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1.
Cancers (Basel) ; 14(13)2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35805063

RESUMO

Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54-26.82, p < 10-5; BRCA2: OR = 77.71, 95% CI = 58.71-102.33, p < 10-5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59-7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02-36.02, p < 10-5; ATM: OR = 3.36, 95% CI = 0.89-8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.

2.
BMC Cancer ; 22(1): 706, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761208

RESUMO

BACKGROUND: Clinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers. METHODS: Overall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al. for BC risk discrimination in female BRCA1/2 PV carriers were employed for PRS computation in a curated sample of 295 women of European descent carrying PVs in the BRCA1 (n=183) or the BRCA2 gene (n=112), and did either fulfill the ED criteria (n=162, mean age at diagnosis: 28.3 years, range: 20 to 34 years) or the LD criteria (n=133). Binomial logistic regression was applied to assess the association of standardized PRSs with either ED or LD under adjustment for patient recruitment criteria for germline testing and localization of BRCA1/2 PVs in the corresponding BC or ovarian cancer (OC) cluster regions. RESULTS: For BRCA1 PV carriers, the standardized overall BC PRS displayed the strongest association with ED (odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.16-2.31, p<0.01). Additionally, statistically significant associations of selection for the patient recruitment criteria for germline testing and localization of pathogenic PVs outside the BRCA1 OC cluster region with ED were observed. For BRCA2 PV carriers, the standardized PRS for ER-negative BC displayed the strongest association (OR = 2.27, 95% CI: 1.45-3.78, p<0.001). CONCLUSIONS: PRSs contribute to the development of extreme phenotypes of female BRCA1/2 PV carriers with respect to age at primary BC diagnosis. Construction of optimized PRS SNP sets for BC risk stratification in BRCA1/2 PV carriers should be the task of future studies with larger, well-defined study samples. Furthermore, our results provide further evidence, that localization of PVs in BC/OC cluster regions might be considered in BC risk calculations for unaffected BRCA1/2 PV carriers.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Idade de Início , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Mutação , Neoplasias Ovarianas/genética , Fatores de Risco
3.
Breast Care (Basel) ; 17(2): 208-223, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35702492

RESUMO

Background: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.

4.
Breast Care (Basel) ; 17(2): 199-207, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35702495

RESUMO

Background: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer. Summary: An interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process. Key Messages: The goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures.

5.
Eur J Cancer ; 160: 100-111, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34801353

RESUMO

BACKGROUND: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. PATIENTS AND METHODS: Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. RESULTS: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029). CONCLUSION: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS. GOV IDENTIFIER: NCT02125344.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/análogos & derivados , Epirubicina/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Epirubicina/farmacologia , Feminino , Humanos , Paclitaxel/farmacologia , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Fatores de Risco , Análise de Sobrevida
6.
J Med Genet ; 59(3): 248-252, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33273034

RESUMO

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify BRCA1/2 germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the BRCA1/2 genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. Trial registration number NCT02222883.

7.
J Natl Cancer Inst ; 114(4): 565-570, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-34963005

RESUMO

BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. CONCLUSIONS: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.


Assuntos
Hematopoiese Clonal , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Estudos Retrospectivos
8.
Gesundheitswesen ; 83(S 01): S12-S17, 2021 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-34731888

RESUMO

The national registry "HerediCaRe" for the evaluation and improvement of risk-adjusted prevention in hereditary breast and ovarian cancer is one of six "model registries in health services research" funded by the BMBF. In this paper, we describe and discuss the documentation and IT solution chosen for standardized data collection based on the specific functional requirements previously defined. The documentation is divided into different modules to be used individually for each patient, which are based on a previously defined catalog of documentation items. Due to special functional requirements, a specific data entry application based on ORACLE and ORACLE Forms was developed and implemented. The specific requirements included the integration of graphical pedigree representations, the structured upload of pedigree data and molecular genetic information, the automated transfer of old data from the previous system, as well as the free programmability of complex database queries for central data quality control. A database for patient-independent management of genetic risk variants was seamlessly integrated into the application and linked to the patient-related data. The advantages and disadvantages of the chosen IT solution are critically discussed. Overall, we come to the conclusion that, in view of the complex documentation and the special functional requirements, there are no alternative ready-made software products to the in-house development we have chosen.


Assuntos
Documentação , Neoplasias Ovarianas , Feminino , Alemanha , Humanos , Neoplasias Ovarianas/genética , Sistema de Registros , Software
9.
Breast Care (Basel) ; 16(4): 389-395, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34602945

RESUMO

BACKGROUND: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing. METHODS: A cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing. RESULTS: Overall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process. CONCLUSION: The survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts.

10.
Clin Cancer Res ; 27(23): 6559-6569, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34593530

RESUMO

PURPOSE: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). RESULTS: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. CONCLUSIONS: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Feminino , Genes BRCA2 , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
11.
Geburtshilfe Frauenheilkd ; 81(6): 679-698, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34168381

RESUMO

Introduction Women with a pathogenic BRCA1/2 mutation have a markedly increased lifetime risk of developing breast and/or ovarian cancer. The current preventive treatment alternatives that are offered are an intensified breast cancer screening programme and risk-reducing operations. Before deciding on one option, medical and personal factors such as life situation and individual preferences must be weighed carefully. Decision aids are used internationally to support BRCA1/2 mutation carriers during their decision-making process. In this study these are analysed structurally for the first time and their applicability to the German context is examined. Material and Methods A systematic literature search in five electronic databases and a manual search were performed. The identified decision aids were evaluated with regard to formal criteria, medical content and quality. The qualitative assessment used the criteria of the International Patient Decision Aid Standards Collaboration (IPDASi v4.0), which examined various dimensions (e.g., information, probabilities, values). Results Twenty decision aids, which were published between 2003 and 2019 in Australia (n = 4), the United Kingdom (n = 3), Canada (n = 2), the Netherlands (n = 2) and the USA (n = 9), were included. Nine focus on BRCA1/2 mutation carriers and eleven include other risk groups. Eighteen include risk-reducing operations as decision options, 14 list screening methods for breast and/or ovarian cancer, and 13 describe the possibility of pharmacological prevention by means of selective oestrogen receptor modulators or aromatase inhibitors. Nine of the 20 decision aids meet fundamental quality criteria (IPDASi v4.0 qualification criteria). Conclusion International decision aids can serve formally as a basis for a German decision aid for BRCA1/2 mutation carriers. Some of them differ markedly in content from the recommendations of German guidelines. Only a few achieve a high quality.

12.
Am J Obstet Gynecol ; 225(1): 51.e1-51.e17, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Anticoncepcionais Orais/administração & dosagem , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Adulto , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos
13.
Cancers (Basel) ; 13(1)2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33401422

RESUMO

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.

14.
J Natl Cancer Inst ; 113(7): 893-899, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33372680

RESUMO

BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Mutação , Fatores de Risco
15.
Geburtshilfe Frauenheilkd ; 80(9): 932-940, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32905297

RESUMO

Background BRCA1/2 mutations are the leading cause of hereditary epithelial ovarian cancer (EOC). The German Consortium for Hereditary Breast and Ovarian Cancer has defined inclusion criteria, which are retrievable as a checklist and facilitate genetic counselling/testing for affected persons with a mutation probability of ≥ 10%. Our objective was to evaluate the prevalence of the BRCA1/2 mutation(s) based on the checklist score (CLS). Methods A retrospective data analysis was performed on EOC patients with a primary diagnosis treated between 1/2011 - 5/2019 at the Central Essen Clinics, where a BRCA1/2 genetic analysis result and a CLS was available. Out of 545 cases with a BRCA1/2 result (cohort A), 453 cases additionally had an extended gene panel result (cohort B). Results A BRCA1/2 mutation was identified in 23.3% (127/545) in cohort A, pathogenic mutations in non- BRCA1/2 genes were revealed in a further 6.2% in cohort B. In cohort A, 23.3% (127/545) of patients had a BRCA1 (n = 92) or BRCA2 (n = 35) mutation. Singular EOC (CLS 2) was present in 40.9%. The prevalence for a BRCA1/2 mutation in cohort A was 10.8%, 17.2%, 25.0%, 35.1%, 51.4% and 66.7% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. The mutation prevalence in cohort B was 15.9%, 16.4%, 28.2%, 40.4%, 44.8% and 62.5% for patients with CLS 2, 3, 4, 5, 6 and ≥ 7 respectively. Conclusions The BRCA1/2 mutation prevalence in EOC patients positively correlates with a rising checklist score. Already with singular EOC, the prevalence of a BRCA1/2 mutation exceeds the required 10% threshold. Our data support the recommendation of the S3 guidelines Ovarian Cancer of offering genetic testing to all patients with EOC. Optimisation of the checklist with clear identification of the testing indication in this population should therefore be aimed for.

16.
NPJ Breast Cancer ; 6: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964118

RESUMO

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

17.
NPJ Breast Cancer ; 6: 31, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728620

RESUMO

There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline BRCA1/2 sequence variant affecting function. We report a patient with germline/somatic BRCA1/2 wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months' duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in PALB2 (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic BRCA1/2 wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.

18.
Cancer ; 126(17): 4032-4041, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32557628

RESUMO

BACKGROUND: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program. METHODS: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12. RESULTS: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively). CONCLUSIONS: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping.


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Adulto , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Alemanha/epidemiologia , Heterozigoto , Humanos , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/patologia , Adulto Jovem
19.
JAMA Oncol ; 6(5): 744-748, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163106

RESUMO

Importance: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. Objective: To determine treatment outcome for BC according to germline variant status. Design, Setting, and Participants: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. Main Outcomes and Measures: Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. Results: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). Conclusions and Relevance: Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. Trial Registration: ClinicalTrials.gov Identifier: NCT02125344.


Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Adulto Jovem
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