Cross-sectional clinical cancer genomics community of practice survey analysis of provider attitudes and beliefs regarding the use of deceased family member tissue to guide living family member genetic cancer risk assessment.

Next-generation tumor tissue sequencing techniques may result in the detection of putative germline pathogenic variants (PVs), raising the possibility that germline cancer predisposition could be identified from archival medical tissue samples of deceased relatives. The approach, termed traceback, is designed to inform risk management recommendations for living family members. Provider perspectives regarding traceback testing have not yet been explored, so we conducted a cross-sectional survey of Clinical Cancer Genomics Community of Practice providers regarding their attitudes and beliefs toward traceback testing. Self-reported demographics, provider characteristics, attitudes and perceived barriers were collected. We evaluated responses in the context of whether providers had previous experience with traceback testing. Data were analyzed using chi-square and Fisher's exact testing. Among 207 respondents (of 816 eligible), most were women (89.4%), white (85.5%), and not Hispanic or Latino (89.7%). US-based providers represented the majority of respondents (87.4%). Relatively, few providers 32 of 207 (15.5%) had previous experience with traceback. Among the individuals without experience in traceback, 84.0% thought there would be barriers to implementation; however, only 68.8% of individuals with previous traceback experience agreed (p = .04). Respondents in both groups thought that traceback would be valuable in their practice (82.6%, p = .22) and that they would feel comfortable discussing the concept (83.6%, p = .83), interpreting the results (72.2%, p = .24), and discussing the results with their patients (80.7%, p = .38). Patient interest and cost were seen as less of a barrier by those with experience with traceback testing. Recurrent themes obtained in open-ended responses are also presented. Overall, providers believe that traceback would be a valuable tool in their practice. Individuals with previous experience identified less barriers with implementation of this testing, highlighting an area for future research and education.

Germline mutations and age at onset of lung adenocarcinoma.

BACKGROUND: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. METHODS: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. RESULTS: Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. CONCLUSIONS: Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

BACKGROUND: Breast cancer (BC) is the most common cancer and related cause of mortality among Hispanics, yet susceptibility has been understudied. BRCA1 and BRCA2 (BRCA) mutations explain less than one-half of hereditary BC, and the proportion associated with other BC susceptibility genes is unknown. METHODS: Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53). RESULTS: Forty-nine (4.6%) pathogenic or likely pathogenic variants (PVs) in 47 of 1054 participants (4.5%), including 21 truncating frameshift, 20 missense, 5 nonsense, and 4 splice variants, were identified in CHEK2 (n = 20), PALB2 (n = 18), ATM (n = 5), TP53 (n = 3), BRIP1 (n = 2), and CDH1 and NF1 (both n = 1) and none were identified in NBN, PTEN, STK11, RAD51C, or RAD51D. Nine participants carried the PALB2 c.2167_2168del PV (0.85%), and 14 carried the CHEK2 c.707T>C PV (1.32%). CONCLUSIONS: Of 1054 BRCA-negative, high-risk Hispanic women, 4.5% carried a PV in a cancer susceptibility gene, increasing understanding of hereditary BC in this population. Recurrent PVs in PALB2 and CHEK2 represented 47% (23 of 49) of the total, suggesting a founder effect. Accurate classification of variants was enabled by carefully controlling for ancestry and the increased identification of at-risk Hispanics for screening and prevention.

Do Neighborhood Demographics Modify Walking Group Intervention Effectiveness in Urban Neighborhoods?

OBJECTIVES: We assessed the effects of neighborhood composition on effectiveness of the Walk Your Heart to Health (WYHH) intervention in promoting physical activity and reducing cardiovascular risk (CVR) in low-to-moderate-income, predominantly non-Latino Black (NLB) and Latino communities. METHOD: Multilevel models assessed modifying effects of neighborhood composition on (1) WYHH adherence/participation at 8 weeks and 32 weeks, (2) associations between participation and steps, and (3) associations between steps and CVR. RESULTS: Approximately 90% of participants were women. Neither neighborhood poverty nor racial composition modified intervention participation at 8 weeks. At 32 weeks, residents of high percentage-NLB neighborhoods that also had high poverty rates had reduced participation. Neighborhood composition did not modify associations between participation and steps or between steps and CVR. Neighborhood percentage poverty and NLB were positively associated with CVR. CONCLUSION: Positive associations between participation in the WYHH program and physical activity, and CVR did not differ by neighborhood composition. Efforts to address challenges to long-term participation are warranted for residents of racially segregated, high-poverty neighborhoods. Residents of racially segregated neighborhoods with high concentrations of poverty experience disproportionately high risk for cardiovascular disease and can benefit from interventions such as WYHH that increase physical activity and reduce CVR.

Multi-directional communication between decision makers and environmental health researchers: a qualitative inquiry.

It has been three decades since key leaders gathered to pave a path toward healthier and more just environments and recommendations were made to improve communication between scientists and community stakeholders who can influence decision making. Since that time, community engaged research has flourished while building the capacity of researchers to engage in the work of making change to those environments has lagged. The purpose of this study was the development of guidelines to inform interactions between researchers and decision makers and influencers who participate in the policy change process. This community engaged, pragmatic and iterative inquiry includes insight from a review of existing resources and key informant interviews. Resulting guidelines were piloted, and formative evaluation by community stakeholders informed and resulted in refinement to the guidelines. Strategies for communicating and disseminating scientific evidence are presented as well as tactics that sensitise researchers to the nuances of policy makers' realities so they may serve as a resource for dealing with complex information and decisions. We provide tactics and archived resources in an on-line toolkit that we have cultivated over time to foster effective communication between scientists and those who have a stake in ensuring that decisions are evidence informed.

Inter-rater reliability of the food environment audit for diverse neighborhoods (FEAD-N).

Studies have shown that neighborhood food environments are important influences on dietary intake and may contribute to health disparities. While instruments with high reliability have been developed to assess food availability, price, and quality, few measures to assess items associated with the physical and social features of food stores have been developed. Yet, recent qualitative studies have documented aspects associated with such features of urban food stores that are barriers to food acquisition. We assessed the reliability of measures to assess multiple components of the food environment-including physical and social store features--in three geographically distinct and diverse communities in Detroit, Michigan, using the Food Environment Audit for Diverse Neighborhoods (FEAD-N). Using the FEAD-N, four trained observers conducted observations of 167 food stores over a 10-week period between October and December 2008. To assess inter-rater reliability, two trained observers independently visited, on the same day, a random subset of 44 food stores. Kappa statistics and percent agreement were used to evaluate inter-rater reliability. Overall, the instrument had mostly high inter-rater reliability with more than 75% of items with kappa scores between 0.80 and 1.00, indicating almost perfect reliability. More than half of the physical store features and 47% of the social store features had almost perfect reliability and about 37% and 47%, respectively, had substantial reliability. Measuring factors associated with the physical and social environment of food stores with mostly high reliability is feasible. Systematic documentation of the physical and social features of food stores using objective measures may promote a more comprehensive understanding of how neighborhood food environments influence health.

Closing the loop: action research in a multimodal hereditary cancer patient conference is an effective tool to assess and address patient needs.

This paper describes the use of action research in a patient conference to provide updated hereditary cancer information, explore patient and family member needs and experiences related to genetic cancer risk assessment (GCRA), elicit feedback on how to improve the GCRA process, and inform future research efforts. Invitees completed GCRA at City of Hope or collaborating facilities and had a BRCA mutation or a strong personal or family history of breast cancer. Action research activities were facilitated by surveys, round table discussions, and reflection time to engage participants, faculty, and researchers in multiple cycles of reciprocal feedback. The multimodal action research design effectively engaged conference participants to share their experiences, needs, and ideas for improvements to the GCRA process. Participants indicated that they highly valued the information and resources provided and desired similar future conferences. The use of action research in a patient conference is an innovative and effective approach to provide health education, elicit experiences, identify and help address needs of high-risk patients and their family members, and generate research hypotheses. Insights gained yielded valuable feedback to inform clinical care, future health services research, and continuing medical education activities. These methods may also be effective in other practice settings.

Clonal Hematopoiesis and Mosaicism Revealed by a Multi-Tissue Analysis of Constitutional TP53 Status.

BACKGROUND: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management. METHODS: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. RESULTS: Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases. CONCLUSIONS: We demonstrated an effective approach and tools for discerning germline TP53 status. IMPACT: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.

Development and evaluation of a decision aid for BRCA carriers with breast cancer.

BRCA+ breast cancer patients face high risk for a second breast cancer and ovarian cancer. Helping these women decide among risk-reducing options requires effectively conveying complex, emotionally-laden, information. To support their decision-making needs, we developed a web-based decision aid (DA) as an adjunct to genetic counseling. Phase 1 used focus groups to determine decision-making needs. These findings and the Ottawa Decision Support Framework guided the DA development. Phase 2 involved nine focus groups of four stakeholder types (BRCA+ breast cancer patients, breast cancer advocates, and genetics and oncology professionals) to evaluate the DA's decision-making utility, information content, visual display, and implementation. Overall, feedback was very favorable about the DA, especially a values and preferences ranking-exercise and an output page displaying personalized responses. Stakeholders were divided as to whether the DA should be offered at-home versus only in a clinical setting. This well-received DA will be further tested to determine accessibility and effectiveness.

A community-based participatory planning process and multilevel intervention design: toward eliminating cardiovascular health inequities.

The elimination of persistent health inequities requires the engagement of multiple perspectives, resources, and skills. Community-based participatory research (CBPR) is one approach to developing action strategies that promote health equity by addressing contextual as well as individual-level factors, and that can contribute to addressing more fundamental factors linked to health inequity. Yet many questions remain about how to implement participatory processes that engage local insights and expertise, are informed by the existing public health knowledge base, and build support across multiple sectors to implement solutions. This article describes a CBPR approach used to conduct a community assessment and action planning process, culminating in development of a multilevel intervention to address inequalities in cardiovascular disease in Detroit, Michigan. The authors consider implications for future efforts to engage communities in developing strategies toward eliminating health inequities.

Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer.

Women with triple negative breast cancer (TNBC) have a high prevalence of BRCA1 mutations, and current clinical guidelines recommend genetic testing for patients with TNBC aged ≤60 years. However, studies supporting this recommendation have included few older women with TNBC. METHODS: Genetic testing results from women aged >60 years with TNBC enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry were included in this analysis. Prevalence of breast cancer-associated pathogenic variants (PVs) was compared across age groups. RESULTS: We identified 151 women with TNBC aged >60 years (median 65 years; SD 5.3). Of these, 130 (86%) underwent genetic testing, and a breast cancer-associated PV was identified in 16 (12.3%; 95% CI 7-19): BRCA1 (n = 6), BRCA2 (n = 5), PALB2 (n = 2), ATM (n = 1) and RAD51C (n = 2). We found no differences in the proportion of patients with close blood relatives with breast (≤50 years) or ovarian cancer (any age) between PV carriers (37.5%) and non-carriers (34.2%) (p = 0.79). Among PV's carriers, the proportion of older women with a BRCA1 PV was lower when compared to younger women (37.5% vs 77.2%; p < 0.01). CONCLUSION: Breast cancer-associated PVs were found in an important proportion of women aged >60 years with TNBC undergoing genetic testing, including greater representation of BRCA2. These results suggest that older women with TNBC should be offered genetic testing, and that their exclusion based on chronologic age alone may not be appropriate.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition.

BACKGROUND: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. METHODS: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. RESULTS: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized. CONCLUSIONS: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications. IMPACT: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.

The Burden of Breast Cancer Predisposition Variants Across The Age Spectrum Among 10 000 Patients.

BACKGROUND/OBJECTIVES: Women diagnosed with breast cancer (BC) at an older age are less likely to undergo genetic cancer risk assessment and genetic testing since the guidelines and referrals are biased toward earlier age at diagnosis. Thus, we determined the prevalence and type of pathogenic cancer predisposition variants among women with a history of BC diagnosed at the age of 65 years or older vs younger than 65 years. DESIGN: Prospective registration cohort. SETTING: The Clinical Cancer Genomics Community Research Network, including 40 community-based clinics in the United States and 5 in Latin America. PARTICIPANTS: Women with BC and genetic testing results. MEASUREMENTS: Sociodemographic characteristics, clinical variables, and genetic profiles were compared between women aged 65 years and older and those younger than 65 years at BC diagnosis. RESULTS: Among 588 women diagnosed with BC and aged 65 years and older and 9412 diagnosed at younger than 65 years, BC-associated pathogenic variants (PVs) were detected in 5.6% of those aged 65 years and older (n = 33) and 14.2% of those younger than 65 years (n = 1340) (P < .01). PVs in high-risk genes (eg, BRCA1 and BRCA2) represented 81.1% of carriers among women aged 65 years and older (n = 27) and 93.1% of those younger than 65 years (n = 1248) (P = .01). BRCA2 PVs represented 42.4% of high-risk gene findings for those aged 65 years and older, whereas BRCA1 PVs were most common among carriers younger than 65 years (49.7%). PVs (n = 7) in moderate-risk genes represented 21.2% for carriers aged 65 years and older and 7.3% of those younger than 65 years (n = 98; P < .01). CHEK2 PVs were the most common moderate-risk gene finding in both groups. CONCLUSION: Clinically actionable BC susceptibility PVs, particularly in BRCA2 and CHEK2, were relatively prevalent among older women undergoing genetic testing. The significant burden of PVs for older women with BC provides a critical reminder to recognize the full spectrum of eligibility and provide genetic testing for older women, rather than exclusion based on chronological age alone. J Am Geriatr Soc 67:884-888, 2019.

Influence of genetic discrimination perceptions and knowledge on cancer genetics referral practice among clinicians.

PURPOSE: To describe nongenetics clinicians' perceptions and knowledge of cancer genetics and laws prohibiting genetic discrimination, attitudes toward the use of cancer genetic testing, and referral practices. METHODS: Invitations to participate were sent to a random stratified sample of California Medical Association members and to all members of California Association of Nurse Practitioners and California Latino Medical Association. Responders in active practice were eligible and completed a 47-item survey. RESULTS: There were 1181 qualified participants (62% physicians). Although 96% viewed genetic testing as beneficial for their patients, 75% believed fear of genetic discrimination would cause patients to decline testing. More than 60% were not aware of federal or California laws prohibiting health insurance discrimination--concern about genetic discrimination was selected as a reason for nonreferral by 11%. A positive attitude toward genetic testing was the strongest predictor of referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001) in stepwise logistic regression analyses. The higher the belief in genetic discrimination, the less likely a participant was to refer (odds ratio: 0.72 [95% confidence interval: 0.518-0.991], P < 0.05), whereas more knowledge of genetic discrimination law was associated with comfort recommending (odds ratio: 1.18 [95% confidence interval: 1.11-1.25], P < 0.001) and actual referral (odds ratio: 3.55 [95% confidence interval: 2.24-5.63], P < 0.001). CONCLUSION: Concerns about genetic discrimination and knowledge deficits may be barriers to cancer genetics referrals. Clinician education may help promote access to cancer screening and prevention.

Validity of models for predicting BRCA1 and BRCA2 mutations.

BACKGROUND: Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood. OBJECTIVE: To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University. DESIGN: Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models. SETTING: Multicenter study across Cancer Genetics Network participating centers. PATIENTS: 3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics. MEASUREMENTS: Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions. RESULTS: The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing. LIMITATION: Three recently published models were not included. CONCLUSIONS: All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations.

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes.

Approximately 5-10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.

Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry.

Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network.

Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline BRCA1- or BRCA2-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083.

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome.Experimental Design: Phase I patients received carboplatin (AUC of 5-6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome.Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit.Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066-76. ©2017 AACR.