Citations

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

Abstract Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.4 or higher, where 0.4 was equivalent to a 50-year-old woman with 1 parent diagnosed with either breast cancer or CRC at 55 years of age. Of 24 486 women assessed, 1243 and 405 were diagnosed with incident breast cancer and CRC, respectively. For breast cancer, menopausal HRT ever use versus never use hazard ratios were 1.27 (95% CI = 1.11 to 1.45) for a breast cancer familial risk score below 0.4 and 1.01 (95% CI = 0.82 to 1.25) for a breast cancer familial risk score of 0.4 or higher (Pdifference = .08). For CRC, menopausal HRT hazard ratios were 0.63 (95% CI = 0.50 to 0.78) for a CRC familial risk score below 0.4 and 1.21 (95% CI = 0.73 to 2.00) for a CRC familial risk score of 0.4 or higher (Pdifference = .03). Associations with menopausal HRT use that apply to the general population may not hold for women at moderate or strong familial risk of these cancers.

Abstract Background: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis. Methods: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied. Results: We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81–1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer. Conclusions: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite–stratified colorectal cancer risk. Impact: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.

Background/Objectives: Multi-gene, multi-cancer, hereditary cancer risk screenings may be useful in cancer prevention and treatment, not only for cancer patients but also for patients’ family members. If genetic cancer screening is to have the widest possible benefit, it must be extended into diverse cancer care settings that serve diverse patient communities, providing cancer patients and their relatives with individualized cancer risk evaluations. Little research, to date, has examined the impact of extending multigenic cancer screening into diverse settings. Without empirical data characterizing the support needs of cancer patients and their family members, we may not adequately satisfy the needs of all patients and risk exacerbating existing disparities in cancer care and outcomes. Methods: We examined patient perspectives on the sharing of genetic results with at-risk family members by surveying a racially diverse sample of cancer patients receiving a multi-gene, multi-cancer risk screen in a community hospital setting. Results: In a survey of 230 cancer patients, we found that intent to share results with family members was high but varied across family member types. More respondents planned to disclose results to at least one sister (82.5%) compared to at least one brother (73.1%). Over one-fourth of participants (27.4%) were either uncertain about sharing or intended to withhold their genomic screening results from at least one at-risk family member eligible for cascade testing. Participants were more likely to withhold their results from a sibling than from a child. Furthermore, intent to share across all family member types was lower if probands failed to identify at least one benefit to sharing. Conclusions: Understanding factors associated with decisions to share results with at-risk relatives in diverse patient populations can help clinicians support cascade genetic cancer screenings in diverse communities and settings.

PURPOSE The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. METHODS Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC ( BRCA1 and BRCA1) and LS ( MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. RESULTS To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). CONCLUSION Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

<sec><b>Objective</b>This paper sought to evaluate the impact of a year-long Health Equity Curriculum (HEC) on the knowledge of health disparities, cross-cultural humility, and empathy among physicians, trainees, and research staff.</sec><sec><b>Background</b>There has been an increase in the inclusion of equity, cultural humility, and the social determinants of health into medical education at various levels. However, the frequency of this education is low and not well quantified or defined. The authors report the results of an education program, namely the HEC, on the knowledge of health disparities, cross-cultural humility, and empathy.</sec><sec><b>Materials and methods</b>The HEC was delivered between March 2020 and May 2021. It included the following four modules: the social determinants of health, cultural humility, health literacy, and unconscious bias. The participants attended lectures and reviewed articles/videos using online modules and reflection assignments. The Jefferson Scale of Empathy (JSE) and the Cross-Cultural Competence Instrument for Health Care Professionals (CCCHP) were administered pre- and post-HEC. The results were statistically analyzed.</sec><sec><b>Results</b>Of the 102 enrolled participants, 46 completed the entire course. The JSE showed a statistically significant improvement in the empathy scores from pre-HEC to post-HEC (p &lt; 0.01). The CCCHP showed a significant improvement from pre-HEC to post-HEC total scores and in subcomponent scores of Motivation/Curiosity, Attitude, and Knowledge (p &lt; 0.05). There were no significant differences in scores for the Skills and Emotions/Empathy subcomponents.</sec><sec><b>Conclusions</b>Enrollment and completion in the HEC were associated with statistically significant improvements in the validated measures of cultural competence and empathy. Scaling this type of content and curriculum can educate professionals on equity and serving diverse communities. A further study is warranted.</sec>

Abstract Background and study aims There is limited consensus on the optimal method for measuring disease severity in familial adenomatous polyposis (FAP). We aimed to systematically review the operating properties of existing endoscopic severity indices for FAP. Methods We searched MEDLINE, EMBASE, and the Cochrane Library from inception to February 2023 to identify randomized controlled trials (RCTs) that utilized endoscopic outcomes or studies that evaluated the operating properties of endoscopic disease severity indices in FAP. Results A total of 134 studies were included. We evaluated scoring indices and component items of scoring indices, such as polyp count, polyp size, and histology. Partial validation was observed for polyp count and size. The most commonly reported scoring index was the Spigelman classification system, which was used for assessing the severity of duodenal involvement. A single study reported almost perfect interobserver and intra-observer agreement for this system. The InSIGHT polyposis staging system, which was used for assessing colorectal polyp burden, has been partially validated. It showed substantial interobserver reliability; however, the intra-observer reliability was not assessed. Novel criteria for high-risk gastric polyps have been developed and assessed for interobserver reliability. However, these criteria showed a poor level of agreement. Other scoring indices assessing the anal transition zone, duodenal, and colorectal polyps have not undergone validation. Conclusions There are no fully validated endoscopic disease severity indices for FAP. Development and validation of a reliable and responsive endoscopic disease severity instrument will be informative for clinical care and RCTs of pharmacological therapies for FAP.