Objective: To validate and assess reliability and understanding of the EORTC-C30 quality of life questionnaire and its breast cancer specific module, the EORTC-BR23. Methods: This study was conducted at the AC Camargo Cancer Hospital, São Paulo, Brazil. A total of 100 women diagnosed with breast cancer were interviewed. Internal consistency, confirmatory factorial analysis, convergent validity, construct validity and degree of understanding were examined. Reliability was assessed by comparison of means at times 1 and 2, inter-class coefficient and Bland-Altman graphics. Results: Cronbach's alpha ranged from 0.72 to 0.86 for the EORTC-C30 and from 0.78 to 0.83 for the EORTC-BR23 questionnaire. Most questions were confirmed in the confirmatory factorial analysis. In the construct validity analysis, the questionnaires were capable of differentiating patients with or without lymphedema, apart from the symptom scales of both questionnaires. Both questionnaires presented a significant correlation in most domains of the SF-36, in the convergent validity analysis. Only a few criticisms were reported concerning questions, and the mean grade of understanding was high (C30 = 4.91 and BR23 = 4.89). The questionnaires presented good rates of reliability, with the exception of the functional scale of the C30 and the symptom scale of the BR23. Conclusions: The EORTC-C30 and EORTC-BR23 quality of life questionnaires were validated, presented good rates of reliability and are easily understood, allowing them to be used in Brazil to assess quality of life among women with breast cancer. Keywords

Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with A v B 3 integrin mediated by the disintegrin domain. Altered expression of A v B 3 integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and A v B 3 integrin might negatively modulate A v B 3 activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for A v B 3 integrin activation. Ablation of ADAM23 enhanced A v B 3 integrin activation by at least 2-to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic A v B 3 integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating A v B 3 integrin activation. [Cancer Res 2009;69(13):5546-52]