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1.
Gynecol Oncol ; 156(3): 552-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31902686

RESUMO

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Idoso , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , Feminino , Recombinação Homóloga , Humanos , Imuno-Histoquímica , Mutação , Estadiamento de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptor ErbB-2/genética , Receptor ErbB-3/genética
2.
Nat Commun ; 10(1): 3935, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477716

RESUMO

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.


Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Epitelial do Ovário/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/metabolismo , Carcinoma Epitelial do Ovário/classificação , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/metabolismo , Análise de Sequência de DNA/métodos , Análise de Sobrevida
3.
Int J Gynecol Cancer ; 27(5): 900-906, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28498256

RESUMO

BACKGROUND: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor-positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. METHODS: Postmenopausal women who had estrogen and/or progesterone receptor-positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). RESULTS: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95% confidence interval [CI], 16%-40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0-2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6-5.7 months). Most patients (83%) progressed within 6 months. Seven patients continued on treatment for longer than 6 months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. CONCLUSIONS: A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them.


Assuntos
Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/metabolismo , Nitrilas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Nitrilas/efeitos adversos , Compostos Organoplatínicos/farmacologia , Estudos Prospectivos , Qualidade de Vida , Análise Serial de Tecidos , Triazóis/efeitos adversos
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