ABSTRACT
INTRODUÇÃO: O adenocarcinoma gástrico (AdG) é responsável por 5,7% de todos os casos novos e por 8,2% das mortes relacionadas a câncer no mundo. A literatura sobre AdG tem enriquecido com a publicação de amplas análises moleculares nos últimos anos, mas boa parte delas carece de dados de sobrevida e do impacto prognóstico das alterações descritas OBJETIVOS: 1) Descrever o perfil mutacional e avaliar o impacto prognóstico das mutações mais relevantes de AdGs em uma coorte de 112 pacientes tratados no A.C. Camargo Cancer Center; 2) Determinar a ancestralidade genômica e seu impacto prognóstico nesta coorte; 3) Investigar o impacto da carga mutacional global do tumor sobre o prognóstico; 4) Buscar novos marcadores moleculares prognósticos através do sequenciamento comparativo do exoma tumoral completo de 24 pacientes da mesma coorte. MÉTODOS: Este é um estudo longitudinal, retrospectivo, com amostragem não-aleatória e consecutiva de 112 pacientes com AdG, independente de estádio clínico, com amostras disponíveis no biobanco institucional e diagnóstico entre 2007 e 2013. O DNA tumoral foi sequenciado com um painel de captura incluindo 99 genes e 24 amostras também tiveram o exoma tumoral completo sequenciado. Utilizamos um pool de 1600 marcadores informativos de ancestralidade para determinar a ancestralidade genômica dos casos. RESULTADOS: Os dez genes mais frequentemente mutados em nossa coorte foram TP53 (30%), LAMA1 (21%), ARID1A (19%), CIC (19%), FAT4 (17%), PKHD1 (16%), KMT2C (15%), MACF1 (15%), PKHDL1 (15%) e BRCA2 (14%). Demonstramos que em uma população etnicamente miscigenada como a brasileira, a ancestralidade genômica asiática per se não representa um fator prognóstico independente e levantamos a hipótese de que em nossa população, a ancestralidade predominante africana talvez esteja associada a um prognóstico adverso. Identificamos a presença de mutações em RHOA como um possível fator associado a prognóstico favorável, dado que ainda carece de validação. Demonstramos que FAT4, ARID1A e BRCA2 são genes frequentemente mutados em nossa coorte e, ao contrário de relatos prévios, não estiveram associados ao prognóstico de pacientes com AdG
INTRODUCTION: Gastric adenocarcinoma (AdG) accounts for 5.7% of all tumors and 8.2% of cancer related deaths worldwide. Comprehensive reports have recently contributed to the molecular characterization of AdG, but most of them have not investigated the possible prognostic impact of the described mutations. OBJECTIVES: 1) To identify molecular alterations and to assess the prognostic impact of the most relevant mutations found in a cohort of 112 AdG patients treated at A.C. Camargo Cancer Center; 2) To determine the genomic ancestry, for the same cohort, and it's prognostic impact; 3) To assess the global tumor mutational burden and it's prognostic impact 4) To screen potential new prognostic molecular alterations through whole exome sequencing (WES) of tumors from 24 patients. METHODS: This is a retrospective longitudinal analysis that recruited 112 AdG patients, all stages, diagnosed between 2007 and 2013, with available tissue at the A.C. Camargo Cancer Center biobank. DNA extracted from tumor samples was sequenced by a targeted gene panel including 99 genes. Twenty-four tumors were also assessed by WES. We used a pool of 1600 ancestry informative markers to infer each individual genomic ancestry. RESULTS: The top 10 mutated genes in our cohort were: TP53 (30%), LAMA1 (21%), ARID1A (19%), CIC (19%), FAT4 (17%), PKHD1 (16%), KMT2C (15%), MACF1 (15%), PKHDL1 (15%) e BRCA2 (14%). Different from other studies, Asian ancestry was not an independent prognostic factor in our ethnically highly-admixed population, but we found worse prognosis in African ancestry. Mutations in RHOA were associated with good prognosis in this cohort, and we also demonstrated that, besides being common among Brazilian AdG patients, mutations in FAT4, ARID1A and BRCA2 had no prognostic impact
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Stomach Neoplasms , Biomarkers, Tumor , Exome Sequencing , Mutation , Retrospective Studies , Cohort StudiesABSTRACT
ABSTRACT In the last module of this consensus, controversial topics were discussed. Management of the disease after progression during first line chemotherapy was the first discussion. Next, the benefits of liver resection in the presence of extra-hepatic disease were debated, as soon as, the best sequence of treatment. Conversion chemotherapy in the presence of unresectable liver disease was also discussed in this module. Lastly, the approach to the unresectable disease was also discussed, focusing in the best chemotherapy regimens and hole of chemo-embolization.
RESUMO Neste último módulo do consenso, abordou-se alguns temas controversos. O primeiro tópico discutido foi o manejo da doença após progressão na primeira linha de quimioterapia, com foco em se ainda haveria indicação cirúrgica neste cenário. A seguir, o painel debruçou-se sobre as situações de ressecção da doença hepática na presença de doença extra-hepática, assim como, qual a melhor sequência de tratamento. O tratamento de conversão para doença inicialmente irressecável também foi abordado neste módulo, incluindo as importantes definições de quando se pode esperar que a doença se torne ressecável e quais esquemas terapêuticos seriam mais efetivos à luz dos conhecimentos atuais sobre a biologia tumoral e taxas de resposta objetiva. Por último, o tratamento da doença não passível de ressecção foi discutida, focando-se nos melhores esquemas a serem empregados e seu sequenciamento, bem como o papel da quimioembolização no manejo destes pacientes.
Subject(s)
Humans , Colorectal Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Brazil , Combined Modality Therapy , Embolization, Therapeutic , Antineoplastic Agents/therapeutic useABSTRACT
INTRODUCTION: In the postmenopausal period, an average of 25 percent of women will present symptomatic ovarian failure requiring hormonal replacement therapy. Estrogen can relieve vasomotor symptoms. Hormonal replacement therapy is generally not recommended for breast cancer patients due to the potential risk of tumor recurrence. To answer the questions about the safety of hormonal replacement therapy in this subgroup of women, it is necessary to establish the acceptance of treatment. METHODS: Between September 1998 and February 2001, a cohort of 216 breast cancer patients were asked to complete a questionnaire. All patients had completed their treatment and were informed about survival rates after breast cancer and hormonal replacement therapy. RESULTS: Among the 216 patients, 134 (62 percent) would refuse hormonal replacement therapy. A hundred patients were afraid of relapse (74.6 percent). Adjuvant tamoxifen therapy was the only statistically significant variable (70.3 percent versus 29.7 percent p=0.003). Understanding clinical stage (p= 0.045) and type of medical assistance (private versus public , p=0.033) also seemed to influence the decision. Early stage disease (p= 0.22), type of surgical procedure (radical versus conservative, p=0.67), adjuvant chemotherapy (p=0.082) or marital status (p=0.98 ) were not statistically significant in decision making. Several patients submitted to adjuvant chemotherapy (41.6 percent) would accept hormonal replacement therapy under medical supervision, as did most of advanced clinical stage patients (58.3 percent; p=0.022). CONCLUSION: There is a high level of rejection for hormonal replacement therapy among breast cancer patients when current data on tumor cure rates, and potential risks of estrogen use is available. Adverse effects of tamoxifen in the adjuvant setting may be the reason for refusal of hormonal replacement therapy