RESUMO
OBJECTIVES: The aim of this study was to provide real-world efficacy and safety data on niraparib maintenance treatment in patients with non-germline (gBRCA)1/2 mutated platinum-sensitive recurrent ovarian cancer. METHODS: This retrospective multi-center cohort study included 94 platinum-sensitive recurrent ovarian cancer patients without known gBRCA1/2 mutation treated in an individual patient access program in Norway. The primary outcome was time from start of niraparib treatment to first subsequent treatment. Secondary endpoints included progression-free survival, safety, and tolerability. RESULTS: After median follow-up of 13.4 months (95% confidence interval (CI) 10.0 to 16.8), 68.1% had progressed and 22.3% had died. Of the entire cohort, 61.7% had commenced a new line of treatment, and 24.5% were still receiving niraparib. The median duration of niraparib treatment was 5.0 months (range 0.4 to 27.3), and the median time to first subsequent treatment was 10.7 months (95% CI 8.4 to 13.0). Patients with elevated CA125 prior to start of niraparib had shorter time to first subsequent treatment (7.3 months, 95% CI 4.2 to 10.3) than patients with normalized CA125 (12.2 months, 95% CI 10.9 to 13.7 (p=0.002). Patients who started on individual dose based on weight and platelet counts had fewer dose reductions (p<0.001) and interruptions (p=0.02). CONCLUSION: In a real-world setting, niraparib maintenance treatment in patients with non-gBRCA1/2 mutated recurrent platinum-sensitive ovarian cancer showed effectiveness comparable with published phase III studies and acceptable safety. Individualized dosing is essential to minimize adverse events. CA125 levels at start of niraparib treatment may help to estimate the individual prognosis.
Assuntos
Neoplasias Ovarianas , Feminino , Humanos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Estudos de Coortes , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Estudos RetrospectivosRESUMO
In colorectal cancer there is a need for molecular markers that can complement the histopathological staging in predicting the likelihood of disease recurrence following curatively intended surgery. B7-H3 is an immunoregulatory protein shown to be overexpressed in several cancer forms, often associated with more advanced disease and poor prognosis. We wanted to examine whether B7-H3 could be a potential prognostic marker in colorectal cancer. Paraffin-embedded samples from 277 colorectal cancer patients were immunostained with anti-B7-H3 antibody. B7-H3 was expressed in the tumor cell cytoplasm and cell membrane in 62% and 46% of the samples, respectively. Unexpectedly, B7-H3 was expressed in the nucleus in 30% of the tumors. The nuclear localization was confirmed by Western immunoblotting of subcellular fractions. Importantly, in colon cancer, nuclear B7-H3 expression was independently and significantly associated with reduced metastasis-free, disease-specific and overall survival. B7-H3 expression in tumor-associated vasculature and fibroblasts was observed in the majority of samples, and endothelial B7-H3 expression was also significantly associated with poor outcome in colon cancer. In rectal cancer patients, the only significant association was between fibroblast B7-H3 expression and shorter metastasis-free survival. Few significant associations to clinicopathological parameters were seen. The results indicate that nuclear B7-H3 might be involved in colon cancer progression and metastasis, and suggest that nuclear B7-H3 could become a useful prognostic marker in colon cancer.
Assuntos
Antígenos B7/biossíntese , Núcleo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos B7/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Membrana Celular/genética , Membrana Celular/metabolismo , Núcleo Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Citoplasma/genética , Citoplasma/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Prognóstico , Adulto JovemRESUMO
B7-H3 is a transmembrane glycoprotein and a member of the B7 family of proteins. It was previously known as an immunoregulatory molecule, shown in recent years to be of clinical significance in different types of cancer. In some tumor types high expression of B7-H3 has been linked to a poor prognosis, whereas in other cancers the opposite effect has been observed. Taken together, the precise role of B7-H3 in tumor immunity is unclear and further investigations are needed. Another aspect of B7-H3 that so far has received little interest is its role in non-immunological systems. We have demonstrated that knockdown of B7-H3 in melanoma and breast cancer cells results in both increased chemosensitivity and decreased metastatic potential. This has been observed in both in vitro and in vivo experiments. Several different signaling pathways seems to be involved, as B7-H3 knockdown can be linked to both higher expression of apoptotic markers and increased phosphorylation of Stat3. Increased knowledge of also the non-immunological role of B7-H3 protein is therefore of great biological and putative therapeutic interest.
