Abstract
Background: Fanconi Anemia (FA) proteins facilitate homologous recombination (HR)-mediated repair of DNA interstrand cross-links. Germline monoallelic, pathogenic/likely pathogenic (P/LP) ...variants in the highly-penetrant (HP) breast cancer (BC) FA genes, BRCA1 (FANCS), BRCA2 (FANCD1) and PALB2 (FANCN)), compromise HR and predispose to hereditary BC. The effects of monoallelic, pathogenic variants in other non-HP BC FA genes upon HR and BC predisposition remain less understood. In this investigation we report the germline mutational landscape of FA gene P/LP variants and somatic molecular consequences of patients with BC diagnoses from City of Hope’s (COH) INSPIRE (Implementing Next-generation Sequencing for Precision Intervention and Risk Evaluation) study.
Methods: COH-INSPIRE is a universal access study open to all patients at COH with a personal and/or family history of cancer. Patients undergo custom panel-based germline genetic testing to detect P/LP single nucleotide variants (SNVs), short insertions/deletions (indels) and exon-level deletions/duplications in 155 cancer-predisposition genes including the HP BC FA genes and 15 non-HP BC FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCO (RAD51C), FANCP (SLX4), FANCQ (ERCC4) and FANCU (XRCC2). Patients’ tumor specimens undergo somatic tumor (>400X)-normal (>180X) whole exome and transcriptome sequencing (>50 million reads). Somatic sequencing identifies P/LP SNVs, indels, copy number events, and fusions. Secondary analyses assessed somatic homologous recombination deficiency (HRD) by examining tumor mutational signatures, as well as an ensemble HRD score derived by combining individual genomic loss of heterozygosity, telomeric allelic imbalance and large-scale molecular transition scores. Reference comparison of germline and somatic features to current FDA therapeutic guidelines and NIH clinical trials registrations determined eligibility for precision therapeutic intervention and clinical trial enrollment.
Results: Of 7,584 patients enrolled in COH-INSPIRE, 1,651 (21.8%) patients had a BC diagnosis. Germline panel testing of BC patients identified 204 (12.4%) with germline P/LP variant in a FA gene. Greater than one third of FA gene-altered BC patients (37.7%) carried a P/LP variant in a non-HP BC FA gene. We observed that BC patients with a non-HP BC FA gene variant may demonstrate HR compromise as evidenced by presence of a Signature 3 mutational profile or an elevated combined HRD score (> 33 and/or > 42). (Table 1) Further, we identified ostensible segregation of triple negative BC in a family harboring a germline pathogenic variant in FANCG. With regard to precision clinical actionability (i.e. qualification for targeted therapeutic intervention PARP inhibitor (PARPi) and/or clinical trial) for patients with advanced stage BC: All patients with germline P/LP HP BC FA gene variant and 20.7% (N=16) of patients with a P/LP FA non-HPBC FA gene variant met criteria for treatment with on/off-label PARPi. 100% of patients with advanced BC with germline P/LP HP BC or non-HPBC FA gene variant qualified for a clinical trial.
Conclusions: Patients with BC often carry a germline monoallelic, P/LP FA gene variant; in more than one third, the FA gene alteration occurs in a non-HP BC FA gene. BC patients harboring a monoallelic germline non-HP BC P/LP FA gene may exhibit somatic mutational signatures and HRD scoring consistent with compromise of HR. Somatic tumor evaluation of BC patients with germline P/LP non-HP BC FA gene variants expands opportunities for precision therapeutic intervention and clinical trial enrollment. Continued appraisal will clarify emerging questions of germline non-HP P/LP FA gene-associated autosomal dominant BC risk and management as well as facilitate optimization of precision BC care.
Table 1 Summary Molecular Features of BC patients with P/LP Variants in FA gene from COH-INSPIRE
Citation Format: Laura Kruper, Kevin McDonnell, Joseph Bonner, Kevin K. Tsang, Veronica Jones, Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Heather Hampel, Wai Park, Gregory E. Idos, Stacy Gray, Stephen Gruber. PD14-03 Reappraising the Fanconi Anemia DNA repair pathway in breast cancer risk and precision intervention: Insights and opportunities from the City of Hope INSPIRE study abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-03.
Genetic healthcare professionals provide genetic cancer risk assessment and follow-up care for patients facing hereditary cancers. To meet the needs of those affected by hereditary colorectal cancer, ...City of Hope and the Hereditary Colon Cancer Foundation collaborated to develop a “Family Day” conference. We describe the development of our conference based upon the Hereditary Colon Cancer Foundation’s “Family Day” program model, with refinements completed using the Participatory Action Research theoretical framework, which incorporated input from conference participants and researchers. Thirty-one participants attended the conference, representing patients with, or families, friends, and caregivers of those with, multiple colorectal cancer predisposition syndromes, including Lynch, familial adenomatous polyposis, and juvenile polyposis. Participants who completed the feedback surveys (
n
= 22) were highly satisfied with the presentation content, ranking the keynote lecture on family communication the highest of the conference events. Participants also provided feedback regarding how to improve future conferences. In conclusion, we share our experience and provide guidance for developing a successful hereditary colon cancer predisposition patient and family conference.
Abstract
Genetic Cancer Risk Assessment (GCRA) clinical referral and testing guidelines are limited for individuals and families with gastric cancer. In part, this is due to a lack of knowledge ...regarding hereditary gastric cancer susceptibility. The Clinical Cancer Genomics Community Research Network registry includes over 15,000 families seen for GCRA at City of Hope and 45 other collaborating sites. The purpose of this research was to identify variants conferring inherited gastric cancer susceptibility for individuals and families in our registry without previously known genetic predisposition. Adult research participants from our IRB-approved registry with a DNA sample and a personal history of gastric cancer were selected. Those with a previously identified genetic predisposition were excluded (n = 8). In families with more than one eligible individual, the individual with earliest onset of disease was selected. All histologies were included (i.e., intestinal and diffuse adenocarcinomas, as well as, gastrointestinal stromal tumors). Of 47 eligible participants, 22 had previously uninformative clinical testing. Germline sequencing was completed using a novel 706 candidate cancer gene panel, which included genes involved in DNA damage response, cell cycle regulation, apoptosis, and the Fanconi anemia, mTOR, JAK-STAT, and RAS-MAPK pathways; known cancer susceptibility genes; and genes frequently mutated in gastric tumors (data from the Catalog of Somatic Variants in Cancer database). Based on 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology Standards and Guidelines, 18 out of 47 research participants had pathogenic or likely pathogenic germline variants. Of the 18, 11 had a first- or second-degree relative with gastric cancer. Variants were identified in established cancer susceptibility genes, such as BRCA2, BRIP1, RAD51C, ATM, FLCN, as well as in genes from rare autosomal recessive conditions, such as FANCC. In conclusion, using a 706 gene panel to test a GCRA cohort, we were able to identify potentially pathogenic variants in 38% of participants with gastric cancer, with nearly half of these variants in clinically actionable genes. The variants identified in this study will need to be further evaluated using segregation studies, tumor studies, and in larger cohorts to establish causality.
Citation Format: Thomas P. Slavin, Kai Yang, Sharon Sand, Tanya Chavez, Danielle Castillo, Joseph Herzog, Ilana Solomon, Christina Rybak, Mariana Niell-Swiller, Bita Nehoray, Aaron Adamson, Kathleen Blazer, Susan Neuhausen, Jeffrey Weitzel, Clinical Cancer Genomics Community Research Network. Identifying hereditary gastric cancer predisposition in the clinical cancer genomics community research network. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2551.
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Background: Older women with BC are less likely to undergo genetic cancer risk assessment since a hallmark of hereditary BC is younger age at onset. Hence there are limited data ...regarding genetic risk assessment findings in older women with BC. We analyzed the clinical characteristics and germline variant profiles of women with history of BC referred for genetic counseling at age ≥ 65 years, enrolled in the Clinical Cancer Genomics Community Research Network registry. Methods: Women age ≥ 65 with a history of BC (invasive or ductal carcinoma in situ) who underwent genetic testing from 1997 to 2016 were included. The profile of those found to have BC-related pathogenic variants was analyzed. Demographic and clinical characteristics for those with and without germline variants were compared using Fisher’s test and x
2
statistics. Results: 1372 women age ≥ 65 with BC were identified. Genetic testing was performed in 75% (n = 1035), among whom 10.4% (n = 108) had a germline variant in a BC-associated gene. High risk gene variants accounted for 85.1% (n = 92): BRCA2 (41.6%, n = 45), BRCA1 (37%, n = 40), PALB2 (5.5%, n = 6) and TP53 ( < 1%, n = 1). Moderate risk gene variants were identified in 16.6% (n = 18): CHEK2 (13.8%, n = 15), ATM (1.8%, n = 2) and NF1 ( < 1%, n = 1). Mean age at BC diagnosis was 56.4 (range 29 - 84) for women with variants and 60.9 (range 20 - 90) for those without (p < .001). 25.9% of women with variants (n = 28) had their first BC diagnosed ≥ age 65, of which 60.7% (n = 17) were BRCA2 and 21.4% (n = 6) were BRCA1 mutations ( BRCA2 was significantly higher in women diagnosed with BC age ≥ 65 p < .001). There was no difference in the mean number of 1st, 2nd and 3rd degree relatives with BC (2.4 range 0-10 vs 2.2 range 0-15) for women with and without variants, respectively, and no difference in stage at diagnosis (Stage I-II in 95% vs 89.5%, p = .4). Women with variants were less likely to have ER/PR positive tumors than those without (66% vs 81.6%, p = .01). Conclusions: BC related susceptibility variants, particularly in BRCA2, are found in a significant number of older women undergoing genetic testing for a first diagnosis of BC ≥ 65. Older women with a clinical suspicion of hereditary BC should not be excluded from genetic testing and counseling based on chronological age alone.
Abstract
Genetic cancer risk assessment (GCRA) is an interdisciplinary medical subspecialty practice that employs a growing arsenal of genetic and genomic tools to identify individuals and families ...with increased risk for cancer, often prior to the onset of disease, when early detection or prevention strategies are most effective. Access to GCRA is a standard of care in most developed countries, but is not available in most of Latin America. In March of 2014, City of Hope in Duarte, CA, conducted a roundtable discussion forum with 16 Latin American physicians representing Brazil, Colombia, Mexico, Peru, and Puerto Rico. The purpose of the roundtable was to explore the current state of GCRA services, including policy, resources, and barriers, in the respective Latin American countries. Thirteen participants attended in-person and 3 via web conference. The session was moderated by a team comprised of 4 bilingual cancer genetics clinicians. Participants were prompted with open-ended discussion questions eliciting perceived needs and the current status of GCRA services in their country, barriers to GCRA practice, and possible approaches to address access barriers. The session was largely conducted in Spanish, recorded, and transcribed. The transcript was coded and thematically analyzed. Preliminary analysis identified barriers to GCRA implementation, including: (1) limited patient and provider knowledge about GCRA, (2) lack of insurance coverage and high patient out-of-pocket costs for GCRA testing, (3) long turnaround time for genetic test results, (4) absence of readily available provider training or expertise, and (5) lack of institutional infrastructure or policy to support the development of GCRA programs. Participants emphasized the importance of collecting evidence to support the efficacy of GCRA in their own populations as an essential step toward building GCRA services in their countries. The findings also point to the need for a multi-level approach that addresses the need for education and training and cost-effective genetic testing, as well as the creation of an evidence-based foundation for the development of policy, infrastructure and resources to implement and sustain GCRA services in Latin America.
Citation Format: Tanya Chavez, Bita Nehoray, Alexandra Obregon-Tito, Charité Ricker, Ilana Solomon, Mariana Niell-Swiller, Christina Ryback, Julio E. Abugattas, Yasser Sullcahuaman, María F. Noriega, Ana I. Orduz, Jorge M. Melo, Ana Chaves, Lenny Gallardo, Cynthia Villarreal, Robin Shaw, Rosa M. Álvarez, Eunice F. Morales, Alicia M. Cock-Rada, Azucena Del Toro, Pamela Mora, Marcia Cruz, María E. Fernández, Kathleen R. Blazer, Jeffrey N. Weitzel. Exploring the climate, barriers, and possible approaches to implementing genetic cancer risk assessment in Latin America: A roundtable discussion. abstract. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A36.
Highlights • Nine recurrent Hispanic mutations were observed in a sample of Hispanic patients seen for genetic cancer risk assessment. • Three of these were previously reported in Spain, confirming ...the influence of Spanish ancestry in Hispanic populations. • This is the largest report of Hispanic MMR mutations in North America.
Views, events, and debates Cooke, Liz
Gender and development,
11/1/2008, 20081101, 2008-11-00, Letnik:
16, Številka:
3
Journal Article
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IMPORTANCE: There remains a lack of randomized trials investigating aspirin monotherapy for symptomatic venous thromboembolism (VTE) prophylaxis following total hip arthroplasty (THA) or total knee ...arthroplasty (TKA). OBJECTIVE: To determine whether aspirin was noninferior to enoxaparin in preventing symptomatic VTE after THA or TKA. DESIGN, SETTING, AND PARTICIPANTS: Cluster-randomized, crossover, registry-nested trial across 31 hospitals in Australia. Clusters were hospitals performing greater than 250 THA or TKA procedures annually. Patients (aged ≥18 years) undergoing hip or knee arthroplasty procedures were enrolled at each hospital. Patients receiving preoperative anticoagulation or who had a medical contraindication to either study drug were excluded. A total of 9711 eligible patients were enrolled (5675 in the aspirin group and 4036 in the enoxaparin group) between April 20, 2019, and December 18, 2020. Final follow-up occurred on August 14, 2021. INTERVENTIONS: Hospitals were randomized to administer aspirin (100 mg/d) or enoxaparin (40 mg/d) for 35 days after THA and for 14 days after TKA. Crossover occurred after the patient enrollment target had been met for the first group. All 31 hospitals were initially randomized and 16 crossed over prior to trial cessation. MAIN OUTCOMES AND MEASURES: The primary outcome was symptomatic VTE within 90 days, including pulmonary embolism and deep venous thrombosis (DVT) (above or below the knee). The noninferiority margin was 1%. Six secondary outcomes are reported, including death and major bleeding within 90 days. Analyses were performed by randomization group. RESULTS: Enrollment was stopped after an interim analysis determined the stopping rule was met, with 9711 patients (median age, 68 years; 56.8% female) of the prespecified 15 562 enrolled (62%). Of these, 9203 (95%) completed the trial. Within 90 days of surgery, symptomatic VTE occurred in 256 patients, including pulmonary embolism (79 cases), above-knee DVT (18 cases), and below-knee DVT (174 cases). The symptomatic VTE rate in the aspirin group was 3.45% and in the enoxaparin group was 1.82% (estimated difference, 1.97%; 95% CI, 0.54%-3.41%). This failed to meet the criterion for noninferiority for aspirin and was significantly superior for enoxaparin (P = .007). Of 6 secondary outcomes, none were significantly better in the enoxaparin group compared with the aspirin group. CONCLUSIONS AND RELEVANCE: Among patients undergoing hip or knee arthroplasty for osteoarthritis, aspirin compared with enoxaparin resulted in a significantly higher rate of symptomatic VTE within 90 days, defined as below- or above-knee DVT or pulmonary embolism. These findings may be informed by a cost-effectiveness analysis. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12618001879257