RESUMO
Ovarian cancer is the most lethal gynecologic malignancy. The long-established primary treatment for ovarian cancer consisted of surgical cytoreduction followed by platinum-based chemotherapy. Unfortunately, this therapeutic approach is related to a high frequency of early relapses. Further chemotherapy is necessary for recurrent disease, but very few patients can be cured. Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in various DNA repair activities. PARP inhibition leads to synthetic lethality in BRCA mutated or homologous recombination deficient tumors. The development of PARP inhibitors has changed the way ovarian cancer patients are treated. Olaparib, niraparib and rucaparib are orally active and have demonstrated efficacy for both maintenance and treatment settings. These three drugs have gained regulatory approval for different clinical circumstances. They have an acceptable toxicity profile and are generally well tolerated. Common class toxicities include hematologic effects, gastrointestinal effects and fatigue. Moreover, new treatment strategies that combine PARP inhibitors with other drugs, such as angiogenic agents, are being explored. The purpose of this review is to describe the evidence that define the current clinical role of PARP inhibitors in ovarian cancer. The implementation of rationally designed new clinical trials will be crucial to facilitate the best selection of patients and to continue improving clinical outcomes.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185) genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3%) and 4 (6.9%) patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA), while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A). We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG) and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA). In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants), 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and10 in BRCA2) were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families.
Assuntos
Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/genética , Genes BRCA1 , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Polimorfismo Genético/genética , Sequência de Bases , Análise Mutacional de DNA , Dados de Sequência Molecular , VenezuelaRESUMO
Aproximadamente 20 % dos casos de câncer de mama familiar estão associados a um dos genes de susceptibilidade hereditária para câncer de mama e ovário, BRCA1 e BRCA2. Recentes trabalhos têm demonstrado o mecanismo de ação destes genes com funções estabelecidas na manutenção da integridade do genoma e no controle da recombinação homóloga. A história familiar, a bilateralidade, o acometimento precoce e achados histopatológicos específicos são fatores sugestivos da presença de mutações nestes genes. Esta revisão sumariza alguns destes conhecimentos, na tentativa de colocá-los no contexto atual das funções destes genes.
Approximately 20% of the cases related to familiar breast cancer are associated to one gene of hereditary susceptibilityfor breast and ovarian cancer, BRCA1 and BRCA2. Recent works have demonstrated the mechanism of action of these genes, with functions well established for maintaining the genome integrity and for controlling homologatesrecombination. Familiar history, bilaterality, precocious diseases, as well as specific histopathologic results areindicative factors of the presence of mutation in these genes. This literature review summarizes some of thisknowledge, trying to understand them in the current functional context of these genes.