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1.
Urol Clin North Am ; 48(3): 365-371, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210491

RESUMO

Germline testing should be performed to support treatment selection for patients with metastatic prostate cancer, and should be identified in patients with high-risk localized disease. Patients with germline BRCA1/2 mutations should be educated regarding additional personal cancer risk, and risk for family members. Guidelines recommend that all men with metastatic prostate cancer should also undergo somatic tissue and germline testing for priority genes BRCA1/2, PALB2, ATM, and MSH2/6. The advent of high throughput sequencing enables patients to be tested for a more comprehensive panel of germline and somatic mutations.


Assuntos
Predisposição Genética para Doença , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Dano ao DNA , Reparo do DNA , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Mutação em Linhagem Germinativa , Humanos , Indóis/uso terapêutico , Masculino , Metástase Neoplásica/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico
2.
N Engl J Med ; 384(25): 2394-2405, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34081848

RESUMO

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Mutação em Linhagem Germinativa , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Mastectomia , Pessoa de Meia-Idade , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Receptor ErbB-2
3.
BMC Med Inform Decis Mak ; 21(1): 180, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090422

RESUMO

BACKGROUND: Women with pathogenic BRCA1 and BRCA2 mutations possess a high risk of developing breast and ovarian cancer. They face difficult choices when considering preventive options. This study presents the development process of the first decision aids to support this complex decision-making process in the German healthcare system. METHODS: A six-step development process based on the International Patient Decision Aid Standards was used, including a systematic literature review of existing decision aids, a topical medical literature review, preparation of the decision aids, focus group discussions with women with BRCA1/2 mutations, internal and external reviews by clinical and self-help experts, and user tests. All reviews were followed by iterative revisions. RESULTS: No existing decision aids were transferable to the German setting. The medical research revealed a need to develop separate decision aids for women with BRCA1/2 mutations (A) without a history of cancer (previvors) and (B) with a history of unilateral breast cancer (survivors). The focus group discussions confirmed a high level of approval for the decision aids from both target groups. Additionally, previvors requested more information on risk-reducing breast surgery, risk-reducing removal of both ovaries and Fallopian tubes, and psychological aspects; survivors especially wanted more information on breast cancer on the affected side (e.g. biological parameters, treatment, and risk of recurrence). CONCLUSIONS: In a structured process, two target-group-specific DAs for previvors/survivors with BRCA1/2 mutations were developed to support decision-making on risk-adapted preventive options. These patient-oriented tools offer an important addition to existing specialist medical care in Germany.


Assuntos
Neoplasias da Mama , Técnicas de Apoio para a Decisão , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Alemanha , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle
4.
Anticancer Res ; 41(6): 2953-2962, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083286

RESUMO

BACKGROUND/AIM: Numerous missense mutations have been determined in the BRCT domain of the BRCA1 gene, affecting localization and interaction of BRCA1 with other proteins. MATERIALS AND METHODS: We examined whether the M1775K and V1809F mutations in the BRCT domain affect BRCA1 cellular localization. Cells were transfected with pEGFP-C3-BRCA1 and detected by fluorescence microscopy. RESULTS: Following induction of DNA damage, cytoplasmic mislocalization was observed for both M1775K and V1809F mutants compared to EGFP-BRCA1wt and the less common variant M1652I. These results indicate that M1775K and V1809F mutations may change the function of the protein by affecting BRCA1 localization. CONCLUSION: There is a correlation between subcellular localization of BRCA1 and diminished DNA repair observed in breast cancer cells, which may be explained by structural variations and altered binding properties of phosphopeptides.


Assuntos
Proteína BRCA1/metabolismo , Genes BRCA1 , Mutação de Sentido Incorreto , Frações Subcelulares/metabolismo , Proteína BRCA1/química , Dano ao DNA , Reparo do DNA , Proteínas de Fluorescência Verde/genética , Humanos , Células MCF-7 , Microscopia de Fluorescência , Domínios Proteicos
5.
Cochrane Database Syst Rev ; 4: CD011395, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33886122

RESUMO

BACKGROUND: Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. OBJECTIVES: To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS: On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. SELECTION CRITERIA: We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. MAIN RESULTS: We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. AUTHORS' CONCLUSIONS: In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Viés , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Science ; 372(6538): 156-165, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833118

RESUMO

Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.


Assuntos
Antineoplásicos/farmacologia , N-Glicosil Hidrolases/antagonistas & inibidores , N-Glicosil Hidrolases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Apoptose , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Replicação do DNA , DNA de Neoplasias/metabolismo , Desoxicitidina Monofosfato/análogos & derivados , Desoxicitidina Monofosfato/metabolismo , Desoxicitidina Monofosfato/farmacologia , Nucleotídeos de Desoxiuracil/metabolismo , Resistencia a Medicamentos Antineoplásicos , Genes BRCA1 , Humanos , Hidrólise , N-Glicosil Hidrolases/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/genética , Mutações Sintéticas Letais , Timidina/análogos & derivados , Timidina/antagonistas & inibidores , Timidina/metabolismo , Timidina/farmacologia , Uracila-DNA Glicosidase/metabolismo
7.
Lancet Oncol ; 22(5): 632-642, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862001

RESUMO

BACKGROUND: In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. METHODS: SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. FINDINGS: Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9-42·9) for olaparib and 41·2 months (32·2-41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI -0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of -3·00, 95% CI -4·78 to -1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20-31·63] vs placebo 17·58 [15·05-20·18]; difference 12·17 months [95% CI 9·07-15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82-35·49] vs placebo 20·24 months [17·36-23·11]; difference 12·92 months [95% CI 9·30-16·54]; p<0·0001) were significantly longer with olaparib than with placebo. INTERPRETATION: The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. FUNDING: AstraZeneca and Merck Sharp & Dohme.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Qualidade de Vida , Progressão da Doença , Método Duplo-Cego , Feminino , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/psicologia , Avaliação de Resultados da Assistência ao Paciente
8.
Cancer Med ; 10(9): 3045-3058, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811746

RESUMO

BACKGROUND: In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum-based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor). METHODS: Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III-IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression-free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA-sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD-L1 expression was scored by immunohistochemistry (IHC). RESULTS: A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss-of-function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD-L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD-L1 protein expression in the GR group. CONCLUSIONS: Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Antígeno B7-H1/metabolismo , Carboplatina/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Procedimentos Cirúrgicos de Citorredução , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genes BRCA1 , Genes BRCA2 , Genes p53 , Humanos , Proteína do Locus do Complexo MDS1 e EVI1/genética , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Proteínas Repressoras/metabolismo , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Sequenciamento Completo do Exoma
10.
Aging (Albany NY) ; 13(6): 8975-8988, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33705352

RESUMO

OBJECTIVE: To evaluate the efficacy of poly ADP ribose polymerase (PARP) inhibitors (PARPis) in breast and ovarian cancer with BRCA (BReast CAncer susceptibility gene) mutation (BRCAm). METHODS: We conducted a meta-analysis of randomized controlled, phase II or III trials by searching of electronic databases from inception to September 1, 2020. The efficacy of PARPis measured by hazard ratios (HRs) and 95% confidence intervals (95% CIs) for progression free survival (PFS) and overall survival (OS) of patients. RESULTS: By addition of PARPis to conventional therapy, breast or ovarian cancer patients carrying BRCAm significantly benefited PFS (breast cancer: HR 0.64, 95% CI=0.55-0.75, P<0.001; ovarian cancer: HR 0.33, 95% CI=0.27-0.42, P<0.001), but OS of patients did not increase significantly in these two cancer types (breast cancer: HR 0.87, 95% CI=0.76-1.01, P=0.065; ovarian cancer: HR 0.78, 95% CI=0.61-1.01, P=0.058). For ovarian cancer patients carrying BRCAm, the use of therapy with PARPis yielded longer PFS at the stage of newly diagnosed than the stage of recurrence (22.5 months vs 9.6 months). CONCLUSION: PARPis were beneficial to all with BRCAm, but they were "most" beneficial to the ovarian cancer subset when administered early after diagnosis, rather than after recurrence.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Feminino , Genes BRCA1 , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Neoplasma ; 68(3): 652-664, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33724863

RESUMO

Hereditary breast and ovarian cancer (HBOC) is primarily associated with mutations in the BRCA1/2 genes. However, causal variants in other high, moderate, and low penetrance genes proportionally increase the risk of breast/ovarian cancer. This study aims to provide data about the mutation spectrum of HBOC-associated genes in Slovak HBOC families and estimate the ratio of BRCA versus non-BRCA causal variants. We used panel sequencing containing 22 high/moderate-risk susceptibility genes and parallel MLPA analysis of BRCA1/2, CHEK2 genes, to analyze 94 individuals with a strong family/personal history of breast and/or ovarian cancer. The analyzed group consisted of 80 patients diagnosed with cancer (85.1%) and 14 healthy individuals (14.9%) with a positive family history of HBOC syndrome. In total, we have identified 22 causal DNA variants (23.4%) showing 15 primary findings in BRCA1/2 genes (68.2%) and 7 positive secondary findings in CHEK2, PALB2, CDH1, and MUTYH genes (31.8%). The most frequent pathogenic alterations were BRCA1 mutations c.181T>G and CNV variant (c.5573-?_c.5701+?)del, known as deletion of exons 21-22. Besides known mutations, the BRCA1 variant c.2794del (p.Val932Leufs*68) and variant c.2480dup (p.Tyr827*) in the CDH1 gene represent the novel, previously unpublished variants that might be population-specific. In conclusion, we provide the first report of multigene panel testing in Slovak HBOC families demonstrating that almost one-third of pathogenic mutations are situated in susceptibility genes other than BRCA1/2. Although multigene panel testing requires precise data filtration and interpretation, it might bring the relevant data for clinical management of the patients.


Assuntos
Neoplasias da Mama , Síndrome Hereditária de Câncer de Mama e Ovário , Neoplasias Ovarianas , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/genética , Eslováquia
12.
Cancer Radiother ; 25(4): 358-365, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33676830

RESUMO

PURPOSE: Breast protontherapy efficiently limits cardiac, lung and contralateral breast exposure, which may clinically translate into better late tolerance profile compared with classic photon techniques. While breast protontherapy is already implemented in the United States and in some European countries, clinical experience of breast cancer protontherapy is currently limited in France. The aim of this study is to evaluate the clinical practice of breast cancer protontherapy at the Institut Curie in order to implement this technique at a larger scale. MATERIALS AND METHODS: Data from all breast cancer patients that have been addressed to the protontherapy centre of Orsay (CPO, Institut Curie) for adjuvant breast protontherapy were retrieved. We analysed why these patients were ultimately treated with protontherapy or not. RESULTS: Between November 2019 and November 2020, eleven breast cancer patients have been evaluated for adjuvant protontherapy at the CPO. Two of them were ultimately treated with proton beams; adjuvant breast protontherapy therapy was well tolerated. The nine other patients were not treated with protontherapy due to lack of availability of protontherapy treatment rooms in acceptable time limits, at the time of patient evaluation. CONCLUSION: Despite dosimetric advantages and excellent clinical tolerance, lack of availability of protontherapy machines currently limits wider implementation of breast protontherapy.


Assuntos
Neoplasias da Mama/radioterapia , Terapia com Prótons , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Cardiotoxicidade/prevenção & controle , Feminino , França , Genes BRCA1 , Humanos , Mutação , Seleção de Pacientes , Terapia com Prótons/estatística & dados numéricos , Lesões por Radiação/prevenção & controle , Radioterapia Adjuvante/estatística & dados numéricos , Radioterapia de Intensidade Modulada , Reirradiação , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/cirurgia , Neoplasias Unilaterais da Mama/tratamento farmacológico , Neoplasias Unilaterais da Mama/genética , Neoplasias Unilaterais da Mama/radioterapia , Neoplasias Unilaterais da Mama/cirurgia , Adulto Jovem
13.
Lancet Oncol ; 22(5): 620-631, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33743851

RESUMO

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.


Assuntos
Genes BRCA1 , Genes BRCA2 , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Comprimidos , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos
14.
Nursing ; 51(4): 58-61, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33759867

RESUMO

ABSTRACT: Patients who learn they carry breast cancer genes 1 and 2 (BRCA1/2) must decide if, when, and how they want to disclose this information to family members who may be affected. This article discusses the psychosocial factors that may influence patient decisions to disclose positive BRCA1/2 results to family members, as well as the role of nurses in educating and advocating for patients and their families.


Assuntos
Neoplasias da Mama/genética , Tomada de Decisões , Revelação , Relações Familiares/psicologia , Genes BRCA1 , Genes BRCA2 , Pacientes/psicologia , Neoplasias da Mama/enfermagem , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Papel do Profissional de Enfermagem , Relações Enfermeiro-Paciente , Defesa do Paciente , Educação de Pacientes como Assunto , Pacientes/estatística & dados numéricos
15.
Am J Hum Genet ; 108(4): 682-695, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33761318

RESUMO

The increasing scope of genetic testing allowed by next-generation sequencing (NGS) dramatically increased the number of genetic variants to be interpreted as pathogenic or benign for adequate patient management. Still, the interpretation process often fails to deliver a clear classification, resulting in either variants of unknown significance (VUSs) or variants with conflicting interpretation of pathogenicity (CIP); these represent a major clinical problem because they do not provide useful information for decision-making, causing a large fraction of genetically determined disease to remain undertreated. We developed a machine learning (random forest)-based tool, RENOVO, that classifies variants as pathogenic or benign on the basis of publicly available information and provides a pathogenicity likelihood score (PLS). Using the same feature classes recommended by guidelines, we trained RENOVO on established pathogenic/benign variants in ClinVar (training set accuracy = 99%) and tested its performance on variants whose interpretation has changed over time (test set accuracy = 95%). We further validated the algorithm on additional datasets including unreported variants validated either through expert consensus (ENIGMA) or laboratory-based functional techniques (on BRCA1/2 and SCN5A). On all datasets, RENOVO outperformed existing automated interpretation tools. On the basis of the above validation metrics, we assigned a defined PLS to all existing ClinVar VUSs, proposing a reclassification for 67% with >90% estimated precision. RENOVO provides a validated tool to reduce the fraction of uninterpreted or misinterpreted variants, tackling an area of unmet need in modern clinical genetics.


Assuntos
Mutação em Linhagem Germinativa/genética , Aprendizado de Máquina , Capacitação de Usuário de Computador , Conjuntos de Dados como Assunto , Genes BRCA1 , Humanos , Reprodutibilidade dos Testes
16.
JCO Oncol Pract ; 17(2): e226-e235, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33567243

RESUMO

PURPOSE: To evaluate timing and outcomes of BRCA testing and definitive surgical treatment among patients with newly diagnosed breast cancer. METHODS: Patient-reported (n = 1,381) and deidentified health-plan (n = 2,369) data were analyzed from a consecutive national series of 3,750 women whose healthcare providers ordered BRCA testing between March 2014 and June 2015, within 1 year following breast cancer diagnosis. RESULTS: Among 1,209 respondents, 54.4% received the genetic test results presurgery, 23.2% tested presurgery but received the results postsurgery, and 22.3% tested postsurgery. Patients aware of mutation-positive results presurgery were more likely to choose bilateral mastectomy (BLM) (n = 32/37) compared with patients who learned of positive results postsurgery (n = 14/32), (odds ratio [OR] = 8.23, 95% CI = 2.55 to 26.59, P < .001). When compared with women tested postsurgery, only women unaware of negative results presurgery had higher BLM rates (adjusted OR = 1.70, 95% CI = 1.07 to 2.69, P = .02). Among women > 50 tested presurgery, those unaware of negative results presurgery were more likely to choose BLM (n = 28/81) compared with those aware of negative results (n = 32/168) (OR = 2.25, 95% CI = 1.23 to 4.08, negative results awareness × age interaction, and P = .007). CONCLUSION: Nearly half of participants did not receive BRCA results presurgery, which limited their ability to make fully informed surgical treatment decisions. This may represent suboptimal care for unaware mutation-positive patients compared with those who were aware presurgery. Women > 50 who test negative are significantly less likely to choose BLM, a costly surgery that does not confer survival advantage, if they are aware of negative results presurgery. These results have important implications for quality of care and costs in the US health system.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Humanos , Mastectomia
17.
Anal Chem ; 93(6): 3308-3314, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33533597

RESUMO

Herein, we constructed a DNA-mediated Au-Au dimer-based surface plasmon coupling electrochemiluminescence (SPC-ECL) sensor. In the SPC-ECL sensing system, graphite phase carbon nitride quantum dots (GCN QDs) worked as an ECL emitter. A DNA rigid chain structure was employed to connect two Au NPs in an equilateral triangle configuration to form the Au-Au dimers. Due to the hot spot effect, the designed Au-Au dimers had a strong electromagnetic field intensity, which can greatly enhance the ECL signal of GCN QDs than a single Au nanoparticle. The gap distance of dimers can be effectively regulated by the DNA length, which resulted in different electromagnetic field intensities. Therefore, the different SPC-ECL amplification effects on the GCN QD signal by Au-Au dimers have been revealed. The maximum ECL signal of GCN QDs can be enhanced fourfold based on the Au-Au dimers with a gap distance of 2 nm. Furthermore, the biosensor showed good analytical performance for the detection of breast cancer susceptibility gene 1 (BRCA1 genes) (1 fM-1 nM) with a detection limit of 0.83 fM. This work provided an effective and precise SPC-ECL sensing mode for the diagnosis and prognosis of breast cancer.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Pontos Quânticos , DNA/genética , Técnicas Eletroquímicas , Genes BRCA1 , Ouro , Limite de Detecção , Medições Luminescentes
19.
BMJ ; 372: n214, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589468

RESUMO

OBJECTIVE: To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. DESIGN: Retrospective, population based diagnostic evaluation. PARTICIPANTS: 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. MAIN OUTCOME MEASURES: Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. RESULTS: Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). CONCLUSIONS: SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.


Assuntos
Neoplasias da Mama/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias da Próstata/diagnóstico , Adulto , Idoso , Neoplasias da Mama/genética , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Genes BRCA1 , Genes BRCA2 , Testes Genéticos/métodos , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Neoplasias da Próstata/genética , Sistema de Registros , Estudos Retrospectivos , Análise de Sequência de DNA
20.
Cancer Sci ; 112(5): 1679-1687, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33606355

RESUMO

Alterations in breast cancer gene 1 (BRCA1), a tumor suppressor gene, increase the risk of breast and ovarian cancers. BRCA1 forms a heterodimer with BRCA1-associated RING domain protein 1 (BARD1) and functions in multiple cellular processes, including DNA repair and centrosome regulation. BRCA1 acts as a tumor suppressor by promoting homologous recombination (HR) repair, and alterations in BRCA1 cause HR deficiency, not only in breast and ovarian tissues but also in other tissues. The molecular mechanisms underlying BRCA1 alteration-induced carcinogenesis remain unclear. Centrosomes are the major microtubule-organizing centers and function in bipolar spindle formation. The regulation of centrosome number is critical for chromosome segregation in mitosis, which maintains genomic stability. BRCA1/BARD1 function in centrosome regulation together with Obg-like ATPase (OLA1) and receptor for activating protein C kinase 1 (RACK1). Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 do not interact, and aberrant expression of these proteins results in abnormal centrosome duplication in mammary-derived cells, and rarely in other cell types. RACK1 is involved in centriole duplication in the S phase by promoting polo-like kinase 1 activation by Aurora A, which is critical for centrosome duplication. Centriole number is higher in cells derived from mammary tissues compared with in those derived from other tissues, suggesting that tissue-specific centrosome characterization may shed light on the tissue specificity of BRCA1-associated carcinogenesis. Here, we explored the role of the BRCA1-containing complex in centrosome regulation and the effect of its deficiency on tissue-specific carcinogenesis.


Assuntos
Proteína BRCA1/deficiência , Carcinogênese/metabolismo , Centrossomo/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adenosina Trifosfatases/metabolismo , Proteína BRCA1/química , Proteína BRCA1/metabolismo , Carcinogênese/genética , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Centrossomo/metabolismo , Centrossomo/ultraestrutura , Instabilidade Cromossômica , Feminino , Proteínas de Ligação ao GTP/metabolismo , Genes BRCA1 , Humanos , Mitose/genética , Proteínas de Neoplasias/metabolismo , Especificidade de Órgãos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Quinase C Ativada/metabolismo , Reparo de DNA por Recombinação , Fuso Acromático/genética , Proteínas Supressoras de Tumor/química , Ubiquitina-Proteína Ligases/química
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