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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.

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.

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]

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

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.

1501Background: Microsatellite instability (MSI) and mismatch repair protein immunohistochemistry (MMR IHC) are standard of care to screen for the 3% of CRCs that arise due to Lynch syndrome (LS). ...

4108Background: Availability of cancer gene mutation panel-based screening will identify increasing numbers of patients who carry diverse germline mutations. Prevalence of mutations and survival by...

1509Background: 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. How...

1503Background: 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 test...

Background: Clinical diagnostic criteria for Li-Fraumeni syndrome (LFS) have evolved with increased utilization of TP53 germline testing and subsequent improved understanding of the diversity of the associated cancer phenotypes. However, data on LFS still suffer from ascertainment bias as patients are typically selected to undergo TP53 testing based on the presence of hallmark features of LFS. Analyzing TP53 mutation carriers identified from multi-gene panel testing, for which the diagnosis of LFS may not have been suspected or was included in a longer differential diagnosis, affords an opportunity to characterize additional TP53 carriers who might not otherwise have been ascertained. Methods: Patients with a deleterious or suspected deleterious germline TP53 mutation were identified from 80,748 consecutive cases that underwent a 25-gene hereditary cancer panel test between September 2013 and March 2015 at a commercial diagnostic laboratory. Patient clinical data were obtained by healthcare provider report on test requisition forms. Each TP53 mutation carrier was evaluated to determine whether the National Comprehensive Cancer Network's (NCCN) guidelines were met for TP53 testing. Results: Eighty-one TP53 mutation carriers were identified and had a total of 115 cancers (0.1% overall prevalence). Among the 76 carriers with at least one cancer, the average age at first diagnosis was 42 years (range 11-76 years) and 24% were first diagnosed older than age 50 years. The most common first cancers were of the breast (n=45), ovary (n=9), and gastrointestinal tract (n=8). Fifty-two of the 75 (69%) women had breast cancer, 44% of which were first diagnosed at 35 years or younger, and 21% were first diagnosed at 50 years or older. Only 27 TP53 carriers met NCCN criteria for TP53 testing, 14 of whom only met based on having early-onset breast cancer. An additional 8 did not meet criteria themselves but had a first- or second-degree relative who did. Among the 28 individuals with more than one primary cancer, 21 (75%) developed their second primary at a site for which increased surveillance is recommended in LFS, but only 4 would have met NCCN criteria for TP53 testing at their first cancer diagnosis. The most common second cancers were of the breast (n=16), gastrointestinal tract (n=4), or kidney (n=2) and occurred an average of 11 years after the first cancer (range 0-36 years). Conclusion: In this analysis, a large proportion of carriers would not have been identified as TP53 testing candidates based on NCCN guidelines. Our data are consistent with other studies demonstrating high second primary cancer risks in LFS, and highlight the value of multigene panel testing in identifying individuals who may be candidates for increased surveillance and/or cancer risk-reducing management options. Citation Format: Rich T, Lotito M, Kidd J, Saam J, Lancaster J. Characterization of Li-Fraumeni syndrome diagnosed using a 25-gene hereditary cancer panel. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD7-03.

Background: Multiple primary cancers within an individual is one of the hallmarks of hereditary cancer predisposition. Technical advances in sequencing and identification of additional cancer susceptibility genes have led to multi-gene panel approaches to determine if patient cancers have a heritable cause. Simultaneous testing of multiple breast cancer associated genes to determine the prevalence, spectrum and combinations of mutations has not yet been evaluated in a large set of patients with two breast cancers. Methods: Patients with two breast cancer diagnoses were identified from 80,748 consecutive cases that underwent a 25-gene hereditary cancer panel test at a commercial diagnostic laboratory. Patient clinical data were obtained by healthcare provider report on test requisition forms. Results: Of 3,182 patients with two breast cancers, 13.3 % (n=424) had a pathogenic variant (PV) in at least one of 19 genes on the panel. PVs were most prevalent within BRCA1, representing 26.3% of the PVs, followed by BRCA2 (21.9%), CHEK2 (13.5%), PALB2 (11%) and ATM (11%). Fourteen patients had PVs in two different genes, including five with CHEK2/PALB2 in combination, which was the only combination observed more than once. PVs were more common among the 33.8% of patients with synchronous breast cancers compared to those with metachronous diagnoses (10.8% vs. 15%) and in the 58.4% who were first diagnosed younger than 50 years old (15.7% vs. 10%). Conclusion: Multiplex testing in women with two primary breast cancers identifies a relatively high percentage with a PV, including those whose first diagnosis was older than 50. While still the most prevalent and clear cause, fewer than half of the PVs identified were in BRCA1 or BRCA2. The observation of 5 cases with double CHEK2/PALB2 PVs is statistically unexpected given their individual prevalence in other studies of high risk women with breast cancer, suggesting a possible synergistic or additive effect. This study adds to our understanding of susceptibility to multiple primary breast cancers, and reaffirms the importance of this circumstance as a prompt for genetic testing. Nonetheless, as 66% of cases had metachronous tumors, it would be preferable to identify those at risk with heritable cancer syndromes at their first diagnosis and enable subsequent prevention or early detection. Citation Format: Weitzel JN, Blazer KR, Nehoray B, Kidd J, Slavin Jr TP, Solomon I, Niell-Swiller M, Rybak C, Saam J, Lancaster J. Multiplex Identification of genetic etiologies among women with bilateral breast cancer using a 25-gene hereditary cancer panel. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD7-02.

San Francisco is in the process of doing something revolutionary: the City is heeding the warning of the moderate damage caused by the Loma Prieta earthquake, and may mandate strong rehabilitation measures for soft-story buildings to prevent catastrophe in future quakes. A study for the City, the Community Action Plan for Seismic Safety (CAPSS), recently estimated the consequences of several moderate to large Bay Area earthquakes on multi-unit, soft-story wood-frame dwellings. The project estimates that tens of thousands of residents of these buildings would be displaced from their homes, many for years, after a large earthquake, but retrofits would greatly reduce these impacts. Remarkably, it was building owner and tenant groups, not structural engineers, who actively led the discussion about whether mandatory mitigation makes sense. The project, with support from many community groups, calls for mandatory retrofit of the most vulnerable of these buildings.

The act of forming an alliance implies a need to be stronger in unison and that there is some common agreement between the parties — they have shared goals for instance. In the commercial world, however, this simple definition needs to be broadened as alliances are created for many reasons, some of which are anti-competitive. In this chapter, we concentrate on alliances that cross national boundaries, and are (presumably) set up to be of benefit to each party so as to increase their reach in one or more aspects of their joint business: specifically they will be alliances in mainland China, located in the southwest region.

1514 Background: Technical advances have upended the established paradigm of testing high penetrance cancer predisposition genes based on syndromic features. National guidelines now include discuss...

1515 Background: Genetic assessment for inherited risk is a key tool for cancer prevention. Genetic testing strategies are evolving in response to expanding information about gene associations and ...

1067 Background: Although triple-negative breast cancer (TNBC) accounts for 15% to 20% of all breast cancers diagnosed in the US, its epidemiology is not well understood. Previous studies have show...

In a locomotive cab structural damage due to collision, derailment or rollover may often block the normal egress routes. These situations require suitable emergency egress systems that provide access both from interior by the crew and from exterior by the rescue team. After incorporation of a removable roof hatch as the primary egress system, a removable windshield and emergency hinge release of the rear door were selected as potential secondary emergency egress alternatives. Simple innovative concepts and cost-effective hardware systems have been developed at Foster-Miller laboratories and installed on mockup assemblies to provide viable solutions to the above two secondary egress systems. Proof of concept demonstration and functionality evaluation were successfully carried out. This paper presents the salient design features and functional evaluation of these novel emergency egress concepts. Feasibility of incorporating these secondary egress systems into new railroad locomotive cab design is briefly discussed.

Although the following observations afford no positive evi­dence of the source of that saline efflorescence, which is so frequently seen on the walls of subterraneous and other build­ings, and which, as consisting principally if not entirely of common nitre, long since gave rise to the name by which that salt is most commonly known; yet as tending to throw some light on a very obscure part of natural history, they will not, perhaps, be unacceptable to this honourable and learned Society. There can be no doubt that the production of saltpetre or nitre, in the situations above alluded to, had been observed long before there existed any general inducement to collect it from those sources; but after the invention and subsequent extensive employment of gunpowder, it became an object not only to search out every natural source of the principal ingre­dient of that important compound, but also to investigate the circumstances of its production; for the purpose either of accelerating the natural process, or of imitating it by artificial means.