): This revised application for funding is part of a multidisciplinary CALGB research project targeting elderly women with breast cancer. This study is a laboratory companion to the clinical trial proposed by the CALGB, entitled,"""""""" A Randomized Trial of Adjuvant Chemotherapy with Standard Regimens, Cyclophosphamide, Methotrexate and Fluorouracil- """"""""CMF"""""""" or Cyclophosphamide and Doxorubicin -""""""""AC"""""""" versus Capecitabine in Women 65 Years and Older with Early?? Stage Breast cancer. The primary aim of the clinical trial is to compare the effectiveness of standard chemotherapy regimens (CMF or AC) with a less toxic, single agent (Capecitabine), with respect to five-year relapse free survival in women 65 years and older with early stage breast cancer. The laboratory companion is designed to evaluate tumor specimens (formalin-fixed paraffin-embedded, FFPE) that are collected as part of the CALGB clinical trial to examine the relationships between biological markers of tumor progression and clinical outcome in elderly women with early stage breast cancer. We have selected tumor markers that are associated with metabolic pathways of chemotherapy action as well as those associated with common pathways of tumor progression. We will evaluate whether specific markers of capecitabine metabolism, thymidylate synthetase, thymidine phosphorylase and dihyodropyrimidine dehydrogenase gene expression (mRNA) can predict recurrence and survival in patients treated with capecitabine. We will also determine whether local regional or distant failure can be predicted in this population based on a tumor marker profile that reflects markers of genetic instability/proliferation in the primary tumors, (protein expression of p53, erbB2/HER2, and KI-67 (MIB-1) as well as markers of invasion and metastasis (angeogenesis, focal adhesion kinase, VEGF and e-cadherin). The expression of these markers will be correlated with conventional markers of tumor size, histologic and nuclear grade, and estrogen and progesterone receptor status. In addition, comparisons of tumor marker expression between elderly and younger populations with node positive breast cancer (patients from this adjuvant chemotherapy trial and CALGB 8541) will be performed. It will also be possible to compare tumor marker expression between elderly patients with stage I and stage II breast cancer (patients from this adjuvant chemotherapy trial and CALGB 9343). Two subcontracts are included in this proposal, one to support the CALGB Pathology Coordinating Office functions at OSU relevant to this study and the other in support of the molecular studies being performed by USC.
| Danenberg, Peter V (2004) Pharmacogenomics of thymidylate synthase in cancer treatment. Front Biosci 9:2484-94 |
