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Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Women with BRCA mutations, at significantly increased risk for breast and ovarian cancer, do not consistently adhere to management guidelines due to lack of awareness and challenges tracking appointments. We developed an iPhone application (app) to help BRCA carriers manage their surveillance. We explored baseline awareness and adherence to surveillance guidelines and analytic data from 21 months of app use. Descriptive statistics were calculated on responses (N = 86) to a survey about surveillance awareness and practices. The majority were aware of breast surveillance guidelines, but only one third were aware of ovarian surveillance guidelines. In practice, the majority reported a clinical breast exam within 6 months, just over half reported a mammogram and breast MRI in the last year, and under half reported ovarian surveillance in the last year. Nearly 50% reported difficulty remembering appointments. Although only 69 received access codes, 284 unique users attempted to enter the app, which was visible in the iTunes store but only available to those with a study code. Evaluation of analytic data demonstrated user engagement with study participants accessing the app 427 times over the 21-month time period (range 2-57; mean = 6.28). Results indicate participants were more likely to know screening guidelines than practice them. There was interest in the app and users were engaged, suggesting app value. We will send a follow-up survey after 18 months of app use for additional evaluation and feedback.

10529 Background: National Comprehensive Cancer Network (NCCN) guidelines recommend testing for highly penetrant breast/ovarian cancer genes in several scenarios, including women with early-onset (≤ 45 years) or metastatic HER-2 negative breast cancer regardless of family history. A 2018 Association of Community Cancer Centers (ACCC) survey (N = 95) showed that > 80% of respondents reported ≤ 50% testing rate of patients with breast cancer who met guidelines. To improve rates of genetic counseling(GC)/testing, ACCC partnered with 15 community cancer programs to support site-directed quality improvement (QI) interventions. Methods: Pre- and post-intervention data from 9/15 partner programs for genetically at-risk women with early-onset or HER-2 negative metastatic breast cancer (MBC) were analyzed. Pre-intervention data were collected between 01/01/2017 and 06/30/2019 while post-intervention data were collected as early as 07/01/2019 and as late as 10/01/2020. QI project scope ranged from creation of testing eligibility education to implementation of a virtual GC clinic. De-identified data collected included: family history documentation; GC appointment; test results; and timing of results relative to surgical date. Results: The pre-intervention cohort included 2691 women and the post- cohort included 3104 women who were eligible for GC. Early-onset patients in the post-intervention group attended a GC appointment 83% (331/401) of the time and 74% (296/401) had genetic test results, with 92% (271/296) receiving results before surgery. Sixty-one percent (1387/2267) of women with HER-2 negative MBC in the post-intervention group received GC, compared to 36% (658/1845) in the pre-intervention group. There was an overall increase in the number of MBC patients with documented test results following GC in the post-intervention cohort (55% (1243/2267) versus 15% (273/1845); p < 0.0001). Rates of GC appointments improved overall, regardless of family history documentation. Rates among those with a documented high-risk family history improved from 57% (729/1284) to 85% (1485/1741) following QI interventions (p < 0.0001). There was also a significantly higher rate of GC provided in the post-intervention group among women with negative family histories (40% (462/1155) versus 23% (181/778); p < 0.0001). GC also increased from 6% (35/629) to 45% (94/208) of women in the post-intervention cohort with no documentation of family history (p < 0.0001). Conclusions: Genetic testing is underutilized in women with breast cancer. Significant improvement was achieved with QI initiatives specifically designed to target easily identified populations meeting guidelines for GC/testing. This project demonstrates the importance of attention to practice-directed strategies aimed at improving identification of risk as well as follow through to GC/testing.

This study aimed to evaluate a unique approach to cancer risk assessment for improved access by smaller rural communities. Local, on-site nurse navigators were trained and utilized as genetic counselor extenders (GCEs) to provide basic risk assessment and offer BRCA1/2 genetic testing to select patients based on a triaging process in collaboration with board-certified genetic counselors (CGCs). From August 2012 to July 2014, 12,477 family history questionnaires representing 8937 unique patients presenting for a screening mammogram or new oncology appointment were triaged. Of these, 8.2 % patients were identified at increased risk for hereditary breast cancer, and 4.2 % were identified at increased risk for other hereditary causes of cancer. A total of 75 of 1130 at-risk patients identified (6.6 %) completed a genetic risk assessment appointment; 23 with a GCE and 52 with a CGC. A review of the completed genetic test requisition forms from a 9-year pre-collaboration time period found that 16 % (20/125) did not appear to meet genetic testing criteria. Overall, there was a fourfold increase in patients accessing genetic services in this study period compared to the pre-collaboration time period. Efficiency of this model was assessed by determining time spent by the CGC in all activities related to the collaboration, which amounted to approximately 16 h/month. Adjustments have been made and the program continues to be monitored for opportunities to improve efficiency. This study demonstrates the feasibility of CGCs and GCEs collaborating to improve access to quality services in an efficient manner.

1526 Background: Current National Comprehensive Cancer Network guidelines for genetic/familial high-risk assessment state that testing for highly penetrant breast/ovarian cancer genes is clinically indicated for women with early onset (≤ 45 years) or metastatic HER-2 negative breast cancer. A recent Association of Community Cancer Centers (ACCC) survey (N = 95) showed that > 80% of respondents reported ≤ 50% testing rate of patients with breast cancer who met guidelines. Given this disconnect, ACCC partnered with 15 community cancer programs to assess practice gaps and support interventions to improve access to genetic counseling (GC)/testing. Methods: Pre-intervention data from 9/15 partner programs for women diagnosed with stages 0-III breast cancer between 01/01/2017 and 06/30/2019 was collected. De-identified variables included: family history documentation, GC appointment/test results, and timing of results relative to treatment decisions. Results: There were 2691 women with stages 0-III breast cancer. Forty-eight percent (1284/2691) had a documented high-risk family history, 57% (729/1284) of whom had a GC appointment. This was a significantly higher rate of GC compared to the 23% (181/778) of women with no family history and 6% (35/629) of women with no documentation of family history (p < 0.0001). Patients ≤ 45 years old attended a GC appointment 72% (199/278) of the time and 49% (135/278) had genetic test results, with 84% (113/135) receiving results before surgery. For women with test results available before surgery, 37% (119/322) had breast conserving surgery, compared to 60% (144/240) with test results disclosed post-operatively (p < 0.0001). Conclusions: Genetic testing is underutilized in a community cohort of women with breast cancer. Further analysis is needed to understand the impact genetic test results have on surgical decisions. Opportunities exist to improve current rates of appropriate GC/testing. ACCC will share results of quality improvement projects to illuminate which strategies hold promise in reducing the hereditary breast cancer GC/testing practice gap.