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Purpose Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2. Methods We analyzed multi-gene panel testing results (09/2013–12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry. Results An association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64–4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84–2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08–1.37) and CHEK2 (OR 1.34, 95% CI 1.21–1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98–1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13–2.56) and BRCA2 (OR 1.25, 95% CI 1.16–1.35). Conclusions Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.

これまで出版されてきた「ひきこもり」に関する書籍が、どのようなテーマで語られてきたかを整理することは、今後のひきこもり対策を考える際に有益となると考えた。そこで、本稿では、書籍のタイトルを一般的な市販の書籍と、政府刊行物のような公的な書籍とに分けてテキストマイニングを用いて分析し、テーマの傾向を探った。その結果を不登校に関する書籍タイトルの分析を行った八尋・キッド（2020）と比較すると、ひきこもりに関する書籍は、市販された書籍、公的に出版された書籍の区別なく、「ひきこもりと不登校の関係性は強い」という視点から書かれる傾向にあることがわかった。実際、ひきこもりと不登校の連続性に着目した見解の存在は大きい。一方で、ひきこもりを不登校とは切り離して考えるべきであるという見解もある。ひきこもり対策が十分効果的に機能しているとは言えない現状を鑑みた場合、「これまでのひきこもり対策は、ひきこもり支援よりも歴史のある不登校支援の方法論を安易に適用させようとしすぎて効果が見られないのではないか」という新たな視点に立つこともできるかもしれない。今後、この視点からの研究を進めていきたい。

PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013–2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53–1.79, p=7.2 × 10(−33)) and synchronous (OR 1.33, 95% CI 1.19–1.50, p=2.4 × 10(−6)) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.

BACKGROUND: TNBC is among the most aggressive subtypes of invasive breast cancer (BC), and accounts for approximately 10-15% of incidental BC diagnoses. TNBC is associated with early age of onset (median age of diagnosis 5.0) and moderate-to-high risks (OR 2.0-5.0) of TNBC. These findings can inform practice guidelines about which genes to test when evaluating breast cancer risk and which PV carriers may benefit from intensive breast screening with magnetic resonance imaging (MRI). Odds ratios for TNBC in germline carriers of PV in hereditary cancer risk genesRisk GenePV Positive with TNBCOR95% CIp-valueHigh RiskBRCA1119321.2419.71-22.88 Citation Format: Michael J Hall, Eric Rosenthal, Susana San Roman, Ryan Bernhisel, John Kidd, Elisha Hughes, Thomas Slavin, Allison Kurian. Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-03.

There is an increasing interest in using multiple types of omics features (e.g., DNA sequences, RNA expressions, methylation, protein expressions, and metabolic profiles) to study how the relationships between phenotypes and genotypes may be mediated by other omics markers. Genotypes and phenotypes are typically available for all subjects in genetic studies, but typically, some omics data will be missing for some subjects, due to limitations such as cost and sample quality. In this article, we propose a powerful approach for mediation analysis that accommodates missing data among multiple mediators and allows for various interaction effects. We formulate the relationships among genetic variants, other omics measurements, and phenotypes through linear regression models. We derive the joint likelihood for models with two mediators, accounting for arbitrary patterns of missing values. Utilizing computationally efficient and stable algorithms, we conduct maximum likelihood estimation. Our methods produce unbiased and statistically efficient estimators. We demonstrate the usefulness of our methods through simulation studies and an application to the Metabolic Syndrome in Men study.

これまで多くの不登校に関する書籍が出版されてきたが、どのようなテーマで語られてきたかを整理することは、今後の不登校問題対策を考える時に有益となろう。本稿では、書籍のタイトルを分析することで、テーマの傾向を探ることを目指した。不登校関連の書籍は、一般的な市販の書籍と、政府刊行物のような公的な書籍とに分かれるため、それぞれ分けて、テキストマイニングによって分析した。その結果、市販の書籍のタイトルには、前向きなイメージを持つ語句が選ばれていたり、今までとは異なる生き方をイメージさせる語句が積極的に使用されていたりすることがわかった。公的に出版された書籍では、不登校の子どもたちの実態を科学的に把握した上で対策を練り、その効果を検証しながら不登校対策のプログラムを開発していきたいという、生徒を指導する側の専門職としての立場で使用する語句が多いことがわかった。また、公的に出版された書籍が学校内での先生や、他の生徒たちとの人間関係に焦点が当てられているのに対し、市販されている書籍では、家庭や家族における人間関係を非常に意識して出版されていることもわかった。公的に出版される書籍は一般の読者は読まないことを考慮すると、専門職の読者も一般の読者も両方とも読む市販の書籍の中に、縦の人間関係と横の人間関係の両方について語った書籍が増えることが望まれる。それによって、不登校当事者にとって有益な情報が効率よく、そしてバランス良く世間に流布され、専門的な読者と一般的な読者の区別をすることなく、どちらにとっても有益な書物が増えていくことになると考えた。

Background Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined and are potentially biased because of the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings. Methods This is a retrospective analysis of 676 667 individuals, 2445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013 and 2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC because of pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal and/or family cancer history, and ancestry. Results Overall, 11.1% of patients with PDAC had a PV. Statistically significantly elevated PDAC risk (2-sided P Conclusions This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly because of adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer.

Purpose: Multiplex gene panel testing (MGPT) is used to identify individuals with an inherited susceptibility to cancer. However, little is known about the uptake of screening and surveillance among patients after MGPT and genetic counseling. The purpose of this study was to measure the uptake of guideline-concordant breast cancer screening after genetic testing and counseling. Patients and Methods: 2,000 patients who met NCCN testing guidelines or had ≥2.5% probability of a pathogenic/likely pathogenic variant (PV) were recruited at three cancer genetics clinics (University of Southern California (USC) Norris Comprehensive Cancer Center, Los Angeles County + USC Medical Center, Stanford Cancer Institute) from July 2014 through November 2016. All patients had 25- or 28-gene MGPT and results were disclosed by a genetic counselor, who provided screening recommendations to patients based on their risk. Post-test surveys were administered at three months, six months, one year, two years, and three years. Results: 1,614/2,000 (80.7%) patients were female and 1,147/1,614 (71.7%) completed at least one survey regarding MRI screening for breast cancer over the three years of longitudinal follow-up. Of these, 94/1,147 (8.2%) patients tested positive for at least one PV in a breast cancer risk gene; 58/94 (61.7%) tested positive for PVs in a high-risk breast cancer gene (BRCA1/2 (n=53), CDH1, PALB2, TP53 (n=5)), and 34/94 (36.2%) of patients tested positive for a PV in a gene characterized as moderate-risk at the time of disclosure (CHEK2, ATM, NBN). MRIs were recommended to 43/58 (74.1%) patients with a high-risk breast cancer gene PV, 20/34 (58.8%) patients with a moderate-risk gene PV, and 171/1,053 (16.2%) patients without a breast cancer risk gene PV. Multivariate logistic regression models revealed that patients with a high-risk gene PV were more likely to undergo MRI screening within 3 months of receiving genetic test results (OR=6.54 95% CI [3.09 - 14.43], p< 0.001), within one year (OR=1.34 95% CI [1.18 - 1.52], p< 0.001), two years (OR=1.43 95% CI [1.24 – 1.65], p< 0.001), and three years (OR=1.44 95% CI [1.25 – 1.66], p< 0.001) when compared to patients without a PV. Patients with a moderate-risk PV were also more likely to have undergone MRI within 3 months of receiving genetic test results (OR=2.89 95% CI [1.05 - 7.81], p=0.036), within one year (OR=1.33 95% CI [1.10 - 1.62], p=0.004), two years (OR=1.31 95% CI [1.09 - 1.59], p=0.004), and three years (OR=1.44 95% CI [1.18 - 1.76], p< 0.001), compared to those without a PV (Table 1). Conclusions: After three years of longitudinal follow up of 2000 patients in this multicenter prospective cohort study, patients with a PV in a breast cancer susceptibility gene were more likely to undergo guideline concordant breast MRI compared to patients without a PV. Carriers of high-risk breast cancer gene PVs were over six times as likely to have undergone MRI compared to patients without PVs within the first three months after genetic results disclosure and counseling. These results demonstrate the effectiveness of MGPT and genetic counseling in guiding patients with PVs in breast cancer susceptibility genes to the appropriate adoption of guideline-concordant screening. Odds ratios of MRI screening in patients carrying PV in breast cancer risk genes. Odds in relation to patients who do not carry a PV High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Percent of patients having undergone an MRI at the specified time points High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Citation Format: Leah A. Naghi, Charite N. Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Hodan, Nicolette M. Chun, John Kidd, Joseph Bonner, Christine Hong, Meredith Mills, Sidney S. Lindsey, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen Grube, Allison W. Kurian, Gregory E. Idos. Uptake of Breast Cancer MRI Screening in Patients After Multiplex Gene Panel Testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-07.

10517 Background: TNBC represents ̃15% of invasive BC. Ancestry-specific variabilities in TNBC risk are well-described, with African American (AA) women experiencing higher incidence and mortality from TNBC than women of other races/ethnicities. Increased risk of TNBC has been associated with both rarer (e.g. RAD51C/D, BARD1) and more commonly detected (e.g. BRCA1/2, PALB2) germline PV in hereditary CA predisposition genes, but less is known about ancestry-specific TNBC risks for PV carriers. Methods: We examined clinical and genetic records from women referred for multigene CA panel testing (9/2013-5/2020). Multivariable logistic regression was used to test associations of PV in 13 genes with risk of TNBC after accounting for age, ancestry, and personal/family CA history. We analyzed each gene in the full cohort, and in subcohorts defined by self-reported ancestry. Effect sizes are expressed as odds ratios with 95% confidence intervals. Seven genes are not reported in ancestry-stratified analyses due to small numbers of PV carriers with TNBC. Results: From 627,219 individuals referred for multigene panel testing, 115,337 (18.4%) women with personal history of BC were identified, of whom 17,951 (15.6%) reported TNBC. Personal history of TNBC was reported more frequently in women of African ancestry (26.9%) than in women of European (13.9%) or Asian (11.7%) or Latinx ancestry (14.9%). Ancestry-stratified risks of TNBC associated with germline PVs are seen in the Table. Conclusions: While small samples sizes limit some gene-specific analyses, comparable ancestry-specific risks of TNBC were seen across the racial/ethnic groups examined here. [Table: see text]

Background Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate‐risk pathogenic variants (PVs). Methods Study participants (N = 1264) were counseled and tested with a 25‐ or 28‐gene panel and completed a 3‐month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). Results The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non‐Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non–English‐speaking. The genetic test results were as follows: 7% had a high‐risk PV, 6% had a moderate‐risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of “never,” “rarely,” or only “sometimes” reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high‐ and moderate‐risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High‐ and moderate‐risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. Conclusions In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. Lay Summary Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate‐risk pathogenic variants (mutations) and among carriers of variants of uncertain significance.This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% “never,” “rarely,” or only “sometimes” reacted negatively to results.Somewhat higher uncertainty and distress were identified among carriers of high‐ and moderate‐risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result.Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results., Multigene panel tests for hereditary cancer have become widespread despite concerns that carriers of moderate‐risk pathogenic variants or uncertain variants could have adverse psychological reactions. This large cohort study of patients undergoing panel testing has found that the psychological response is favorable, regardless of genetic test results.

PURPOSE: The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2. METHODS: We conducted an unmatched case-control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing. RESULTS: Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR, 4.7; 95% CI, 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR, 7.8; 95% CI, 5.2, 11.6), for probands and FDR diagnosed at age

Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

Introduction: National guidelines recommend that women diagnosed with early-onset breast cancer and/or a strong family history receive BRCA1/2 testing to guide treatment decisions. Among newly diagnosed patients, a positive test result will often prompt more aggressive surgical treatment to minimize the risk of second primary cancers. Currently, coverage for genetic counseling and testing for Hereditary Breast and Ovarian Cancer (HBOC) under the Medicaid expansion program of the Affordable Care Act has varied by state, where some states require a copayment for this service. Similarly, there is no mandate to cover risk-reducing surgery for patients found to carry a genetic mutation despite research showing cost-effectiveness. This analysis sought to determine whether genetic testing for HBOC among patients with breast cancer is different for those with Medicaid compared to those with private insurance. Methods: A commercial laboratory database was analyzed for patients with a personal history of breast cancer who underwent testing with a 25-gene hereditary cancer panel from September 2013-February 2016. Patients were eligible for inclusion if they were between ages 18 and 64 at the time of testing and had not undergone previous genetic testing. A total of 17,020 patients with either Medicaid (N=4,313) or one of 5 private payers (N=12,707) were tested during this period. Descriptive statistics, including means for continuous variables and proportions for categorical variables, were calculated. Chi-square tests were used to test associations and differences of positive rates between insurance provider category. Two-tailed p-values are reported, and any p-value less than 0.05 is considered statistically significant. Results: Medicaid patients had a median age of breast cancer diagnosis of 45 compared to 47 for patient with private insurance. Among women with Medicaid insurance, a higher proportion were of African (13.3% vs 6.4%) and Latin American ancestry (16.4% vs 5.3%). The mutation positive rate among patients with Medicaid was 13.0%, which was statistically higher than patients with private insurance (9.5%) (p Positive rate by ancestry MedicaidPrivateOverallAfrican80 (13.9%)72 (8.9%)152 (11.0%)Ashkenazi3 (17.6%)20 (15.3%)23 (15.5%)Asian26 (13.3%)40 (7.5%)66 (9.1%)Caucasian201 (12.9%)171 (9.9%)918 (10.4%)Latin American/Caribbean98 (13.8%)65 (9.6%)163 (11.8%)Native American7 (13.7%)9 (7.9%)16 (9.7%)Neareast/Mideast10 (17.9%)8 (9.3%)18 (12.7%)Multiple49 (12.3%)77 (9.0%)126 (10.0%)None Specified85 (11.3%)199 (8.8%)284 (9.4%)Total559 (13.0%)1207 (9.5%)1766 (10.4%) Conclusions: Overall, the positive mutation rate among individuals with Medicaid insurance was higher than those with private insurance, suggesting the testing requirements applied to this population may be more stringent than those applied to the private insurance population. Consistent genetic testing insurance criteria are necessary for all patients to receive care in line with guidelines following a breast cancer diagnosis. Citation Format: Baron P, Johnson-Isidore K, Miller L, Brown K, Kidd J, Saam J, Lancaster J. Genetic testing for HBOC among women with a personal diagnosis of breast cancer in patients with Medicaid as compared to patients with private insurance [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-10-06.

Next Generation Sequencing (NGS) multigene panels, which are routinely used to assess hereditary cancer risk, can detect both inherited germline variants and somatic variants in cancer-risk genes. We evaluated the frequency and distribution of likely somatic Pathogenic and Likely Pathogenic variants (PVs) detected in220,000 individuals who underwent clinical testing with a 25-gene panel between September 2013 and March 2016. Likely somatic PVs are defined as variants with NGS read frequencies from 10% to 30%. Overall, 137 (0.06%) individuals were identified as carrying likely somatic PVs, most commonly in TP53 (73), CHEK2 (27), and ATM (20). Among this group, a second PV with a NGS read frequency consistent with a germline variant within the same gene or a different gene on the panel was detected in 21 individuals (15.3%), which is similar to the detection rate in our general testing population. Likely somatic PVs accounted for 38.8% of all PVs in TP53. In comparison, likely somatic PVs accounted for1% of PVs in most other genes. Likely somatic PVs were more frequently identified in older individuals (p 0.001). Additional studies are ongoing to further investigate the incidence and clinical implications of somatic variants, enabling the appropriate medical management for these patients.

Background: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. Methods: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. Results: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. Conclusion: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

Purpose Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations. Patients and Methods This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics—University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute—who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). Results Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. Conclusion In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

e13653 Background: The HOXB13 c.251G > A (p.G84E) variant is associated with increased prostate cancer risk, possibly at younger ages. Studies on this variant have focused primarily on men, although genetic testing for hereditary cancer risk is most often performed in women. There remains a need to assess whether male and female carriers of this variant have increased risk for other cancers. Methods: We identified male and female carriers of the HOXB13 c.251G > A (p.G84E) variant among individuals referred for hereditary cancer panel genetic testing from October 2018 – December 2019. Non-carriers had no pathogenic variants in any gene or variants of uncertain significance in HOXB13. Personal and family (1st- and 2nd-degree relative) cancer histories were obtained from provider-completed test request forms. Multivariable logistic regression (MLR) models were conducted separately for males and females to estimate cancer risks for the variant as odds ratios (ORs), and 95% Wald confidence intervals (CIs) adjusted for age, ancestry and personal/family cancer history. Results: The analysis included 197,978 patients: 4.5% (8,998/197,978) male and 95.5% (188,980/197,978) female. The HOXB13 variant was present in 0.44% (40/8,998) of tested males, 45% (18/40) of whom had a diagnosis of prostate cancer. The variant was present in 0.32% (621/188,980) of tested females. Male carriers with prostate cancer were diagnosed at younger ages (median, 56; Interquartile ratio [IQR], 52, 62) than non-carriers (median, 63; IQR, 57,70), but this difference was not statistically significant. The MLR model calculated a 3.30 OR for prostate cancer in male carriers of c.251C > A ( P = 0.01; 95% CI 1.30-8.39). In an analysis combining males and females, carriers were significantly more likely to report prostate cancer in a family member than non-carriers ( P = 3.5 x 10−7; OR 1.61, 95% CI 1.34-1.93). There was no apparent association with increased risk for other cancers among carriers versus non-carriers, or among relatives of carriers compared with relatives of non-carriers. Conclusions: The HOXB13 c.251G > A (p.G84E) variant was associated with significantly increased risk of prostate cancer, confirming previously published studies. We found no evidence of association with other cancers. For unaffected male carriers, who may frequently be identified through testing of a female relative, identification of this HOXB13 variant provides an opportunity for more precise prostate cancer risk stratification and screening.

1538 Background: BRIP1/ FANCJ participates in DNA replication and repair via interactions with BRCA1 and possibly MLH1. Previous studies have reported that pathogenic variants (PV) in BRIP1 are associated with an ~2-fold increase in risk for ovarian cancer (OC) and triple-negative breast cancer (TNBC). Although multigene panel testing for hereditary cancer (CA) has identified BRIP1 PV and uncertain variants (VUS) in patients with diverse CAs including breast (BC), colorectal (CRC) and melanoma (Mel), association with these CA types has not been established. Methods: We examined BRIP1 risks in two independent populations: Fox Chase Cancer Center (FCCC) and Myriad Genetics (MGL). At FCCC, pedigrees of BRIP1 PV ( N= 10) and VUS families ( N= 47) were reviewed. The MGL population included patients referred for testing by multigene panel (9/2013-12/2019) ( N= 586,740). Multivariable logistic regression analysis estimated BRIP1 CA risks as odds ratios (ORs) and 95% confidence intervals (CIs). Models were adjusted for age, sex, ancestry, personal CA history (PHX), and family CA history. Results: In the FCCC cohort, BRIP1 PV carriers ( N= 12) reported PHX of early-onset ( < 50) BC, CRC, and bladder CA. BRIP1 VUS were also identified among several patients with striking PHX and negative panel testing: BC < 40 ( N= 3), bilateral BC ( N= 4), TNBC ( N= 2), CRC < 40 ( N= 3), and a patient with 3 CAs < 40 (CRC, BC, and Mel). All FCCC families with a BRIP1 PV and select VUS families ( N= 6) are seen in the Table. In the MGL population, 0.3% (1,678/586,740) carried a BRIP1 PV. Logistic regression analyses found that female BRIP1 PV carriers have significantly increased risk for OC (OR 2.40, 95% CI 1.93-2.98) and TNBC (OR 1.93, 95% CI 1.52-2.46). Data were insufficient for testing risk of bladder or prostate CA. Findings did not support associations of BRIP1 with CRC, melanoma, endometrial, pancreatic or gastric CA. Conclusions: BRIP1 PV and VUS may be identified in patients with diverse CA histories. These results confirm studies showing that BRIP1 PV are associated with an ~2-fold increased risk of OC and TNBC, but do not support increased risks of CRC, melanoma or endometrial CA in BRIP1 PV carriers. [Table: see text]

Background Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA). Methods Sequencing and LR analysis were conducted in a consecutive series of 376,159 individuals who received clinical testing with a hereditary pan-cancer gene panel from September 2013 through May 2017. NGS dosage analysis was used to evaluate potential deletions or duplications, with controls in place to exclude pseudogene reads. Samples positive for a putative LR based on NGS were confirmed using a comprehensive approach that included targeted microarray-CGH and/or MLPA analysis, with further examination as needed to ascertain the nature of the LR. Results A total of 3461 LRs were identified and classified as a deleterious mutation (DM), suspected deleterious mutation (SDM) or variant of uncertain significance. Pathogenic LRs (DM/SDM) accounted for the majority of LRs (67.7%), the largest proportion of which were deletions (86.1%), followed by duplications (11.3%), insertions (1.8%), triplications (0.5%), and inversions (0.3%). Several cases presented illustrate that the laboratory approach employed here can ensure consistent identification and accurate characterization of LRs. In the absence of this comprehensive testing strategy, 9% of LRs identified in this testing population might have been missed, potentially leading to inappropriate medical management in as many as 210 individuals referred for hereditary cancer testing. Conclusions These data show that copy number analysis using NGS coupled with confirmatory testing reliably detects and characterizes LRs. Further, LRs comprise a substantial proportion (7.2%) of pathogenic variants identified by the test. A robust and accurate LR identification strategy is an essential component of a high-quality genetic testing program, enabling clinicians to optimize patient medical management decisions.

Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016. The majority of individuals (92.8%) met testing criteria for Hereditary Breast and Ovarian Cancer (HBOC) and/or Lynch syndrome (LS). Overall, 17,340 PVs were identified in 17,000 (6.7%) of the tested individuals. The PV positive rate was 9.8% among individuals with a personal cancer history, compared to 4.7% in unaffected individuals. PVs were most common in BRCA1/2 (42.2%), other breast cancer (BR) genes (32.9%), and the LS genes (13.2%). Half the PVs identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2 . Similarly, half of PVs identified in individuals who met only LS testing criteria were in non-LS genes. These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single-syndrome testing.

1525 Background: Guidelines recommend consideration of prophylactic surgery for patients with a germline pathogenic variant in some cancer predisposition genes. We assessed surgery utilization in a prospective, multi-institutional cohort study of MGPT. Methods: 2000 patients had MGPT and completed questionnaires at 3, 6, and 12 months. Patients reported surgical utilization and indication (treatment or prevention). Surgery utilization was assessed according to cancer history and MGPT test results: Positive, pathogenic variant; VUS, variant of uncertain significance; Negative, benign variants. Results: Overall, 12.9% (198/1537) of patients reported surgery after MGPT (median follow-up 13 months). Only 31.3% (62/198) of patients specified that their surgery was preventive. Preventive surgery utilization was significantly higher among patients who tested positive (n=30, 14.9%) compared to those testing negative (n=20, 2.3%, p

Breast MRI screening is recommended for women with a20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone.Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a20% lifetime risk for breast cancer (ATM, CHEK2, PALB2, TP53, PTEN, CDH1, and STK11). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at20% lifetime risk on the basis of family history.In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM, CHEK2, or PALB2. Only 24.7% of all women with PVs found in any gene reached the20% lifetime risk threshold using the Claus model.Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.

Background Panel-based genetic testing has identified increasing numbers of patients with pancreatic ductal adenocarcinoma (PDAC) who carry germline mutations. However, small sample sizes or number of genes evaluated limit prevalence estimates of these mutations. We estimated prevalence of mutations in PDAC patients with positive family history. Methods We sequenced 25 cancer susceptibility genes in lymphocyte DNA from 302 PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreatic Research Registry. Kindreds containing at least two first-degree relatives with PDAC met criteria for Familial Pancreatic Cancer (FPC), while the remaining were familial, but not FPC. Results Thirty-six patients (12%) carried at least one deleterious mutation in one of 11 genes. Of FPC patients, 25/185 (14%) were carriers, while 11/117 (9%) non-FPC patients with family history were carriers. Deleterious mutations (n) identified in PDAC patients were BRCA2 (11), ATM (8), CDKN2A (4), CHEK2 (4), MUTYH/MYH (3 heterozygotes, not biallelic), BRCA1 (2), and 1 each in BARD1, MSH2, NBN, PALB2, and PMS2. Novel mutations were found in ATM, BARD1, and PMS2. Conclusions Multiple susceptibility gene testing in PDAC patients with family history of pancreatic cancer is warranted regardless of FPC status, and will inform genetic risk counseling for families.

It is well documented that histopathologic examination is sometimes inadequate for accurate and reproducible diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature has been clinically validated as an adjunctive diagnostic test to differentiate benign nevi from malignant melanomas. This study aimed to quantify the impact of this test on diagnosis and treatment recommendations made by dermatopathologists. Diagnostically challenging melanocytic lesions encountered during routine dermatopathology practice were submitted for gene expression testing and received a melanoma diagnostic score (MDS). Submitting dermatopathologists completed a survey documenting pre-test diagnosis, level of diagnostic confidence, and recommendations for treatment. The survey was repeated after receiving the MDS. Changes between the pre- and post-test surveys were analyzed retrospectively. When the MDS was available as part of a comprehensive case evaluation in diagnostically challenging cases, definitive diagnoses were increased by 56.6% for cases that were initially indeterminate and changes in treatment recommendations occurred in 49.1% of cases. Treatment recommendations were changed to align with the test result in 76.6% of diagnostically challenging cases. The MDS impacts diagnosis and treatment recommendations by dermatopathologists confronted with diagnostically challenging melanocytic lesions. Increased data are needed in order to completely understand how use of the MDS will translate from dermatopathology to clinical practice.

BACKGROUND As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. METHODS A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. RESULTS PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%), and partner and localizer of BRCA2 (PALB2) (9.3%). The prevalence of PVs in BRCA1, PALB2, BRCA1-associated RING domain 1 (BARD1), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and RAD51 paralog C (RAD51C) was statistically higher among women with TNBC. The PV rate was higher among women aged 59 years, and relatively constant (8.5%-9.0%) among women who were diagnosed between ages 40 and 59 years. CONCLUSIONS These results demonstrate that panel testing increased the number of women identified as carrying a PV in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years. Cancer 2017;123:1721–1730. © 2017 American Cancer Society.

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

// Takashi Eguchi 1, 2 , Kyuichi Kadota 3, 4 , Jamie Chaft 5 , Brent Evans 6 , John Kidd 6 , Kay See Tan 7 , Joe Dycoco 1 , Kathryn Kolquist 6 , Thaylon Davis 6 , Stephanie A. Hamilton 6 , Kraig Yager 6 , Joshua T. Jones 6 , William D. Travis 3 , David R. Jones 1 , Anne-Renee Hartman 6 , Prasad S. Adusumilli 1, 8 1 Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Division of Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan 3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA 7 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8 Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Prasad S. Adusumilli, email: adusumip@mskcc.org Keywords: molecular prognostic score, CCP score, chemotherapy, adjuvant therapy, overall survival Received: February 08, 2016 Accepted: April 16, 2016 Published: May 2, 2016 ABSTRACT Purpose: The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes. Methods: Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer–specific mortality as the primary outcome. Results: In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer–specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14–2.24; P =0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer–specific mortality (HR=1.77; 95% CI, 1.18–2.66; P =0.006). Five-year lung cancer–specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P

1582Background: Cancer screening guidelines recommend that germline carriers with a pathogenic variant (PV) in a CRC susceptibility gene should undergo more frequent colonoscopy screening. We asses...

1581Background: Cancer screening guidelines recommend that germline carriers with a pathogenic variant (PV) in a breast cancer susceptibility gene undergo more intensive breast screening including ...

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.

e13032 Background: Approximately 85% of male breast cancer (MBC) patients test negative for a BRCA mutation, and the role of genetic predisposition is unclear. Cancer risk counseling for unaffected relatives of BRCA-negative MBC patients relies on accurate cancer risk estimates, but there is limited data on the risk of breast cancer (BC) for relatives of these men. We characterized the association between MBC and family history of BC in patients who test negative for BRCA mutations in order to facilitate cancer risk counseling and to explore the possibility of unidentified MBC susceptibility alleles. Methods: We performed a case-control study of patients who had full length sequencing and large-rearrangement analysis for germline mutations in BRCA1/2 or the mismatch repair (MMR) genes at a commercial laboratory from 2006-2012. Cases were MBC patients who tested negative for a BRCA1/2 mutation (n = 3,647); controls were male colon cancer patients who tested negative for mutations in MMR genes (n = 4,269). Information on family history of BC was ascertained from test request forms completed by the ordering healthcare provider at the time of testing. Unconditional multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between family history of BC in first- (FDR) and second-degree relatives (SDR) and MBC with adjustment for potential confounders (age, ethnicity, year of testing). Results: Compared to controls, MBC cases had higher odds of BC in a FDR or SDR (OR = 4.7; 95% CI 4.1, 5.3). Associations were strongest for family history of BC in 1 female FDR (OR = 3.9; 95% CI: 3.3, 4.6), ≥2 female FDR (OR = 7.5; 95% CI 5.0, 11.4), BC in a FDR < 45 years old (for cases diagnosed < 45, OR = 6.9; 95% CI 3.9, 12.4), a male FDR or SDR with BC (OR = 17.9; 95% CI 7.6, 42.1), and both a male and female FDR or SDR with BC (OR = 15.7; 95%CI 4.4, 55.3). Conclusions: MBC patients who test negative for a BRCA mutation have significantly higher odds of reporting family members affected by breast cancer, particularly with affected FDR < 45 years old, multiple affected relatives, and male relatives with BC. This data can guide risk counseling in MBC families, and suggests the existence of unidentified MBC susceptibility alleles.

1576 Background: Sequencing more genes increases the chance of finding a pathogenic mutation and/or a variant of uncertain significance (VUS). Little is known about potential harms of multiplex testing for cancer risk, such as unwarranted surgery or adverse psychological effects. Methods: We conducted a prospective trial of sequencing 25 genes : APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were eligible if they met standard testing guidelines or predictive models estimated ≥2.5% mutation probability. Participants were surveyed 3 months post-test: the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale measured distress, uncertainty and positive experiences. We report on the fully accrued trial (N = 2000). Results: 1998/2000 (99.9%) participants currently have reported results: 12.1% tested positive for a pathogenic mutation (Pos), 34.5% had VUS only and 53.5% tested negative (Neg). Median age was 51, 81% were female, 40% Hispanic, and 72% had a cancer history. Self-reported preventive surgery rates were low (mastectomy 9.3%, hysterectomy 1.5%, oophorectomy 1.6%), with no difference between VUS and Neg patients (p = 0.346). Most patients never or rarely had thoughts of cancer affecting daily activities (Pos 59.5%, VUS 66.9%, Neg 71.0%), never regretted testing (Pos 84.1%, VUS 90.0%, Neg 93.6%), and wanted to know all results, even those that doctors do not fully understand (Pos 81.7%, VUS 78.8%, Neg 77.1%). Pos patients had higher MICRA distress and uncertainty scores than VUS and Neg patients, whose distress and uncertainty scores did not differ significantly (p = 0.165, p = 0.129). Relatives of Pos patients completed genetic testing (30.4%) more often than VUS (5.8%) or Neg patients (5.1%, p < 0.001). Conclusions: After multiplex testing of 2000 diverse patients, few reported preventive surgery at 3 months; VUS patients had no more distress, regret or uncertainty than Neg patients. Pos patients most often advised relatives to test, suggesting that participants understood the implications of test results. Longer-term follow-up of test-related outcomes is underway. Clinical trial information: NCT02324062.

Purpose Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2 , as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone. Methods Women were tested with a 25-gene hereditary cancer panel including BRCA1/2 and 7 additional genes known to be associated with a >20% lifetime risk for breast cancer ( ATM , CHEK2 , PALB2 , TP53 , PTEN , CDH1 , and STK11 ). Women found to carry pathogenic variants (PVs) were evaluated with the Claus model to assess whether they would have been found to be at >20% lifetime risk on the basis of family history. Results In total, 9,751 PVs in the selected breast cancer risk genes were identified in 9,641 women. BRCA1/2 accounted for 59.1% of the PVs, and 38.8% were in ATM , CHEK2 , or PALB2 . Only 24.7% of all women with PVs found in any gene reached the >20% lifetime risk threshold using the Claus model. Conclusions Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.

In this paper, we discuss non-linear methodologies that can be employed to devise real-time algorithms suitable for guidance and control of spacecrafts during asteroid close-proximity operations. Combination of optimal and sliding control theory provide the theoretical framework for the development of guidance laws that generates thrust commands as function of the estimated spacecraft state. Using a Lyapunov second theorem one can design non-linear guidance laws that are proven to be globally stable against unknown perturbations with known upper bound. Such algorithms can be employed for autonomous targeting of points of the asteroid surface (soft landing , Touch-And-Go (TAG) maneuvers). Here, we theoretically derived and tested the Optimal Sliding Guidance (OSG) for close-proximity operations. The guidance algorithm has its root in the generalized ZEM/ZEV feedback guidance and its mathematical equations are naturally derived by a proper definition of a sliding surface as function of Zero-Effort-Miss and Zero-Effort-Velocity. Thus, the sliding surface allows a natural augmentation of the energy-optimalguidance via a sliding mode that ensures global stability for the proposed algorithm. A set of Monte Carlo simulations in realistic environment are executed to assess the guidance performance in typical operational scenarios found during asteroids close-proximity operations. OSG is shown to satisfy stringent requirements for asteroid pinpoint landing and sampling accuracy.