Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 239
Filtrar
1.
Genet Med ; 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107166

RESUMO

PURPOSE: Integrating genomic data into the electronic health record (EHR) is key for optimally delivering genomic medicine. METHODS: The PennChart Genomics Initiative (PGI) at the University of Pennsylvania is a multidisciplinary collaborative that has successfully linked orders and results from genetic testing laboratories with discrete genetic data in the EHR. We quantified the use of the genomic data within the EHR, performed a time study with genetic counselors, and conducted key informant interviews with PGI members to evaluate the effect of the PGI's efforts on genetics care delivery. RESULTS: The PGI has interfaced with 4 genetic testing laboratories, resulting in the creation of 420 unique computerized genetic testing orders that have been used 4073 times to date. In a time study of 96 genetic testing activities, EHR use was associated with significant reductions in time spent ordering (2 vs 8 minutes, P < .001) and managing (1 vs 5 minutes, P < .001) genetic results compared with the use of online laboratory-specific portals. In key informant interviews, multidisciplinary collaboration and institutional buy-in were identified as key ingredients for the PGI's success. CONCLUSION: The PGI's efforts to integrate genomic medicine into the EHR have substantially streamlined the delivery of genomic medicine.

3.
Clin Genet ; 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36089892

RESUMO

Inherited biallelic pathogenic variants (PVs) in BRCA2 cause Fanconi Anemia complementation group D1 (FA-D1), a severe pediatric bone marrow failure and high-risk cancer syndrome. We identified biallelic BRCA2 PVs in a young adult with multiple basal cell carcinomas, adult-onset colorectal cancer and small cell neuroendocrine carcinoma, without bone marrow failure. No PVs were identified in any other known cancer susceptibility gene, and there was no evidence of reversion mosaicism. The proband's deceased sister had a classic FA-D1 presentation and was shown to carry the same biallelic BRCA2 PVs. A lymphoblastoid cell line derived from the proband demonstrated hypersensitivity to DNA damaging agents, and bone marrow showed aberrant RAD51 staining. Family expansion demonstrated the presence of BRCA2 related cancers in heterozygous family members. Our data highlight the striking phenotypic differences which can be observed within FA-D1 families and expands the clinical spectrum of FA-D1 to include adult presentation with a constellation of solid tumors not previously thought of as characteristic of Fanconi Anemia. Early recognition of this syndrome in a family could prevent further morbidity and mortality by implementation of hereditary breast and ovarian cancer screening and treatment strategies for heterozygous family members.

4.
Lancet Oncol ; 23(8): 1009-1020, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35810751

RESUMO

BACKGROUND: Establishing alternatives to lifelong chemotherapy for patients with advanced pancreatic cancer has been proposed to address chemotherapy resistance and cumulative toxicity. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in this setting, and concurrent immune checkpoint blockade could offer synergistic tumour control. The aim of this study was to test the safety and antitumour activity of maintenance with PARP inhibition combined with immune checkpoint blockade in patients with advanced pancreatic cancer who had a stable response to platinum-based chemotherapy. METHODS: We conducted an open-label, randomised, phase 1b/2 study of niraparib plus anti-PD-1 (nivolumab) or anti-CTLA-4 (ipilimumab) therapy for patients with advanced pancreatic cancer whose cancer had not progressed after at least 16 weeks of platinum-based therapy. Patients were randomly assigned (1:1) via permuted block randomisation (block sizes 2 and 4) to niraparib 200 mg orally per day plus either nivolumab 240 mg intravenously every 2 weeks (later changed to 480 mg intravenously every 4 weeks based on manufacturer update) or ipilimumab 3 mg/kg intravenously every 4 weeks for four doses. The primary endpoints were safety and progression-free survival at 6 months. Treatment groups were not compared for activity, which was assessed in each group against a clinically meaningful progression-free survival at 6 months of 44% (null hypothesis). Superiority of a treatment regimen could be declared if 6-month progression-free survival was 60%, and inferiority if 6-month progression-free survival was 27%. All patients who received at least one dose of study treatment and had at least one post-treatment assessment of response according to Response Evaluation Criteria in Solid Tumours version 1.1 were included in the efficacy population. The safety population consisted of all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03404960, and enrolment is completed and follow-up is ongoing. FINDINGS: 91 patients were enrolled between Feb 7, 2018, and Oct 5, 2021 and were randomly assigned to niraparib plus nivolumab (n=46) or niraparib plus ipilimumab (n=45). Of these patients, 84 were evaluable for the progression-free survival endpoint (niraparib plus nivolumab=44; niraparib plus ipilimumab=40). Median follow-up was 23·0 months (IQR 15·0-31·5). 6-month progression-free survival was 20·6% (95% CI 8·3-32·9; p=0·0002 vs the null hypothesis of 44%) in the niraparib plus nivolumab group; and 59·6% (44·3-74·9; p=0·045) in the niraparib plus ipilimumab group. Ten (22%) of 46 patients in the niraparib plus nivolumab group and 23 (50%) of 45 patients in the niraparib plus ipilimumab group had a grade 3 or worse treatment-related adverse event. The most common grade 3 or worse adverse events in the niraparib plus nivolumab group were hypertension (in four [8%] patients), anaemia (two [4%]), and thrombocytopenia (two [4%]) whereas in the niraparib plus ipilimumab group these were fatigue (in six [14%]), anaemia (five [11%]), and hypertension (four [9%]). There were no treatment-related deaths. INTERPRETATION: The primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer. FUNDING: Bristol Myers Squibb, GlaxoSmithKline, the Basser Center Young Leadership Council, The Konner Foundation, The Pearl and Philip Basser Innovation Research Award, the Anonymous Foundation, and the US National Institutes of Health.


Assuntos
Hipertensão , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Hipertensão/induzido quimicamente , Inibidores de Checkpoint Imunológico , Indazóis , Ipilimumab , Nivolumabe/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológico , Piperidinas , Platina , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos
5.
Cancer Cell ; 40(6): 559-564, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35700704

RESUMO

Given the renewed interest in vaccine development sparked by the COVID-19 pandemic, we are revisiting the current state of vaccine development for cancer prevention and treatment. Experts discuss different vaccine types, their antigens and modes of action, and where we stand on their clinical development, plus the challenges we need to overcome for their broad implementation.


Assuntos
COVID-19 , Vacinas Anticâncer , Neoplasias , COVID-19/prevenção & controle , Vacinas Anticâncer/uso terapêutico , Humanos , Neoplasias/prevenção & controle , Pandemias/prevenção & controle
6.
Clin Cancer Res ; 28(17): 3742-3751, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35736817

RESUMO

PURPOSE: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer-testing laboratory. EXPERIMENTAL DESIGN: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. RESULTS: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. CONCLUSIONS: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.


Assuntos
Neoplasias da Mama , Genes BRCA2 , Monofosfato de Adenosina , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Variação Genética , Humanos
7.
Hum Mol Genet ; 31(18): 3133-3143, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-35554533

RESUMO

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Herança Multifatorial/genética , Receptores de Estrogênio/genética , Fatores de Risco
8.
Front Cardiovasc Med ; 9: 833171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35242827

RESUMO

OBJECTIVE: Animal models suggest that BRCA1/2 mutations increase doxorubicin-induced cardiotoxicity risk but data in humans are limited. We aimed to determine whether germline BRCA1/2 mutations are associated with cardiac dysfunction in breast cancer survivors. METHODS: In a single-center cross-sectional study, stage I-III breast cancer survivors were enrolled according to three groups: (1) BRCA1/2 mutation carriers treated with doxorubicin; (2) BRCA1/2 mutation non-carriers treated with doxorubicin; and (3) BRCA1/2 mutation carriers treated with non-doxorubicin cancer therapy. In age-adjusted analysis, core-lab quantitated measures of echocardiography-derived cardiac function and cardiopulmonary exercise testing (CPET) were compared across the groups. A complementary in vitro study was performed to assess the impact of BRCA1 loss of function on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) survival following doxorubicin exposure. RESULTS: Sixty-seven women with mean (standard deviation) age of 50 (11) years were included. Age-adjusted left ventricular ejection fraction (LVEF) was lower in participants receiving doxorubicin regardless of BRCA1/2 mutation status (p = 0.03). In doxorubicin-treated BRCA1/2 mutation carriers and non-carriers, LVEF was lower by 5.4% (95% CI; -9.3, -1.5) and 4.8% (95% CI; -9.1, -0.5), respectively compared to carriers without doxorubicin exposure. No significant differences in VO2max were observed across the three groups (poverall = 0.07). Doxorubicin caused a dose-dependent reduction in viability of iPSC-CMs in vitro without differences between BRCA1 mutant and wild type controls (p > 0.05). CONCLUSIONS: BRCA1/2 mutation status was not associated with differences in measures of cardiovascular function or fitness. Our findings do not support a role for increased cardiotoxicity risk with BRCA1/2 mutations in women with breast cancer.

9.
JCO Precis Oncol ; 6: e2100159, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35201851

RESUMO

PURPOSE: Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation-associated cancers. MATERIALS AND METHODS: Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn. RESULTS: We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter-hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2-mutant PTEN loss and BRCA1 promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression (P = .0030), cytolytic index (P = .034), and cytokine expression but higher homologous recombination deficiency scores (P = .00013). Large-scale state transitions were the primary discriminating feature (P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ (P = .05), CD8+ (P = .012), and FOXP3+ (P = .0087) T cells; decreased PRF1 expression (P = .041); and lower immune costimulatory and inhibitory molecule expression. CONCLUSION: Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2-associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias Ovarianas , Proteína BRCA1/genética , Carcinoma Epitelial do Ovário/genética , Metilação de DNA/genética , Humanos , Neoplasias Ovarianas/genética , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas/genética
10.
Cancer ; 128(7): 1381-1391, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34890045

RESUMO

BACKGROUND: Enthusiasm for precision oncology may obscure the psychosocial and ethical considerations associated with the implementation of tumor genetic sequencing. METHODS: Patients with advanced cancer undergoing tumor-only genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial were randomized to a web-based genetic education intervention or usual care. The primary outcomes were knowledge, anxiety, depression, and cancer-specific distress collected at baseline (T0), posteducation (T1) and after results (T2). Two-sided, 2-sample t tests and univariate and multivariable generalized linear models were used. RESULTS: Five hundred ninety-four patients (80% from NCI Community Oncology Research Program sites) were randomized to the web intervention (n = 293) or usual care (n = 301) before the receipt of results. Patients in the intervention arm had greater increases in knowledge (P for T1-T0 < .0001; P for T2-T0 = .003), but there were no significant differences in distress outcomes. In unadjusted moderator analyses, there was a decrease in cancer-specific distress among women (T0-T1) in the intervention arm but not among men. Patients with lower health literacy in the intervention arm had greater increases in cancer-specific distress and less decline in general anxiety (T0-T1) and greater increases in depression (T0-T2) in comparison with those receiving usual care. CONCLUSIONS: Web-based genetic education before tumor-only sequencing results increases patient understanding and reduces distress in women. Refinements to the intervention could benefit low-literacy groups and men.


Assuntos
Neoplasias , Ansiedade , Feminino , Humanos , Masculino , Oncologia , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , Qualidade de Vida
11.
J Gen Intern Med ; 37(8): 1862-1869, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34173196

RESUMO

PURPOSE: Engaging primary care providers (PCPs) in BRCA1/2 testing and results disclosure would increase testing access. The BRCA Founder OutReach (BFOR) study is a prospective study of BRCA1/2 founder mutation screening among individuals of Ashkenazi Jewish descent that sought to involve participants' PCPs in results disclosure. We used quantitative and qualitative methods to evaluate PCPs' perspectives, knowledge, and experience disclosing results in BFOR. METHODS: Among PCPs nominated by BFOR participants to disclose BRCA1/2 results, we assessed the proportion agreeing to disclose. To examine PCP's perspectives, knowledge, and willingness to disclose results, we surveyed 501 nominated PCPs. To examine PCPs' experiences disclosing results in BFOR, we surveyed 101 PCPs and conducted 10 semi-structured interviews. RESULTS: In the BFOR study overall, PCPs agreed to disclose their patient's results 40.5% of the time. Two hundred thirty-four PCPs (46.7%) responded to the initial survey. Responding PCPs were more likely to agree to disclose patients' results than non-responders (57.3% vs. 28.6%, p<0.001). Among all respondents, most felt very (19.7%) or somewhat (39.1%) qualified to share results. Among PCPs declining to disclose, insufficient knowledge was the most common reason. In multivariable logistic regression, feeling qualified was the only variable significantly associated with agreeing to disclose results (OR 6.53, 95% CI 3.31, 12.88). In post-disclosure surveys (response rate=55%), PCPs reported largely positive experiences. Interview findings suggested that although PCPs valued the study-provided educational materials, they desired better integration of results and decision support into workflows. CONCLUSION: Barriers exist to incorporating BRCA1/2 testing into primary care. Most PCPs declined to disclose their patients' BFOR results, although survey respondents were motivated and had positive disclosure experiences. PCP training and integrated decision support could be beneficial. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03351803), November 24, 2017.


Assuntos
Médicos de Atenção Primária , Atitude do Pessoal de Saúde , Humanos , Atenção Primária à Saúde/métodos , Estudos Prospectivos , Inquéritos e Questionários
12.
Eur Urol ; 81(6): 559-567, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34711450

RESUMO

BACKGROUND: Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa). OBJECTIVE: To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 2391 localized PrCa patients was carried out. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males. RESULTS AND LIMITATIONS: AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort. CONCLUSIONS: DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing. PATIENT SUMMARY: In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.


Assuntos
Mutação em Linhagem Germinativa , Neoplasias da Próstata , Estudos Transversais , Reparo do DNA/genética , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias da Próstata/genética
13.
Genet Med ; 24(1): 119-129, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34906479

RESUMO

PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética
14.
Genet Med ; 24(3): 564-575, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906490

RESUMO

PURPOSE: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). METHODS: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. RESULTS: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. CONCLUSION: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Internet , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Estados Unidos
15.
J Clin Oncol ; 39(35): 3918-3926, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34672684

RESUMO

PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
16.
Cancer Prev Res (Phila) ; 14(11): 1033-1040, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34341011

RESUMO

Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least 1 EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%), and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years [interquartile range (IQR), 53-67 years] and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, 2 individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC; however, the effectiveness of PDAC surveillance in this population requires further study. PREVENTION RELEVANCE: BRCA1/BRCA2/ATM/PALB2 carriers have increased pancreatic ductal adenocarcinoma (PDAC) risk, yet are typically not eligible for PDAC surveillance in the absence of PDAC family history. Herein we describe outcomes of PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, showing that PDAC surveillance can be considered in this high-risk group.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Estudos Retrospectivos
17.
Breast Cancer Res Treat ; 189(3): 827-835, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34342765

RESUMO

PURPOSE: Black women are more likely than non-Hispanic White women to be diagnosed with triple negative breast cancer (TNBC), an aggressive subtype with limited treatment options. The study objective was to evaluate the associations of known breast cancer risk factors, including breast density, with TNBC among Black women. METHODS: This study included Black women who underwent screening mammography between the ages of 40-84 years at a University of Pennsylvania Health System between 2010 and 2015. Cox proportional hazard models using multiple imputation with chained equations were used to estimate hazard ratios and 95% confidence intervals for risk factors for ER/PR+/HER2- and TNBC. RESULTS: Among 25,013 Black women, there were 330 incident breast cancers (1.3%) during a mean follow-up of 5.8 years; 218 (66.1%) ER/PR+ HER- and 61 (18.1%) TNBC. Having dense breasts (heterogeneously dense or extremely dense) vs. non-dense breasts (almost entirely fatty or scattered areas of fibroglandular density) increased risk of ER/PR+/HER2- breast cancer almost 80% (HR 1.79, 95% CI 1.32-2.43) and TNBC more than twofold (HR 2.53, 1.45-4.44). Older age was associated with an increased risk for ER/PR+/HER2- (HR 1.04, 1.03-1.06) and TNBC (HR 1.03, 1.00-1.05). Having a BMI of > 30 kg/m2 was associated with an increased risk (HR 2.77, 1.05-7.30) for TNBC and an increased risk of ERPR+/HER2- breast cancer in postmenopausal but not pre-menopausal women (p-interaction = 0.016). CONCLUSION: Our results suggest that breast density and obesity are strong risk factors for TNBC among Black women. Understanding breast cancer subtype specific risk factors among Black women can help improve risk assessment.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Detecção Precoce de Câncer , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Receptor ErbB-2 , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/epidemiologia
18.
Cancer Med ; 10(18): 6456-6467, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34464510

RESUMO

BACKGROUND: Breast cancer is a heterogeneous disease, divided into subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Subtypes have different biology and prognosis, with accumulating evidence of different risk factors. The purpose of this study was to compare breast cancer risk factors across tumor subtypes in a large, diverse mammography population. METHODS: Women aged 40-84 without a history of breast cancer with a screening mammogram at three United States health systems from 2006 to 2015 were included. Risk factor questionnaires were completed at mammogram visit, supplemented by electronic health records. Invasive tumor subtype was defined by immunohistochemistry as ER/PR+HER2-, ER/PR+HER2+, ER, and PR-HER2+, or triple-negative breast cancer (TNBC). Cox proportional hazards models were run for each subtype. Associations of race, reproductive history, prior breast problems, family history, breast density, and body mass index (BMI) were assessed. The association of tumor subtypes with screen detection and interval cancer was assessed using logistic regression among invasive cases. RESULTS: The study population included 198,278 women with a median of 6.5 years of follow-up (IQR 4.2-9.0 years). There were 4002 invasive cancers, including 3077 (77%) ER/PR+HER2-, 300 (8%) TNBC, 342 (9%) ER/PR+HER2+, and 126 (3%) ER/PR-HER2+ subtype. In multivariate models, Black women had 2.7 times higher risk of TNBC than white women (HR = 2.67, 95% CI 1.99-3.58). Breast density was associated with increased risk of all subtypes. BMI was more strongly associated with ER/PR+HER2- and HER2+ subtypes among postmenopausal women than premenopausal women. Breast density was more strongly associated with ER/PR+HER2- and TNBC among premenopausal than postmenopausal women. TNBC was more likely to be interval cancer than other subtypes. CONCLUSIONS: These results have implications for risk assessment and understanding of the etiology of breast cancer subtypes. More research is needed to determine what factors explain the higher risk of TNBC for Black women.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/epidemiologia , Mama/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Índice de Massa Corporal , Mama/diagnóstico por imagem , Densidade da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco
19.
JCO Precis Oncol ; 52021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34322652

RESUMO

PURPOSE: Breast cancer risks for CHEK2 and ATM pathogenic variant (PV) carriers are modified by an 86-single nucleotide polymorphism polygenic risk score (PRS) and individual clinical factors. Here, we describe comprehensive risk prediction models for women of European ancestry combining PV status, PRS, and individual clinical variables. MATERIALS AND METHODS: This study included deidentified clinical records from 358,095 women of European ancestry who received testing with a multigene panel (September 2013 to November 2019). Model development included CHEK2 PV carriers (n = 4,286), ATM PV carriers (n = 2,666), and women negative for other breast cancer risk gene PVs (n = 351,143). Odds ratios (ORs) were calculated using multivariable logistic regression with adjustment for familial cancer history. Risk estimates incorporating PV status, PRS, and Tyrer-Cuzick v7.02 were calculated using a Fixed-Stratified method that accounts for correlations between risk factors. Stratification of PV carriers into risk categories on the basis of remaining lifetime risk (RLR) was assessed in independent cohorts of PV carriers. RESULTS: ORs for association of PV status with breast cancer were 2.01 (95% CI, 1.88 to 2.16) and 1.83 (95% CI, 1.68 to 2.00) for CHEK2 and ATM PV carriers, respectively. ORs for PRS per one standard deviation were 1.51 (95% CI, 1.37 to 1.66) and 1.45 (95% CI, 1.30 to 1.64) in CHEK2 and ATM PV carriers, respectively. Using the combined model (PRS plus Tyrer-Cuzick plus PV status), RLR was low (≤ 20%) for 24.2% of CHEK2 PV carriers, medium (20%-50%) for 63.8%, and high (> 50%) for 12.0%. Among ATM PV carriers, RLR was low for 31.5% of patients, medium for 58.5%, and high for 9.7%. CONCLUSION: In CHEK2 and ATM PV carriers, risk assessment including PRS, Tyrer-Cuzick, and PV status has the potential for more precise direction of screening and prevention strategies.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Heterozigoto , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Adulto Jovem
20.
J Clin Oncol ; 39(31): 3430-3440, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292776

RESUMO

PURPOSE: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Testes Genéticos , Humanos , Prognóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...