Letter to the editor

Gastric cancer is an important cause of cancer death worldwide and in Brazil. Given the recent studies on this disease's mortality and survival rates in our country, we offer a view on future research possibilities

Survival and prognosis of young adults with gastric cancer

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 Sa˜o Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (p40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: X66 years; N=94). Differences were assessed through Pearson’s w2 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; po0.01) 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

Breast-conserving surgery in locally advanced breast cancer submitted to neoadjuvant chemotherapy. Safety and effectiveness based on ipsilateral breast tumor recurrence and long-term follow-up

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

Association of family risk and lifestyle/comorbidities in ovarian cancer patients

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

Somatic mutations in breast and serous ovarian cancer young patients:a systematic review and meta-analysis

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 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

Cadherins and repressor tumor factor expression in breast cancer patients in the presence or absence of malignant cells in bone marrow

OBJETIVO: Acredita-se que o perfil gênico do tumor é diferente daquele do tecido normal. Além disso, é possível que o tumor adquira características que lhe conferem potencial de gerar metástases em sítios específicos. A expressão tumoral de Caderinas 3 e 11 (envolvidas em adesão e migração celular), e de CBX3 (repressor transcricional) pode estar relacionada a maior agressividade e potencial invasivo em pacientes com câncer de mama (CM). Nosso objetivo é comparar a expressão de Caderina 3, Caderina 11 e CBX3 em tumor e tecido mamário normal adjacente e correlacionar a expressão tumoral destes genes com colonização da medula óssea (MO) por células tumorais. MÉTODOS: Amostras de tumor, tecido normal peritumoral e MO foram obtidas de 30 pacientes com CM estadio clínico I-III. A expressão de Caderina 3, Caderina 11 e CBX3 foi avaliada por RT-PCR em tempo real. A presença de células malignas em MO foi determinada por detecção da expressão de citoqueratina 19 por Nested-RT-PCR. RESULTADOS: Dezessete pacientes (56,7%) apresentaram células malignas em MO. Houve maior expressão de Caderina 3 e Caderina 11, mas não de CBX3 em tumor em relação ao tecido normal. Não encontramos associação entre expressão tumoral de Caderina 3, Caderina11 e CBX3 e a presença de células malignas em MO. CONCLUSÃO: A hiperexpressão de Caderina 3 e 11 em tumores em relação ao tecido normal sugere que estes transcritos possa mestar relacionados à carcinogênese. A expressão tumoral de Caderina 3, Caderina 11 e CBX3 não parece associada com a disseminação para a MO.PURPOSE: Gene profile is believed to be different in tumor and normal tissue. Besides, it is possible that tumor acquires characteristics that provide ability to develop metastasis in specific sites. Tumoral expression of Cadherins 3 and 11 (involved with adhesion and cellular migration) and CBX3 (transcriptional repressor) may be related to aggressiveness and lower survival in breast cancer (BC) patients. Our purpose is to compare tumoral and normal mammary tissue expression of Cadherin 3, Cadherin 11 and CBX3 and to correlate tumoral expression of these genes with bone marrow (BM) colonization by tumoral cells. METHODS: Samples of tumor, normal tissue and BM were obtained from 30 BC patients stage I-III. Expression of Cadherin 3, Cadherin 11 and CBX3 were analysed by RT- PCR-Real Time. Malignant cells in BM were determined by CK19 expression in Nested-PCR. RESULTS: Seventeen patients (56,7%) had malignat cells in BM. There was hiperexpression of Cadherin 3 and Cadherin11, but not of CBX3, in tumor in relation to normal tissue. We did not fi nd association between tumor expression of Cadherin 3, Cadherin 11 and CBx3 and presence of tumor cells in BM. CONCLUSIONS: Hiperexpression of Cadherin 3 and Cadherin 11 in tumor in relation to normal tissue suggests that these genes can be associated to carcinogenesis. Tumor expression of Cadherin 3, Cadherin 11 and CBX3 were not associated to BM dissemination

Germline and Somatic mutations in postmenopausal breast cancer patients

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

Cost effectiveness of the cancer prevention program for carriers of the BRCA1/2 mutation

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

Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil

Introduction The contribution of CDH1 germline variants to gastric cancer burden among young adults is unknown in Brazil. We aimed to evaluate the frequency of CDH1 germline variants and the diet/lifestyle habits in early age onset gastric cancer (EOGC, A, c.387G>T, c.1676G>A, and c.1806C>A. The MLPA results revealed no rearrangements and CDH1 transcription analysis for variants of interest were inconclusive. EOGC patients had a higher red (OR:2.6, 95%CI:1.4-4.9) and processed (OR:3.1, 95%CI:1.6-6.0) meat intake and higher fruit consumption (OR:0.4, 95%IC:0.3-0.7) compared to eating habits of the Brazilian population. Conclusions No unequivocal pathogenic germline CDH1 variants were identified in Brazilian EOGC patients. Dietary habits may be associated with the EOGC development