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1.
J Clin Oncol ; : JCO1901304, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31461380

RESUMO

PURPOSE: Talazoparib has demonstrated efficacy in patients with BRCA-positive metastatic breast cancer. This study evaluated the pathologic response of talazoparib alone for 6 months in patients with a known germline BRCA pathogenic variant (gBRCA-positive) and operable breast cancer. METHODS: Eligibility included 1 cm or larger invasive tumor and gBRCA-positive disease. Human epidermal growth factor receptor 2-positive tumors were excluded. Twenty patients underwent a pretreatment biopsy, 6 months of once per day oral talazoparib (1 mg), followed by definitive surgery. Patients received adjuvant therapy at physician's discretion. The primary end point was residual cancer burden (RCB). With 20 patients, the RCB-0 plus RCB-I response rate can be estimated with a 95% CI with half width less than 20%. RESULTS: Twenty patients were enrolled from August 2016 to September 2017. Median age was 38 years (range, 23 to 58 years); 16 patients were gBRCA1 positive and 4 patients were gBRCA2 positive. Fifteen patients had triple-negative breast cancer (estrogen receptor/progesterone receptor < 10%), and five had hormone receptor-positive disease. Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. One patient chose to receive chemotherapy before surgery and was not included in RCB analyses. RCB-0 (pathologic complete response) rate was 53% and RCB-0/I was 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Toxicities were managed by dose reduction and transfusions. Nine patients required dose reduction. CONCLUSION: Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353).

3.
Br J Cancer ; 121(2): 180-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

4.
Am Soc Clin Oncol Educ Book ; 39: e34-e44, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31099680

RESUMO

There is an increasing need for genetic counseling and testing for individuals diagnosed with cancer, as treatment may be affected by the results. In addition, the identification of individuals before a diagnosis of cancer allows for optimal surveillance and early detection and prevention of cancer. With the recognition that as much as 10% of all cancers are hereditary, there is a growing need to improve access to genetic counseling and genetic testing, both before and at the time of diagnosis. This article focuses on models of identifying at-risk patients, including underserved communities; providing genetic counseling and testing in community practices; using telehealth; and collaborating with nongenetics health care providers and technological solutions to maximize efficiency and access.

5.
Breast Cancer Res Treat ; 176(3): 545-556, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054033

RESUMO

PURPOSE: The carbohydrate sialyl LewisX (sLeX) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLeX and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLeX and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLeX and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLeX using a cut-off of 8 U/mL as previously defined. RESULTS: Median serum sLeX was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLeX > 8 U/mL have a significantly shorter progression-free survival (PFS) (P = 0.0074) and overall survival (OS (P = 0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P = 0.001 and P < 0.001, respectively) and PFS (P = 0.010 and P < 0.001, respectively). sLeX, MCP-1 and IP-10 remained significant in multivariate survival analysis. CONCLUSION: Elevated serum sLeX was associated with invasive cancer but not DCIS. High serum sLeX levels were associated with inflammatory mediators and may play a role in facilitating local invasion of breast tumor. Furthermore, serum MCP-1, IP-10 and sLeX may have prognostic value in breast cancer.

6.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
7.
Nat Commun ; 10(1): 431, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683880

RESUMO

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Neoplasias de Cabeça e Pescoço/genética , Padrões de Herança , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/patologia , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Transtornos Mentais/etnologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/patologia , Fumar/etnologia , Fumar/genética , Fumar/fisiopatologia
8.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

9.
J Clin Oncol ; : JCO2018786558, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30240327

RESUMO

PURPOSE: This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. PATIENTS AND METHODS: Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. RESULTS: ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. CONCLUSION: Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

10.
Cancer Res ; 78(18): 5419-5430, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054336

RESUMO

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

11.
JAMA Oncol ; 4(9): 1207-1213, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29879283

RESUMO

Importance: Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC. Objective: To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC. Design, Setting, and Participants: Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR. Intervention: Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks. Main Outcomes and Measures: The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR. Results: Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor-positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression. Conclusions and Relevance: This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers. Trial Registration: ClinicalTrials.gov Identifier: NCT01036087.

12.
Cancer Med ; 7(6): 2718-2726, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29733510

RESUMO

Although multigene panel testing is increasingly common in patients with cancer, the relationship between its use among breast cancer patients with non-BRCA mutations or variants of uncertain significance (VUS) and disease management decisions has not been well described. This study evaluated the rate and predictive factors of CPM patients who underwent multigene panel testing. Three hundred and fourteen patients with breast cancer who underwent multigene panel testing between 2014 and 2017 were included in the analysis. Of the 314 patients, 70 elected CPM. Election of CPM by gene status was as follows: BRCA carriers (42.3%), non-BRCA carriers (30.1%), and VUS (10.6%). CPM election rates did not differ between non-BRCA carriers and BRCA carriers (P = 0.6205). Among non-BRCA carriers, negative hormone receptor status was associated with CPM (P = 0.0115). For those with a VUS, hormone receptor status was not associated with CPM (P = 0.1879). Although the rate of CPM between BRCA carriers and non-BRCA carriers was not significantly different, the predictors of CPM were different in each group. Our analyses shed the light on the increasing use of CPM among patients who are non-BRCA carriers as well those with a VUS. Our study elucidates the differing predictive factors of CPM election among BRCA carriers, non-BRCA carries, and those with a VUS. Our findings reveal the need for providers to be cognizant that non-BRCA genes and VUS drive women to elect CPM despite the lack of data for contralateral breast cancer risk associated with these genes.

13.
J Genet Couns ; 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29770910

RESUMO

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

14.
Cancer ; 124(11): 2299-2305, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29579338

RESUMO

BACKGROUND: Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. METHODS: We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival. RESULTS: A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P < .0001). Age >50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival. CONCLUSION: IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

15.
Hum Mutat ; 39(5): 593-620, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

16.
Cancer ; 124(4): 664-666, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29266190
18.
Cancer ; 124(3): 466-474, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29044548

RESUMO

BACKGROUND: Inflammatory breast cancer (IBC) often affects women at a relatively young age. To the authors' knowledge, the rate of BRCA variants among patients with IBC is not known. To determine the association between BRCA status and IBC, the authors evaluated its rate and compared the clinicopathologic characteristics of patients with IBC with those of patients with other breast cancers (non-IBC). METHODS: Patients who presented at the study institution's cancer genetics program and who underwent BRCA genetic testing were included in the current study. The authors compared clinicopathologic data between patients with IBC and those with non-IBC using propensity score matching to identify predictors. RESULTS: A total of 1789 patients who underwent BRCA genetic testing (1684 with non-IBC and 105 with IBC) were included. BRCA pathogenic variants were found in 27.3% of patients with non-IBC and 18.1% of patients with IBC (P = .0384). After propensity score matching, there were no significant differences noted between patients with IBC and those with non-IBC, including the rate of BRCA pathogenic variants (P = .5485). However, a subgroup analysis of the 479 patients with BRCA pathogenic variants demonstrated that patients with IBC (19 patients) were diagnosed at significantly younger ages compared with patients with non-IBC (P = .0244). CONCLUSIONS: There was no clear association observed between BRCA pathogenic variants and IBC. However, among patients who tested positive for BRCA pathogenic variants, those with IBC were younger at the time of diagnosis compared with those with non-IBC breast cancers. These results confirm that genetic testing is important for patients with IBC who meet the current clinical criteria for genetic testing in breast cancer. Cancer 2018;124:466-74. © 2017 American Cancer Society.

19.
Oncologist ; 22(6): 655-666, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28469042

RESUMO

Hereditary breast cancer syndromes are associated with an increased risk of breast cancer and constitute a unique patient population, making up approximately 5%-10% of breast cancer cases in the United States. By virtue of the germline mutations that define these syndromes, invasive breast cancers in these patients have unique mechanisms that can be rationally targeted for therapeutic opportunities distinct from standard of care treatments in nongermline mutation associated breast cancers. This review intends to describe existing data on several of the most common hereditary breast cancer syndromes, including BRCA-related breast cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer syndrome, specifically focusing on rational therapeutics utilized in these distinct patient subgroups and completed or ongoing clinical trials evaluating their efficacy. By exploiting the distinct biologic features associated with these syndromes, tailored treatment strategies have the potential for improved efficacy and lower toxicity. Knowledge of the emergence of these targeted cancer therapies is critical for appropriate management in these patients, extending beyond treatment to highlight the need for appropriate genetic screening to allow for early recognition of these patients and therefore appropriate treatment. IMPLICATIONS FOR PRACTICE: Molecular testing allows for identification of germline mutations that place individuals at high risk for breast cancer and that are associated with distinct histopathology and molecular characteristics that define the invasive breast cancer cases that these patients develop. These unique characteristics may ultimately provide rational targets for systemic treatments with improvements in both morbidity and efficacy. Identification of patients with these germline mutations is important for not only appropriate screening and prophylaxis, but knowledge of therapies specifically targeting several of the most common hereditary breast cancer syndromes is essential to ensure appropriate treatment of invasive breast cancers in these patients.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/terapia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Estados Unidos/epidemiologia
20.
Nat Genet ; 49(5): 680-691, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346442

RESUMO

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Metanálise como Assunto , Mutação , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteínas de Ligação a Telômeros/genética
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