الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most common malignant disease in women, with an increasing incidence worldwide especially in developing countries. In Egypt, breast cancer is the most prevalent cancer among women as it constitutes 29% of the National Cancer Institute cases.
Anthracycline-containing therapies are superior to cyclophosphamide, methotrexate and 5-fluorouracil (CMF) combinations. However, all anthracyclines produce cardiac damage that can result in serious complications. Because no predictive biomarker for response to chemotherapy is currently available to guide the choice of cytotoxic chemotherapy for breast cancer, the choice of drugs is usually empiric and 30%-70% of patients fail to respond. Moreover, financing cancer treatment is a major challenge especially for developing countries. This elucidates the importance of the predictive factors in tailoring of chemotherapy.
The aim of the present work was to study the possible predictive value of HER2/neu protein, TOPOIIα gene, BRCA1 gene methylation and hormone receptors (ER/PR) for the outcome of FAC adjuvant chemotherapy. The predictive value was assessed in high risk female breast cancer patients as regards: (i) DFS and OS over the study period and (ii) type and time of relapse over the study period.
In order to achieve this goal, 50 high risk female breast cancer patients, with operable breast cancer, were randomly recruited from the Clinical Oncology department of Alexandria Main University Hospital. All of them have received FAC adjuvant chemotherapy between January 2007 and December 2007. The studied patients’ breast tumor samples were obtained from formalin fixed/paraffin-embedded tissue blocks, from the archives of the Pathology Department of Alexandria Main University Hospital before chemotherapy treatment. Patients were followed for 2 years to detect local recurrence or distant metastasis. In addition, cardiotoxicity from anthracyclines and deaths were recorded. All tumor samples were subjected to full histopathological examination and to hormone receptor (ER and PR) state determination by IHC analysis. Besides, tumors were subjected to: (i) determination of HER2/neu protein state by IHC, (ii) determination of TOPOIIα gene state by semi-quantitative PCR analysis and (iii) determination of BRCA1 gene methylation state by MSP analysis.
Kaplan-Meier survival analysis showed that positive HER2/neu protein score, TOPOIIα gene aberrations, methylated BRCA1 gene, negative ER and negative combined ER/PR proteins states were associated with a statistically significantly superior 2-year DFS after FAC therapy. Moreover, BRCA1 gene methylation and ER protein states might be considered as independent predictors for the outcome of FAC adjuvant chemotherapy while HER2/neu protein and TOPOIIα gene mightn’t. Consequently, when proved by large-scale studies with longer follow-up periods, BRCA1 gene methylation and ER protein might be considered when planning chemotherapy for such patients. In addition, large-scale prospective studies are needed to clearly define the predictive value HER2/neu protein and TOPOIIα gene predictive value.
Another point of interest in the current results was the significant relation between HER2/neu protein state and TOPOIIα gene state, as TOPOIIα gene aberrations were detected in 91.7% of positive HER2/neu protein cases. Additionally, there was a subset of HER2/neu negative tumors that were FAC-sensitive probably due to interplay of other factors which gives further support to the use of a panel of predictive markers for tailoring of chemotherapy.
In the current study, patients having BRCA1 gene methylation were found to be at risk of having distant metastasis. Consequently, when proved by large-scale studies, such patients would be recommended for intensified follow-up and treatment. On the other hand, the other studied biomarkers failed to show a statistically significant relation to the type of relapse. None of the studied biomarkers proved to be a statistically significant predictor to the time of relapse as well.
Finally, although being statistically insignificant, 2-year DFS rate of triple (ER, PR and HER2/neu)-negative-FAC-treated patients was slightly better than that of non-TNBC cases. On the other hand, the 2-year OS of FAC-treated TNBC patients was slightly worse than that of non-TNBC patients. TNBC, being an important category having no specific or targeted therapy, requires detailed study to reveal the possible therapeutic options for such patients.