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Background: Gastric cancer is a leading cause of cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in gastric cancer, we developed the Gastric Cancer Registry (GCR), a North American repository of clinical and cancer genomics data. Methods: Participants self-enrolled online. Entry criteria into the GCR included the following: (i) diagnosis of gastric cancer, (ii) history of gastric cancer in a first- or second-degree relative, or (iii) known germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed survey. Some participants provided specimens of saliva and tumor samples. Tumor samples underwent exome sequencing, whole-genome sequencing, and transcriptome sequencing. Results: From 2011 to 2021, 567 individuals registered and returned the clinical questionnaire. For this cohort 65% had a personal history of gastric cancer, 36% reported a family history of gastric cancer, and 14% had a germline CDH1 mutation. 89 patients with gastric cancer provided tumor samples. For the initial study, 41 tumors were sequenced using next-generation sequencing. The data was analyzed for cancer mutations, copy-number variations, gene expression, microbiome, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers’ access to these datasets. Conclusions: The GCR is a unique, North American gastric cancer registry which integrates clinical and genomic annotation. Impact: Available for researchers through an open access, web-based explorer, the GCR Genome Explorer will accelerate collaborative gastric cancer research across the United States and world.

Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3497.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected patients, leading to colorectal cancer (CRC), and is an ideal model to study early transition to CRC. We performed deep multi-omic profiling of 135 normal mucosal, benign and dysplastic polyps and adenocarcinoma samples from 6 FAP patients who consented to broad data sharing. Whole genome sequencing indicates that spatially separated polyps from the same donor harbor numerous mutations in common, but evolve independently, consistent with a model of polyclonal origin and spreading. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during early hyperplasia, dysplasia and cancer formation. These involve processes such as cell proliferation, immune response, alterations in metabolism (including amino acids, lipids), hormones, and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin/NSAIDs, a common preventative treatment of FAP patients. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in cancer formation and potential mechanisms of pharmaceutical prophylaxis.

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

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 As genetic testing expands, patients are increasingly found to carry pathogenic variants in cancer susceptibility genes that are less familiar to most clinicians, specifically genes other than those causing hereditary breast ovarian cancer syndrome ( BRCA1 and BRCA2) and Lynch syndrome. Little is known about the subsequent behaviors of such patients in terms of managing cancer risks and informing relatives. Methods All adult patients who were counseled and tested at the Stanford Cancer Genetics Clinic from January 2013 to July 2015 and had a pathogenic variant in a non- BRCA1/2, non–Lynch syndrome gene were invited to participate in a telephone interview about adherence to risk-reducing recommendations, genetic testing by relatives, and new cancer incidence. Results Fifty-seven (40%) of 142 eligible patients were successfully contacted, and all 57 patients participated; median follow-up was 677 days (range, 247 to 1,401 days). Most patients (82%; 95% CI, 70% to 90%) recalled that a risk-reducing intervention (screening, medication, or surgery) was recommended, and most patients (85%; 95% CI, 72% to 93%) adhered to the recommendation. Nearly all patients (91%; 95% CI, 81% to 97%) shared results with relatives, and most patients (78%; 95% CI, 64% to 88%) reported that a relative was subsequently tested. During the follow-up period, 9% of patients (95% CI, 3% to 19%) developed second cancers, and in 14% of patients (95% CI, 7% to 26%), a first-degree relative developed cancer, some of which were detected by recommended screening. Conclusion Patients with a pathogenic variant in a less familiar cancer susceptibility gene report high adherence to risk-reducing interventions. Furthermore, in the 57 carriers and subsequently tested relatives with two years of follow-up, a total of three cancers (one in a proband and two in relatives) were detected through interventions recommended on the basis of the pathogenic variant. These results suggest a potential benefit of genetic counseling and testing for pathogenic variants in less familiar genes.

Research on the communication of genetic test results has focused predominately on non-Hispanic White (NHW) mutation-positive families with high-risk hereditary cancer conditions. Little is known about this process for racially and ethnically diverse individuals or for those with mutations in moderate risk genes. The communication behaviors of study participants who carry a gene mutation were analyzed 3 months after disclosure of genetic test results. Participants were queried about communication of their results, as part of a prospective study of multi-gene panel genetic testing. The responses of particpants who tested positive were analyzed by race/ethnicity and by level of cancer risk (high vs. moderate). Of the 216 mutation-positive study participants, 136 (63%) responded. Self-reported race/ethnicity was 46% NHW, 41% Hispanic, 10% Asian, and 2% Black. The majority (99.0%, n = 135) had shared their results with someone and 96% had told a family member (n = 130). Hispanic respondents were less likely to have told a healthcare provider about their results than NHW (29% vs. 68%, p < .0001). Asian respondents were less likely than NHW to encourage family members to undergo testing (OR = 0.1, p = .03); but Asian family members were more likely to undergo testing (OR = 8.0, p = .03). There were no differences in communication between those with a mutation in a high- or moderate-risk gene. Three months post genetic testing, communication of results was very high; 30% reported a family member underwent genetic testing. Further studies are needed to better understand the communication process in individuals from diverse racial/ethnic backgrounds.

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.

1549 Background: While germline pathogenic variants (PVs) in BRCA1/2 account for a large proportion of hereditary breast cancer (BC), PVs in PALB2, CHEK2 and ATM are increasingly detected. However, the phenotype and clinical features of invasive BC with these PVs have not been fully described. Methods: We identified patients with a PV or likely PV in PALB2, CHEK2 or ATM tested clinically at Stanford between 2014 - 2019 who provided informed consent to be included in a prospective cancer genetics registry. Data on baseline demographics, genetic testing history, and clinicopathologic features of diagnosed BC were collected. For patients with a subsequent diagnosis of metastatic BC, we calculated disease-free interval (DFI). Results: 130 patients met inclusion criteria for analysis: ATM (N=39), CHEK2 (N=58), PALB2 (N=33). Nearly all (98.5%) were women, with 2 male BC in ATM carriers. Non-Hispanic White ethnicity was most common in ATM (64.1%, 95% CI 48.4%-77.3%) and CHEK2 carriers (69.0%, 95% CI 56.1%-79.4%), but comprised only 39.4% (95% CI 24.7%-56.4%) in PALB2 carriers. Asian/Pacific Islander (24.2%, 95% CI 12.6%-41.3%) and Hispanic (30.3%, 95% CI 17.3%-47.5%) ethnicities were enriched among PALB2 mutation carriers. In total, 97.7% learned of their PV status only after a preceding diagnosis of BC and 43.1% were diagnosed with BC at age ≤ 45. Data regarding invasive BC subtypes, incidence of subsequent primary BC, and metastatic recurrence are listed below in the table. Additional data on stage, grade and sites of metastatic spread will be presented. Conclusions: We observed clinically important differences in the spectrum of BC subtypes among carriers of ATM, CHEK2 and PALB2 PVs, in addition to racial/ethnic differences with Asian/Pacific Islander and Hispanic ethnicity enriched among carriers of PALB2 PVs. [Table: see text]

Background: Multiplex gene sequencing panels (MGP) are increasingly used for assessment of hereditary breast cancer risk. Compared to testing for BRCA1 and BRCA2 (BRCA1/2) only, testing more genes increases the likelihood of identifying a deleterious mutation (DM) and/or a variant of uncertain significance (VUS), which might cause distress, uncertainty or regret about testing. Little is known about the patient experience of MGP testing. Methods: We conducted a prospective study of MGP testing, using a panel of 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, and TP53. Participants were enrolled at three medical centers and were eligible if they met standard genetic testing guidelines or if they had a ≥2.5% probability of a DM in any gene on the panel, as calculated by predictive models (e.g. IBIS, Penn II, MMRPro). Participants were surveyed about their experiences with MGP testing including distress and uncertainty at baseline (before test results disclosure) and three months later. The 25-item Multidimensional Impact of Cancer Risk Assessment (MICRA) scale measured distress, uncertainty and positive experiences at three months after testing. We present a planned interim analysis after enrolling 500 of 2000 total participants. Results: Of 500 participants, 332 (66%) were referred for suspicion of hereditary breast/ovarian cancer syndrome. Of these 332, 97% were female, 79% were white, 43% were Hispanic and 33% were Spanish-speaking only; for 25%, high school was their highest level of education. A total of 48% had breast cancer, 5% had ovarian cancer, and 7% had another cancer: 11% had a DM and 35% had VUS in one or more genes. At study entry most participants thought about cancer rarely or not at all (69%, 95% confidence interval (CI) 58%-77%), and few (7%, CI 3%-14%) had thoughts of cancer that affected their daily lives; results were unchanged three months later, after genetic results disclosure (Chi-squared test, p-value >0.1). MICRA scores at three months were low for distress (mean score 2 out of a possible 30) and uncertainty (mean score 7 out of 45), and high for positive testing experiences (mean score 9 out of 15). Most (82%, CI 72%-88%) participants wanted to know all of their MGP results even if the clinical relevance was not fully understood, and most (87%, CI 79%-93%) never regretted learning their MGP results. Conclusions: Among diverse participants of a prospective, multi-center MGP testing trial, cancer- and genetic testing-related distress were low at entry and remained low three months later. These results provide no evidence for an increase in distress or uncertainty after MGP. Longer-term follow-up in a larger cohort is underway. Citation Format: Kurian AW, Idos G, McDonnell K, Ricker C, Sturgeon D, Culver J, Lowstuter K, Hartman A-R, Allen B, Rowe-Teeter C, Kingham KE, Koff RB, Lebensohn A, Chun NM, Petrovchich IM, Mills MA, Hong C, Ladabaum U, Ford JM, Gruber SB. The patient experience in a prospective trial of multiplex gene panel testing for cancer risk. [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 P2-09-07.

Gene panels for hereditary breast and ovarian cancer risk assessment are gaining acceptance, even though the clinical utility of these panels is not yet fully defined. Technical questions remain, however, about the performance and clinical interpretation of gene panels in comparison with traditional tests. We tested 1105 individuals using a 29-gene next-generation sequencing panel and observed 100% analytical concordance with traditional and reference data on >750 comparable variants. These 750 variants included technically challenging classes of sequence and copy number variation that together represent a significant fraction (13.4%) of the pathogenic variants observed. For BRCA1 and BRCA2, we also compared variant interpretations in traditional reports to those produced using only non-proprietary resources and following criteria based on recent (2015) guidelines. We observed 99.8% net report concordance, albeit with a slightly higher variant of uncertain significance rate. In 4.5% of BRCA-negative cases, we uncovered pathogenic variants in other genes, which appear clinically relevant. Previously unseen variants requiring interpretation accumulated rapidly, even after 1000 individuals had been tested. We conclude that next-generation sequencing panel testing can provide results highly comparable to traditional testing and can uncover potentially actionable findings that may be otherwise missed. Challenges remain for the broad adoption of panel tests, some of which will be addressed by the accumulation of large public databases of annotated clinical variants.

Background: Advances in DNA sequencing technology have fueled the development of multigene panels for hereditary cancer testing. While such assays are potentially both practical and affordable for routine clinical genetic testing, there remains uncertainty regarding their proper application and interpretation. Among the unanswered questions are which patients are appropriate candidates for such expanded testing; what is the likelihood that finding deleterious variants will alter risk assessment and management, and what is the prevalence of variants of unknown significance (VUS) that may create uncertainty for providers and anxiety for patients. Methods: 821 patients who met NCCN guidelines for BRCA1/2 testing for hereditary breast/ovarian cancer (HBOC) were prospectively recruited at two major academic medical centers. These patients received traditional BRCA1/2 tests as part of their clinical care and also were later tested for a panel of 29 known cancer risk genes. This panel also re-tested BRCA1/2. Both sequence changes and deletions/duplications were reported, and the panel-testing laboratory was blind to the earlier results. Panel testing results were validated by comparison with the earlier data or by independent testing using established technologies. Family history information was collected directly by genetic counselors. Results: 13.8% of the patients carried BRCA1 or BRCA2 mutations, with >99% concordance between the traditional and panel results for these two genes. 53 (7.6%) of the BRCA1/2-negative patients carried mutations in other cancer risk genes. Some of these findings confer a high risk for breast/ovarian cancer (e.g. TP53), while others (i.e. CHEK2, BRIP1, PALB2, RAD51C, CDKN2A, ATM, and NBN) confer a moderate increase in risk. 10 of these 55 patients were positive for genes involved in Lynch syndrome (MLH1, MSH2, MSH6, and PMS2), although breast and ovarian cancer are not uniformly accepted as part of this syndrome. 40% of these patients were heterozygous carriers of pathogenic variants in MUTYH, which have a less clear impact on breast/ovarian cancer, although this rate (3%) is higher than the expected carrier frequency in this population. About 60% of patients had one or more VUS in the 29 genes. The rate of VUS was highly gene dependent, with ATM, APC, and PTCH1 providing the largest number. A small but significant subset of patients did not have personal or family histories consistent with the classical presentation of their identified mutation. Nevertheless, a majority of the non-BRCA1/2 findings would have prompted consideration of a management change for the tested patient even considering the personal and family cancer history. Conclusions: Multigene panel testing for hereditary cancer risk assessment increased the yield of findings with potential clinical impact for almost 8% of patients. This is consistent with prior data from our laboratory and others. This study, carried out in a uniform clinical practice setting and with data collected directly by health care providers, provides a representative view of the benefit from such testing in an unselected patient population. Citation Format: Leif Ellisen, Allison Kurian, Stephen Lincoln, Andrea Desmond, Meredith Mills, Kristen Shannon, Michelle Gabree, Michael Anderson, Yuya Kobayashi, Federico Monzon, James Ford. Clinical evaluation of multigene testing for hereditary breast and ovarian cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-04.

432 Background: Gastric cancer (GC) is the fifth leading cancer diagnosis and third frequent cause of cancer death globally. GC results from a cascade of molecular and genetic changes owing to environmental and genetic factors. While there are known risks to GC, more is to be learned about its development so to establish effective screens for early stages of cancer. Methods: The Gastric Cancer Registry (GCR) was built to investigate GC and discover informative genomic biomarkers. The GCR comprises medical, family, and social history and genomics data from patients with GC, a family history of GC, and/or a known mutation in the gene CDH1. Samples of saliva and gastric tumors are collected when available. The GCR allows us to leverage several genome sequencing datasets to construct a complete molecular landscape of GC. Early analysis of GC tissue includes whole exome sequencing (WES) to identify mutations, whole genome sequencing (WGS) for copy number variation, and RNA sequencing (RNAseq) for expression profiling. Results are used to inform of clonal neoantigens, microbiome, and immune cell populations. Saliva will be analyzed with linked reads sequencing to unearth germline mutations not picked up in standard clinical gene panels. Results: Datasets from 455 patients and samples from 159 patients have been collected. In a pilot study, we pinpointed specific mutations using WES and revealed extensive changes in genome copy number involving clinically actionable genes through WGS. Most tumors had a high degree of genomic instability and exhibited candidate markers for treatment decisions and response. Additionally, we found that RNAseq revealed tumor subgroups through gene expression signatures. Conclusions: The GCR is an informative resource enabling the identification of biomarkers for GC. With the GCR we are integrating expertise in translational cancer genomics with molecular biology, statistics, and bioinformatics to build a platform for discovery and the development of tools that will ultimately improve the detection, treatment, and prevention of GC.

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

PurposeWe examined racial/ethnic differences in the usage and results of germ-line multiple-gene sequencing (MGS) panels to evaluate hereditary cancer risk.MethodsWe collected genetic testing results and clinical information from 1,483 patients who underwent MGS at Stanford University between 1 January 2013 and 31 December 2015.ResultsAsians and Hispanics presented for MGS at younger ages than whites (48 and 47 vs. 55; P = 5E-16 and 5E-14). Across all panels, the rate of pathogenic variants (15%) did not differ significantly between racial groups. Rates by gene did differ: in particular, a higher percentage of whites than nonwhites carried pathogenic CHEK2 variants (3.8% vs. 1.0%; P = 0.002). The rate of a variant of uncertain significance (VUS) result was higher in nonwhites than whites (36% vs. 27%; P = 2E-4). The probability of a VUS increased with increasing number of genes tested; this effect was more pronounced for nonwhites than for whites (1.1% absolute difference in VUS rates testing BRCA1/2 vs. 8% testing 13 genes vs. 14% testing 28 genes), worsening the disparity.ConclusionIn this diverse cohort undergoing MGS testing, pathogenic variant rates were similar between racial/ethnic groups. By contrast, VUS results were more frequent among nonwhites, with potential significance for the impact of MGS testing by race/ethnicity.

Women with BRCA1 or BRCA2 (BRCA1/2) mutations face difficult decisions about managing their high risks of breast and ovarian cancer. We developed an online tool to guide decisions about cancer risk reduction (available at: http://brcatool.stanford.edu ), and recruited patients and clinicians to test its feasibility. We developed questionnaires for women with BRCA1/2 mutations and clinicians involved in their care, incorporating the System Usability Scale (SUS) and the Center for Healthcare Evaluation Provider Satisfaction Questionnaire (CHCE-PSQ). We enrolled BRCA1/2 mutation carriers who were seen by local physicians or participating in a national advocacy organization, and we enrolled clinicians practicing at Stanford University and in the surrounding community. Forty BRCA1/2 mutation carriers and 16 clinicians participated. Both groups found the tool easy to use, with SUS scores of 82.5–85 on a scale of 1–100; we did not observe differences according to patient age or gene mutation. General satisfaction was high, with a mean score of 4.28 (standard deviation (SD) 0.96) for patients, and 4.38 (SD 0.89) for clinicians, on a scale of 1–5. Most patients (77.5 %) were comfortable using the tool at home. Both patients and clinicians agreed that the decision tool could improve patient–doctor encounters (mean scores 4.50 and 4.69, on a 1–5 scale). Patients and health care providers rated the decision tool highly on measures of usability and clinical relevance. These results will guide a larger study of the tool’s impact on clinical decisions.

The prevalence and penetrance of BRCA1 and BRCA2 (BRCA1/2) mutations may differ between Asians and whites. We investigated BRCA1/2 mutations and cancer risk factors in a clinic-based sample. BRCA1/2 mutation carriers were enrolled from cancer genetics clinics in Hong Kong and California according to standardized entry criteria. We compared BRCA mutation position, cancer history, hormonal and reproductive exposures. We analyzed DNA samples for single-nucleotide polymorphisms reported to modify breast cancer risk. We performed logistic regression to identify independent predictors of breast cancer. Fifty Asian women and forty-nine white American women were enrolled. BRCA1 mutations were more common among whites (67 vs. 42 %, p = 0.02), and BRCA2 mutations among Asians (58 vs. 37 %, p = 0.04). More Asians had breast cancer (76 vs. 53 %, p = 0.03); more whites had relatives with breast cancer (86 vs. 50 %, p = 0.0003). More whites than Asians had breastfed (71 vs. 42 %, p = 0.005), had high BMI (median 24.3 vs. 21.2, p = 0.04), consumed alcohol (2 drinks/week vs. 0, p

Purpose Women with BRCA1 or BRCA2 (BRCA1/2) mutations must choose between prophylactic surgeries and screening to manage their high risks of breast and ovarian cancer, comparing options in terms of cancer incidence, survival, and quality of life. A clinical decision tool could guide these complex choices. Methods We built a Monte Carlo model for BRCA1/2 mutation carriers, simulating breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years and prophylactic mastectomy (PM) and/or prophylactic oophorectomy (PO) at various ages. Modeled outcomes were cancer incidence, tumor features that shape treatment recommendations, overall survival, and cause-specific mortality. We adapted the model into an online tool to support shared decision making. Results We compared strategies on cancer incidence and survival to age 70 years; for example, PO plus PM at age 25 years optimizes both outcomes (incidence, 4% to 11%; survival, 80% to 83%), whereas PO at age 40 years plus MRI screening offers less effective prevention, yet similar survival (incidence, 36% to 57%; survival, 74% to 80%). To characterize patients' treatment and survivorship experiences, we reported the tumor features and treatments associated with risk-reducing interventions; for example, in most BRCA2 mutation carriers (81%), MRI screening diagnoses stage I, hormone receptor-positive breast cancers, which may not require chemotherapy. Conclusion Cancer risk-reducing options for BRCA1/2 mutation carriers vary in their impact on cancer incidence, recommended treatments, quality of life, and survival. To guide decisions informed by multiple health outcomes, we provide an online tool for joint use by patients with their physicians ( http://brcatool.stanford.edu ).

Background Prior research suggests that the prevalence and penetrance of BRCA1/2 mutations may be different in Asians compared with Caucasians. Such differences in penetrance could be related to genetic, as well as hormonal, reproductive and lifestyle factors. Methods: Chinese and Caucasian BRCA1/2 mutation carriers were recruited from genetics clinics in Hong Kong and California. We compared personal and family history of cancer, as well as hormonal, reproductive and lifestyle exposures between racial groups. Breast density was estimated using BIRADS breast composition categories on mammogram. We analyzed DNA samples for single-nucleotide polymorphisms (SNPs) that may modify BRCA-associated cancer risk, and compared the prevalence between groups. A multivariable analysis of potential modifiers of cancer risk is underway. Results: Forty-two Chinese women from Hong Kong and forty-nine Caucasian women from California were enrolled. BRCA1 mutations were more common in Caucasian women (63% vs. 43%, P=0.05), while BRCA2 mutations were more common among Chinese women (57% vs. 33%, P=0.02). More Chinese women had a personal history of breast cancer (91% vs. 53%) and ovarian cancer (12% vs. 4%). In contrast, significantly more Caucasian women had a family history of breast and ovarian cancer. On average, Caucasian women had higher parity, breastfed more, had less dense breasts on mammogram, and more often underwent prophylactic oophorectomy, all of which are protective against breast cancer in the general population. However, Caucasian women also consumed more alcohol and had higher average BMI. Risk associated alleles in RAD51, MAP3K1 and TOX3/TNRC9 were more common in Chinese women; risk associated alleles in FGFR2 and RASSF1 were similar in frequency between groups. Results of the multivariable analysis are pending and will be presented. Discussion: We found notable differences between Chinese and Caucasian women in the proportion of BRCA1 versus BRCA2 mutations, and in the distribution of hormonal, reproductive and lifestyle factors, and SNPs associated with breast cancer risk. Such variations in risk-modifying factors may contribute to differences in BRCA mutation penetrance. Enhanced understanding of racial differences in BRCA1/2 mutation epidemiology may inform targeted cancer screening and prevention strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-10.

Background The combination of gemcitabine, platinum and inhibition of DNA repair results in synergistic chemosensitivity in triple-negative and BRCA1-deficient breast cancer cell lines. This study was designed to assess efficacy, safety and predictors of response to iniparib, a small molecule whose mechanism of action is under investigation, in combination with GC in early-stage triple-negative and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled patients with clinical stage I-IIIA (T ≥1cm by MRI) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and HER2−negative or BRCA1/2 mutation-associated BC. Neoadjuvant gemcitabine (1000 mg/m2; IV; D1, 8), carboplatin (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles with enrollment of 36 patients. The protocol was further amended to increase the patient number with expansion to additional centers. Prior to expansion, reporting of interim safety and efficacy results was specified. The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive carcinoma in the breast and axilla. Pathologic response was assessed using the residual cancer burden (RCB) index. Secondary endpoints included safety, radiographic response by MRI, breast conservation eligibility and correlation of baseline gene expression with response. Results: The pre-expansion cohort consisted of 13 patients assigned to 4 cycles of treatment and 36 patients assigned to 6 cycles of treatment. Among these 49 patients (50 tumors), median tumor size is 35 mm, and median age is 48 years. The overall pCR rate is 34% (95% CI = 22–48); the pCR rate at 6 cycles is 41% (95% CI = 26–57). RCB 0/I was observed in 5/13 pts (38%; 95% CI = 18–64) treated with 4 cycles; 21/37 (57%; 95% CI = 41–71) treated with 6 cycles; and 9/9 pts (100%) with known BRCA1/2 mutations. Two pts experienced disease progression, two locoregional relapse, and three distant relapse. Among 45 tumors with Affymetrix-based RNA microarray gene expression data, 39/45 (87%) are classified as basal-like, 3/45 (7%) luminal B, and 3/45 (7%) normal breast-like. Most common G3/4 adverse events include neutropenia (31%), anemia (10%), and elevated ALT/AST (10%). Alopecia and chemotherapy-induced amenorrhea were uncommon. Analyses of secondary endpoints are ongoing and will be presented. Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-08.

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 ...

To the Editor: For women who inherit a high risk of developing breast cancer, early detection is a key strategy to reduce morbidity and mortality (1). Multiple studies have found that standard mammographic screening often fails to detect breast cancer early in women at high inherited risk of breast cancer, prompting inclusion of emerging methods such as magnetic resonance imaging (MRI) into high-risk screening protocols (2– 13). The evaluation of breast duct cells is also under investigation as a potential cancer risk assessment technique. Approximately 80 percent of breast cancers originate in the ductal system, and early changes of the ductal epithelium, which might predate malignant transformation, have been reported (14–16); for these reasons, analysis of duct cells is a rational approach to risk stratification and biomarker development. At this time, understanding of the normal breast ductal anatomy, including an appreciation of variation in the number of ducts per breast, continues to evolve (17). A prior anatomic study on mastectomy specimens has also reported wide variation in the proportion of breast volume drained by individual ducts (18). With increasing study of intraductal approaches, a better comprehension of ductal structure and the appearance of the ductal system on MRI has practical relevance. We undertook a pilot study of a novel technique, magnetic resonance (MR) galactography, which combines MRI and intraductal evaluation. Our goals were to map the breast ductal system, quantify the breast volume drained by individual ducts, and evaluate sources of prior cytologic atypia in high-risk women.

Background Women with mutations in the BRCA1 or BRCA2 cancer susceptibility genes face unique choices regarding management of their high risk for breast and ovarian cancer that impact their reproductive options. In order to explore women’s preferences for management of elevated cancer risk, we evaluated the decisions of BRCA1/2 mutation carriers about contraception, prophylactic surgery, and family planning. Methods An internet-based questionnaire assessing high-risk women’s preferences about cancer risk management and reproductive options was designed, pilot-tested and administered electronically to 284 participants of an internet-based advocacy group for women with BRCA1/2 mutations. Results Two hundred and thirteen eligible participants completed the majority of the survey. Mean age was 34 years; 66% were BRCA1 mutation carriers and 34% were BRCA2 mutation carriers. Most women (92%) had used oral contraceptive pills. About 88% of responders reported frequent or extreme worry about transmitting the mutation to their children. Despite their high level of worry, few responders said they would likely consider using assisted reproduction technologies such as a pregnancy surrogate (3%), cryopreservation of oocytes or embryos (8%), or pre-implantation genetic diagnosis (PGD) to select embryos without BRCA1/2 mutations (13%). Conclusions Although they expressed substantial concern about transmitting BRCA1/2 mutations to their children, only a minority of the high-risk women surveyed were likely to consider currently available assisted reproductive strategies. Further research is necessary to explore the risk management preferences of patients with inherited cancer predisposition, and to incorporate these preferences into clinical care.

Our purpose is to describe the appearance of breast ductal enhancement found on magnetic resonance imaging (MRI) after breast ductal lavage (DL). We describe a novel etiology of enhancement in a ductal pattern on postcontrast MRI of the breast. Knowledge of the potential for breast MRI enhancement subsequent to DL, which can mimic the appearance of a pathologic lesion, is critical to the care of patients who undergo breast MRI and DL or other intraductal cannulation procedures.

Importance The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown. Objective To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort. Design, setting, and participants Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations. Interventions We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals. Main outcomes and measures We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history. Results Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients. Conclusions and relevance In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.

1528 Background: Next-generation sequencing technology enables more comprehensive germline genetic testing, including genes whose cancer risks are less well-characterized (particularly among patients with less striking family histories). Little is known about patient outcomes, particularly adherence to risk-reducing recommendations and family testing. Methods: We attempted a phone interview ≥3 times with each adult patient who had a germline pathogenic or likely pathogenic mutation found in an emerging cancer gene (defined as any gene other than BRCA1/2 or the Lynch Syndrome genes MLH1, MSH2/6, PMS2) at a single academic cancer genetics clinic from January 2013-July 2016. Results: Of 143 eligible patients, 53 (37%) were successfully contacted and all consented to participate. Median follow-up was 677 days (range 247–1401) and age was 52 years (21-82). Two-thirds (68%) had personal cancer history and 93% had a first-degree relative with cancer. Mutations in genes associated with named syndromes ( APC=5 , CDH1=3 , TP53=3, PTEN=2) were found in 23% (many of whom lacked family history typical of these syndromes) whereas 77% had mutations in less well-characterized genes ( MYH=10, CHEK2=10, ATM=6, PALB2=6 , NBN=3, RAD51C=2, RAD51D=2, SDHB=1, CDKN2A=1, MRE11A=1, RAD50=1, FLCN=1). Conclusions: Two years after panel testing, patients with germline mutations in less well-characterized genes reported high rates of adherence to recommendations, family communication and testing. Limitations include a relatively low response rate and a single academic center; this may bias toward a “best-case” scenario. Larger, population-based studies will be crucial to understand the real-world outcomes of germline multiple-gene panel testing and its contribution to precision oncology. [Table: see text]

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.

1523 Background: Mutation carrier prediction models are clinically useful tools for identifying candidates for genetic counseling and testing. Consensus guidelines recommend germline genetic testing for those with a carrier probability (CP) of approximately 5% or higher. However, prediction models may perform less well among racial/ethnic minorities. Our hypothesis is that pathogenic mutations (PM) are identifiable in a clinically meaningful fraction of racially/ethnically diverse patients with a CP of < 5%. Methods: We conducted a multicenter prospective clinical trial of patients undergoing cancer-risk assessment using a 25 gene panel, which include 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 recruited from August 2014 to November 2016 at three centers. Patients were enrolled if they met standard clinical criteria for genetic testing or were predicted to have a ≥2.5% probability of inherited cancer susceptibility using validated prediction models. We evaluated the CP of patients with a PM in BRCA1, BRCA2, and/or a mismatch repair (MMR) gene using the following models: (1) BRCApro, (2) MMRpro and (3) PREMM1,2,6. Results: Of 2000 patients enrolled in this cohort, 80.6% are female (n = 1612). Regarding race/ethnicity, the cohort is 40.1% Non-Hispanic White (n = 802), 37.4% Hispanic (n = 748), 11.5% Asian (n = 230), 3.9% Black (n = 78), and 7.1% Other (n = 142). Among 241 (12.1%) patients who tested positive for a pathogenic mutation, 76 (31.5%) patients had a BRCA1 or BRCA2 mutation. Of those, 52 (68.4%) patients had a BRCApro CP of < 5%. Thirty-eight (15.8%) patients had a pathogenic mutation in an MMR gene: 19 (50.0%) had an MMRpro CP of < 5%, while 13 (34.2%) had a PREMM1,2,6 CP of < 5%. The racial/ethnic distribution of BRCA1/2 or MMR mutation carriers is similar to that of the whole cohort. Conclusions: In a diverse cohort of patients undergoing 25-gene multiple-gene panel testing, half or more carriers of BRCA1/2 or MMR mutations had a CP of < 5%, the consensus guideline-recommended cutoff for genetic testing. These results support a lower threshold for genetic testing guidelines. Clinical trial information: NCT02324062.

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 Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample. Methods Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at −80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants. Results In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes. Conclusion Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

While reports of long bone fracture repair in new world camelids are limited, clinical cases are more frequently encountered. Options from repair have been similar to those chosen for small ruminants. The use of an interlocking intramedullary nail for a comminuted mid-diaphyseal femoral fracture proved to be successful. Based on the relatively straight and narrow shape of the femur of new world camelids and the results of this case, the interlocking intramedullary nail may be a suitable option for long bone fracture repair in these species.

Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9–74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1–38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0–25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5–34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

Background: Multiple-gene germline sequencing panels are increasingly used to evaluate hereditary cancer risk. However, little is known about the results of such testing in racially/ethnically diverse populations. Methods: Patients who presented to the Stanford University Clinical Cancer Genetics Program from 1/1/2013 to 12/31/2015 and underwent multiple-gene panel testing were included in the cohort (N=1,483). Information on demographics, personal and family history of cancer, and tumor characteristics was collected at time of clinic visit. Odds ratios and 95% confidence intervals were calculated for mutation status by different patient and tumor characteristics, including race/ethnicity. Results were compared using the chi-square test and considered significant if P Results: Most patients (92%) were female. Patients were 51% Non-Hispanic White (NHW), 19% Asian, 14% Hispanic, 10% Ashkenazi Jewish, 5% other, and 1% unknown. Eighty-nine genes were tested in at least one patient; panel size ranged from six to 62 genes, with a median of 25 genes. The frequency of pathogenic or likely pathogenic mutations was 15% for any panel-tested gene, 5.5% for BRCA1/2, and 5.3% for other breast cancer-associated genes; mutation frequencies were similar between NHW, Asian, Hispanic, and Ashkenazi Jewish patients. Variables significantly associated with the carriage of a pathogenic BRCA1/2 mutation included personal or family history of ovarian cancer and personal history of triple-negative breast cancer (TNBC). No variable was significantly associated with the presence of a pathogenic mutation in the other breast cancer genes. The odds ratios for carrying a BRCA1/2 mutation with personal history of ovarian cancer (4.1 [2.2-7.3]), family history of ovarian cancer (3.1 [1.9-4.9]), and TNBC relative to other breast cancer subtypes (6.0 [2.9-12.4]) did not differ significantly between NHWs and non-Whites. The frequency of variants of unknown significance (VUS) in any panel-tested gene was higher in non-Whites (36%) than in NHWs (27%) (P=2E-4), with the highest odds ratio relative to NHWs among Asians (2.0 [1.5-2.7], vs 1.3 [0.9-1.7] among Hispanics and 1.2 [0.8-1.7] among Ashkenazi Jews). The odds ratio of finding a VUS for non-Whites compared to NHWs was similar for any panel (1.5 [1.2-1.9]), for BRCA1/2 (1.3 [0.8-2.3]), and for other known breast cancer-associated genes (1.5 [1.1-1.9]). Conclusions: In this diverse cohort tested for hereditary cancer risk with multiple-gene panels, frequencies of pathogenic mutations were similar between racial/ethnic groups. By contrast, frequencies of VUS were significantly higher among non-Whites compared to NHWs. This higher VUS rate renders multiple-gene panel testing less informative for non-White patients. Efforts toward VUS re-classification, particular among non-Whites, are urgently needed to address this genetic information disparity. Citation Format: Caswell-Jin* JL, Gupta* T, Hall E, Petrovchich IM, Mills MA, Kingham KE, Koff R, Chun NM, Levonian P, Lebensohn AP, Ford JM, Kurian AW. Multiple-gene panel testing for hereditary cancer risk reveals a racial/ethnic disparity in genetic information [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 PD8-06.

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...

PurposeThere are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.Patients and MethodsWe evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.ResultsBRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P ≥ .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P ≤ 3 × 10−7). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 × 10−30); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.ConclusionBoth BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

Background: Emerging evidence demonstrates the effectiveness of targeted gene sequencing panels as a practical method for the diagnosis of inherited susceptibility to breast cancer. Sequencing of multiple high and moderate risk genes simultaneously accelerates the discovery of deleterious mutations (DM) or variants of unknown significance (VUS). However, a consequence of Multiplex Gene Panel (MGP) testing is the discovery of unexpected DMs in high or moderate risk genes other than BRCA1 or BRCA2 (BRCA1/2). The overall clinical utility and incremental gain of information conferred by MGP testing in hereditary cancer risk assessment is still unknown. Methods: We are conducting a multicenter prospective cohort study of patients undergoing cancer-risk assessment using a 25 gene sequencing panel, which includes APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Patients were recruited from August 2014 to June 2015 at three medical centers. Patients are enrolled if they meet standard criteria for genetic testing or are predicted to have a ≥ 2.5% probability of inherited susceptibility to cancer calculated by validated risk prediction models. We present a planned interim analysis after enrolling 500 of 2000 total participants. Results: HCP testing was performed for 332 patients referred for clinical suspicion of hereditary breast and ovarian cancer (HBOC). In this cohort, 96.7% were female (n=321) and the mean age was 50 years (standard deviation, SD=12.2); race/ethnicity was 43.1% Hispanic (n=143), 37% Non-Hispanic White (n=123), 4.2% Black (n=14), 10.5% Asian (n=35), and 1.8% other (n=6). Among this cohort, 37 tested positive for one deleterious mutation (DM) (11.1%: 95% confidence interval (CI), 8.2% to 15%) and 118 patients carried at least one variant of uncertain significance (VUS) (35.5%: 95% CI, 30.6% to 69%). Excluding BRCA1 or BRCA2, 14 patients (4.3%: 95% CI, 2.6% to 7.2%) have a DM in ATM (n=3), CHEK2 (n=2), MSH6 (n=1), MUTYH (n=3), PALB2 (n=1), PMS2 (n=1), RAD51C (n=2), and TP53 (n=2). In a patient with an unexpected PMS2 mutation, enhanced cancer surveillance based on Lynch Syndrome guidelines was recommended. Among 160 patients with a history of invasive breast cancer or breast DCIS, 19 patients carried a DM (11.8 %: 95 CI, 7.7% to 17.8%). Conclusion: In this multicenter prospective cohort study among a diverse group of participants undergoing 25-gene MGP testing, 11.1% of participants tested positive for a DM. Among participants testing negative for BRCA1 and BRCA2, MGP testing identified DMs in 4.3% of participants prompting clinically appropriate risk reduction recommendations and enhanced cancer surveillance. Ongoing recruitment and long-term follow-up are in progress. Citation Format: Idos GE, Kurian AW, Mcdonnell KJ, Ricker CN, Sturgeon DY, Culver JO, Lowstuter K, Hartman A-R, Allen B, Teeter C-R, Kingham KE, Koff R, Lebensohn A, Chun NM, Mills MA, Petrovchich I, Hong C, Ladabaum U, Ford JM, Gruber SB. Interim analysis of multiplex gene panel testing for inherited susceptibility to breast cancer. [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 PD7-01.

Background The practice of genetic testing is rapidly evolving with the recent introduction of multi-gene panels. While the prevalence of non-BRCA1/2 mutations in HBOC patients is now well documented, the clinical impact of these findings is not yet fully understood. Objectives We sought to measure how often and in which ways non-BRCA1/2 findings might change patient management recommendations in a representative clinical cohort. Design/method We used similar 25 or 29 gene panels to test over 1000 BRCA1/2-negative patients, all of whom were enrolled prospectively at three academic medical centres and all met NCCN guidelines for HBOC evaluation. We established a uniform algorithm based on current practice guidelines to recommend management actions for the non-BRCA1/2 positive individuals, and we evaluated which of these recommendations would represent changes in management above and beyond any recommendations based on personal and family history alone. Results 63 patients were identified with pathogenic or likely pathogenic mutations in non-BRCA1/2 genes. We found that the majority of these findings (52%) would result in consideration of additional screening and/or prevention measures for the patient. Moreover, we found that genetic testing of 70% of first-degree family members would also be warranted given the potential management changes in these individuals if found to be mutation positive. Conclusions In appropriately referred patients, multi-gene panel testing yields clinically relevant findings with potential management impact for more patients than does BRCA1/2 testing alone.

1513 Background: Genetic testing for hereditary breast and ovarian cancer is evolving with the recent introduction of multi-gene panels, although the clinical impact of such panels is as yet poorly...

Objective Prophylactic mastectomy (PM) is often considered, but variably chosen by women at high inherited risk of breast cancer; few data exist on patient tolerance of intensive breast screening as an alternative to PM. We performed an evaluation of high-risk women's tolerance of a breast screening protocol using clinical breast examination, mammography, breast magnetic resonance imaging (MRI) and ductal lavage (DL), and of change in attitudes toward PM after screening. Design A questionnaire assessing tolerance of screening procedures and change in opinion towards PM was designed and administered to 43 study participants, after a median follow-up of 13 months. Responses were evaluated according to patient characteristics, including type of study-prompted interventions, BRCA mutation status, and prior history of cancer, via univariate analysis. Results Most patients [85.3% (68.9–95.1%)] were more opposed or unchanged in their attitudes towards PM after study participation, with only 14.7% (5.0–31.1%) less opposed (P = 0.017) despite a short-interval follow-up MRI rate of 71.7% and a biopsy rate of 37%. Lower rates of maximal discomfort were reported with mammogram [2.8% (0–14.5%)] and MRI [5.6% (0–18.7%)] than with DL [28.6% (14.6–46.3%)], with P = 0.035. Conclusions Most high-risk women tolerated intensive breast screening well; they were not more inclined towards PM after participating. Future studies should prospectively evaluate larger numbers of high-risk women via multivariate analysis, to determine characteristics associated with preference for breast screening vs. PM.

Objective: Nipple fluid production and atypical breast duct cells in women at high risk of breast cancer have been associated with further increased risk. Most publications on ductal lavage for cell collection report cannulating fluid-yielding ducts only. We report lavage of fluid-yielding and non–fluid-yielding ducts in women at high inherited breast cancer risk. Methods: A pilot breast cancer screening study including ductal lavage was conducted in 75 women at high inherited risk, 56 (74.7%) of whom had BRCA1/2 mutations. Ductal lavage was attempted in any duct identifiable with a catheter. Results: Ducts were successfully catheterized in 60 of 75 patients (80%). Successfully catheterized patients were younger (median age 41 versus 53 years, P = 0.0003) and more often premenopausal (51.7% versus 20%, P = 0.041). Thirty-one successfully catheterized patients [51.6%, 95% confidence interval (39.4-63.9%)] had non–fluid-yielding ducts only. Seventeen patients [28.3% (18.5-40.9%)] had atypical cells. Twelve of seventeen [70.6% (46.8-87.2%)] samples with atypia were from non–fluid-yielding ducts. Patients with non–fluid-yielding ducts (versus fluid-yielding ducts) were more likely to have had prior cancer (48.4% versus 17.2%, P = 0.014) or chemotherapy (45.2% versus 17.2%, P = 0.027); this was also true in patients with atypia from non–fluid-yielding ducts. Conclusion: Successfully lavaged women were younger and more often premenopausal. Atypical cells can be found in non–fluid-yielding ducts in patients at high inherited breast cancer risk. Non–fluid-yielding ducts, and atypia from non–fluid-yielding ducts, are more common in patients with prior cancer and chemotherapy. Larger studies are needed to identify risk factors and prognostic significance associated with atypia and non–fluid-yielding ducts in high-risk populations, and define their role as biomarkers.

7 Background: Multiple-gene sequencing panels are entering clinical practice. We report on research testing with a custom sequencing panel comprising 43 genes and 32 cancer-associated variants among patients referred for assessment of hereditary breast and ovarian cancer risk. Methods: Patients referred to the Stanford Cancer Genetics Program for clinical BRCA1 and BRCA2 (BRCA1/2) mutation testing from 2002-2012 were invited to donate a blood sample for research on an Institutional Review Board-approved protocol. Blood samples were frozen at -80 degrees, and DNA extracted after

9535 Background: Atypical breast duct cells in patients at increased risk of breast cancer have been predictive of subsequent breast cancer. It has been reported that women whose breasts yield no f...