OBJECTIVES: In breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations. METHODS: Forty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated. RESULTS: The overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations. CONCLUSIONS: Data obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

ABSTRACT OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

OBJECTIVES: Survival data for young adults (YA) with gastric cancer is conflicting and scarce in Brazil. The aim of this study was to compare the clinicopathological factors and survival rates of younger and older patients with gastric cancer. METHODS: Hospital registries for 294 gastric cancer patients from a reference cancer hospital in São Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (≤40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: ≥66 years; N=94). Differences were assessed through Pearson’s χ2 test, Kaplan-Meier analysis, Log rank test and Cox regression. RESULTS: More YA were diagnosed with advanced disease (clinical stage III/IV: 86.7% YA, 69.9% OA, and 67% E); however, fewer E patients underwent surgery (64.3% YA, 72.7% OA, and 52.4% E). The median overall survival among all patients was 16 months, and the overall survival rate was not significantly different among the age groups (p=0.129). There were no significant differences in the disease-free survival rate. Metastatic disease at diagnosis (HR=4.84; p<0.01) was associated with an increased hazard of death for YA. CONCLUSION: Overall survival was similar among age groups. Metastatic disease at diagnosis was the only factor associated with a poorer prognosis in YA. These results suggest that younger patients deserve special attention regarding the detection of early stage disease.

OBJECTIVES: Cancer in young adults represents a great challenge, both biologically and socially, and understanding the unique characteristics of neoplasms in this age group is important to improving care. We aimed to evaluate the most common carcinomas and their characteristics, such as histological type and clinical stage, in young adults in the largest cancer hospital in Latin America. METHODS: The hospital registry was consulted for the period between 2008 and 2014. Young adults were defined as individuals aged 18 to 39 years, and older adults were defined as individuals aged 40 years and older. Differences between age groups were assessed through chi-square tests. RESULTS: Of the 39,389 patients included, 3,821 (9.7%) were young adults. Among the young adults, the most frequent cancer types were the following: breast, lymph node, colorectal, thyroid, testicle, hematopoietic and reticuloendothelial, uterine cervix, brain, soft tissue and stomach; these sites accounted for 74.5% of the observed tumors. Breast, colorectal and stomach cancers were more frequently diagnosed at advanced stages in young adults than in older adults (p<0.001). The most common histological types were infiltrating ductal carcinoma (86.12%) for breast cancer, adenocarcinomas not otherwise specified (45.35%) for colorectal cancer, squamous cell carcinoma not otherwise specified (65.26%) for uterine cervix cancer, signet ring cell adenocarcinomas (49.32%) for stomach cancer and adenocarcinomas not otherwise specified (50.79%) for lung cancer. CONCLUSION: Young adults are diagnosed with cancer at more advanced stages, indicating that health professionals should be aware of cancer incidence in this age group. It is necessary to develop a better understanding of cancer in young adults and to implement dedicated health care strategies for these patients.

ABSTRACT OBJECTIVE: To analyze the cost effectiveness of the diagnostic program for the germline mutation in BRCA1/2 genes and of preventative strategies for the relatives of patients diagnosed with ovarian cancer associated with this mutation. METHODS: The study analyzed the cost effectiveness by developing an analysis of the Markov decision process from the perspective of the National Health System. The strategies compared reflect upon the adoption of genetic testing and preventative strategies for relatives or the usual care currently proposed. The incremental cost-effectiveness ratio was expressed in terms of cost per case avoided. The sensitivity analysis was performed in a univariate and deterministic manner. RESULTS: The study showed increments for effectiveness and for costs when performing genetic testing and adopting prophylactic measures for family members. The incremental cost-effectiveness ratio was estimated at R$908.58 per case of cancer avoided, a figure considered lower than the study's cost-effectiveness threshold (R$7,543.50). CONCLUSIONS: The program analyzed should be considered a cost-effective strategy for the national situation. Studies in various other countries have reached similar conclusions. One possible ramification of this research might the need to perform a budgetary-impact analysis of making the program one of the country's health policies.

OBJECTIVE: To evaluate ipsilateral breast tumor recurrence after breast-conserving surgery for locally advanced breast cancer. METHODS: A retrospective observational cohort study was performed in patients with locally advanced breast cancer submitted to breast-conserving surgery after neoadjuvant chemotherapy based on an adriamycin-cyclophosphamide-paclitaxel regimen. We evaluated the clinical, pathologic, immunohistochemistry, and surgical factors that contribute to ipsilateral breast tumor recurrence and locoregional recurrence. A Kaplan-Meier analysis and Cox model were used to evaluate the main factors related to disease-free survival. RESULTS: Of the 449 patients who received neoadjuvant chemotherapy, 98 underwent breast-conserving surgery. The average diameter of the tumors was 5.3 cm, and 87.2% reached a size of up to 3 cm. Moreover, 86.7% were classified as clinical stage III, 74.5% had T3-T4 tumors, 80.5% had N1-N2 axilla, and 89.8% had invasive ductal carcinoma. A pathologic complete response was observed in 27.6% of the tumors, and 100.0% of samples had free margins. The 5-year actuarial overall survival rate was 81.2%, and the mean follow-up was 72.8 months. The rates of ipsilateral breast tumor recurrence and locoregional recurrence were 11.2% and 15.3%, respectively. Multifocal morphology response was the only factor related to ipsilateral breast tumor recurrence disease-free survival (p=0.04). A multivariate analysis showed that the pathologic response evaluation criteria in solid tumors (RECIST)-breast cutoff was the only factor related to locoregional recurrence disease-free survival (p=0.01). CONCLUSIONS: Breast-conserving surgery is a safe and effective therapy for selected locally advanced breast tumors.

Resumo Objetivo: avaliar se mutações somáticas em câncer de mama e seroso de ovário estão associados com pacientes jovens. Métodos: com base no COSMIC, foram selecionados os cinco genes mais frequentes mutados em câncer de mama e seroso de ovário. Em seguida, realizou-se uma revisão sistemática no PubMed. Pacientes jovens foram classificadas com ≤35 anos e ≤40 anos para câncer de mama e seroso de ovário, respectivamente. Classificaram-se também as pacientes em grupos etários de ≤30 anos, separados a cada 10 anos. Resultados: vinte e seis (1.980 pacientes, 111 jovens) e 16 estudos (598, 41 jovens) foram selecionados para câncer de mama e seroso de ovário, respectivamente. Em câncer de mama, pacientes jovens apresentaram baixa frequência de mutações somáticas em PIK3CA. Tumor HER2 negativo foi associado a mutações somáticas em PIK3CA no grupo etário mais avançado, e em tumores ER positivos foi observada uma tendência a essa associação. Mutações somáticas em TP53 foram observadas em 20% dos tumores, em ambos os grupos (≤35 anos vs. ≥35 anos). Mutações somáticas em PTEN, CDH1 e GATA3 foram analisadas em 16 pacientes e apenas uma apresentou mutação em PTEN. Em câncer seroso de ovário, mutações somáticas em TP53 foram detectadas em mais que 50% dos tumores; entretanto, foram mais frequentes em pacientes idosas. Conclusão: a frequência de mutações somáticas nos genes selecionados não foi associada com pacientes jovens. Embora muito comum em pacientes com câncer seroso de ovário, mutações somáticas em TP53 foram mais frequentes em pacientes mais velhas.

Summary Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤35 and ≤40 years, respectively. Age groups were also classified in <30years and every 10 years thereafter. Results: twenty six (1,980 patients, 111 younger) and 16 studies (598, 41 younger), were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER) status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. Conclusion: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.

Resumo Objetivos: analisar fatores que possam indicar uma predisposição familiar ao câncer de ovário em pacientes com este diagnóstico. Métodos: em estudo de coorte prospectiva realizado no Instituto do Câncer do Estado de São Paulo (ICESP), foram incluídas 51 mulheres diagnosticadas com câncer de ovário entre janeiro de 2009 e dezembro de 2011. Predisposição familiar para câncer de ovário foi definida como um risco maior de 10% de apresentar uma mutação em BRCA1/2, de acordo com o sistema de pontes de Manchester, um método validado para avaliar a probabilidade de detecção de mutação nesses genes. Cada paciente foi entrevistada com um questionário padronizado, abordando fatores de risco para câncer de ovário e outros fatores que pudessem influenciar o risco de desenvolver a doença. O impacto dos fatores avaliados na probabilidade de detecção da mutação foi avaliado com regressões logísticas. Resultados: dezessete das 51 pacientes referiram história familiar de câncer de mama e/ou ovário, quatro pacientes apresentavam antecedente pessoal de câncer de mama ou endométrio, 11 haviam sido diagnosticadas antes dos 50 anos e 12 apresentaram um risco maior que 10% de predisposição familiar a câncer de ovário. Pacientes com comorbidades como hipertensão, diabetes, disfunções hormonais, dislipidemia e distúrbios psiquiátricos apresentaram menor risco de predisposição familiar ao câncer de ovário (OR: 0.22; IC 95%: 0.06-0.88; p=0.03). Conclusão: neste estudo, apresentar alguma comorbidade foi associado a um menor risco de ter uma predisposição familiar ao câncer de ovário. Outros fatores associados ao risco de câncer de ovário não tiveram nenhum impacto sobre esta predisposição.

Summary Objectives: to analyze factors that might indicate familial predisposition for ovarian cancer in patients diagnosed with this disease. Methods: in a prospective single center cohort study at the Institute of Cancer of the State of São Paulo (ICESP), 51 women diagnosed with ovarian cancer were included. Familial predisposition for ovarian cancer was defined as having a higher than 10% chance of having a BRCA1/2 mutation according to the Manchester scoring system, a validated method to assess the likelihood of mutation detection. Each patient was interviewed with a standardized questionnaire on established risk factors for ovarian cancer and other factors that might influence the risk to develop ovarian cancer. Logistic regression analyses were performed to estimate the impact of the evaluated factors on the likelihood of mutation detection, by calculating odds ratios and 95% confidence intervals. Results: seventeen out of 51 patients had a family history of breast and/or ovarian cancer, four patients had a history of breast or endometrial cancer, 11 were diagnosed before the age of 50, and 12 presented a risk of familial predisposition to ovarian cancer higher than 10%. Patients with comorbidities, such as hypertension, diabetes, hormonal disorders, dyslipidemia and psychiatric conditions, presented a lower chance of having a familial predisposition for ovarian cancer (OR: 0.22; 95% CI: 0.06-0.88; p=0.03). Conclusion: in this study, having comorbidities was associated with a lower risk of having a familial predisposition for ovarian cancer. Other factors associated with the risk of ovarian cancer did not have an impact on this predisposition.

Cancer-associated fibroblasts (CAF) influence tumor development at primary as well as in metastatic sites, but there have been no direct comparisons of the transcriptional profiles of stromal cells from different tumor sites. In this study, we used customized cDNA microarrays to compare the gene expression profile of stromal cells from primary tumor (CAF, n = 4), lymph node metastasis (N+, n = 3) and bone marrow (BM, n = 4) obtained from breast cancer patients. Biological validation was done in another 16 samples by RT-qPCR. Differences between CAF vs N+, CAF vs BM and N+ vs BM were represented by 20, 235 and 245 genes, respectively (SAM test, FDR < 0.01). Functional analysis revealed that genes related to development and morphogenesis were overrepresented. In a biological validation set, NOTCH2 was confirmed to be more expressed in N+ (vs CAF) and ADCY2, HECTD1, HNMT, LOX, MACF1, SLC1A3 and USP16 more expressed in BM (vs CAF). Only small differences were observed in the transcriptional profiles of fibroblasts from the primary tumor and lymph node of breast cancer patients, whereas greater differences were observed between bone marrow stromal cells and the other two sites. These differences may reflect the activities of distinct differentiation programs.

OBJETIVO: Na tentativa de melhorar a acurácia dos modelos preditivos de resposta à quimioterapia neoadjuvante em câncer de mama, utilizou-se a tecnologia de cDNA microarray para determinar o perfil transcricional dos tumores. A avaliação de assinaturas gênicas, associadas à predição de resposta à quimioterapia neoadjuvante, é o objeto desta revisão. MÉTODOS: Foi realizada busca no banco de dados eletrônico http://www.ncbi.nlm.nih.gov/pubmed/, usando as palavras "breast cancer" AND "neoadjuvant/primary chemotherapy" AND "gene expression profile/microarray". Recuperaram-se 279 publicações, excluindo-se as repetições, selecionando-se para exposição aquelas consideradas mais relevantes pelos autores. RESULTADOS: O número de publicações acerca desse assunto vem crescendo ao longo dos anos, chegando a mais de 50 em 2010, abordando resposta a diferentes quimioterápicos como antraciclinas, taxanos, isoladamente ou em associação. Os primeiros estudos são do início da década passada e utilizaram plataformas de microarray produzidas pelos pesquisadores. Trabalhos mais recentes utilizam plataformas de microarray comerciais, cujos dados são depositados em bancos públicos, permitindo análise de um número maior de amostras. Foram identificados vários perfis transcricionais associados à resposta patológica completa. Outros autores utilizaram como desfecho a resposta clínica ao tratamento, determinando, nesse caso, um painel preditivo de resistência ao esquema quimioterápico em questão. Essa questão também é fundamental, pois pode contribuir para individualizar o tratamento, permitindo que pacientes resistentes a determinado agente quimioterápico sejam submetidos a outro esquema terapêutico. CONCLUSÃO: A identificação de pacientes responsivos à quimioterapia é de fundamental interesse e, apesar de passos importantes terem sido dados, o assunto merece estudos adicionais em vista de sua complexidade.

OBJECTIVE: To improve the accuracy predictive models of response to neoadjuvante chemotherapy in breast cancer, cDNA microarray technology was used to study tumor transcriptional profile. Gene signatures associated with predicting the response to neoadjuvante chemotherapy are the subject of this review. METHODS: The data base http://www.ncbi.nlm.nih.gov/pubmed/ search was conducted by using the words "breast cancer" AND "neoadjuvante/primary chemotherapy" AND "gene expression profile/microarray". After excluding the repeats and selecting the publications considered most relevant by the authors to be presented, 279 publications were retrieved. RESULTS: The number of publications regarding this subject has been increasing over the years, reaching over 50 in 2010, including the response to different chemotherapeutic drugs, such as anthracyclines and taxanes either alone or in combination. The first studies are from early last decade and used microarray platforms produced by the investigators. Recent studies have used commercial microarray platforms whose data have been stored in public databases, allowing for the analysis of a higher number of samples. Several transcriptional profiles associated with the complete pathological response were identified. Other authors used the clinical response to treatment as an endpoint, and, in this case, a predictive panel of resistance to the chemotherapeutic regimen at issue was determined. This is also a key issue, as it can contribute to individualize treatment, allowing patients resistant to a certain chemotherapeutic agent to be offered another therapeutic regimen. CONCLUSION: Identifying patients responsive to chemotherapy is of essential interest and despite major steps have been taken, the issue warrants further studies in view of its complexity.