incorrect clinical diagnoses were made, or opportunities for diagnoses were delayed. In 3 cases, errors or challenges arose related to medical intervention after testing or reported genetic diagnosis. In 2 cases, physicians provided incorrect information related to the inheritance pattern of a syndrome. In 2 cases, there were challenges related to the interpretation of genetic variants. In 2 cases, challenges arose after direct-to-consumer testing. One case involved test results that should never have been reported based on sample quality. In 1 case, a patient presented a falsified test result. In 5 cases, multiple errors were made. DISCUSSION: As genetic testing continues to become more complicated and common, it is critical that patients and nongenetics providers have access to accurate and timely genetic counseling information. Even as multiple medical bodies highlight the value of genetic counselors (GCs), tension exists in the genomics community as GCs work toward licensure and Medicare provider status. It is critical that health care communities leverage, rather than restrict, the expertise and experience of GCs so that patients can benefit from, and not be harmed by, genetic testing. In order to responsibly democratize genomics, it will be important for genetics and nongenetic health care providers to collaborate and use alternative service delivery models and technology solutions at point of care. To deliver on the promise of precision medicine, accurate resources and tools must be utilized.

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

Adverse Events in Genetic Testing: The Fourth Case Series.

PURPOSE: In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. METHODS: An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. RESULTS: All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. DISCUSSION: As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.

Breast Cancer Genetics and Indications for Prophylactic Mastectomy.

As more genetic information becomes available to inform breast cancer treatment, screening, and risk-reduction approaches, clinicians must become more knowledgeable about possible genetic testing and prevention strategies, including outcomes, benefits, risks, and limitations. The aim of this article is to define and distinguish high- and moderate-risk breast cancer predisposition genes, summarize the clinical recommendations that may be considered based on the identification of pathogenic variants (mutations) in these genes, and indications for risk-reducing and contralateral prophylactic mastectomy.