ABSTRACT
BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , ErbB Receptors/metabolism , Genes, erbB-2 , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Metastasis , PTEN Phosphohydrolase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Adult , Aged , Antibodies, Monoclonal, Humanized , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Trastuzumab , Treatment OutcomeABSTRACT
Breast cancer is a major health problem, and disease control depends on an effective healthcare system. A registry-based tool to monitor the quality of breast cancer care could be useful. The aim of this study was to develop a population survival model for breast cancer based on the Nottingham Prognostic Model (NPM). To this end, 1452 cases of breast cancer diagnosed in the Umbria Region, Italy, during the period 1994-1996 were studied. An extensive search for routinely available variants in prognosis and treatment was performed. In about 80% of cases complete information on factors included in the NPM was available. The Cox model was used to assess the prognostic value of study factors. Nodal stage was the most important prognostic factor. In women who did not undergo axillary dissection (17%) the risk of death was twice that in women with no affected nodes, but they received chemotherapy with the same frequency. Radiotherapy was also less frequently used in this group. Grading was a significant prognostic factor only when women over 80 were excluded. Population survival models based on data from cancer registries may provide a tool that can be used to evaluate healthcare systems and the effectiveness of interventions. The inclusion of older women in our models decreased the significance of many established prognostic factors because of the frequency of incomplete evaluation and less aggressive treatment in these patients. Not undergoing surgical axillary dissection was associated with a worse prognosis and with less aggressive treatment.
Subject(s)
Breast Neoplasms/mortality , Registries/statistics & numerical data , Aged , Aged, 80 and over , Breast Neoplasms/therapy , Cohort Studies , Female , Humans , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Survival AnalysisABSTRACT
Biopsies were taken from the vastus lateralis muscle of 26 chronic uremic patients before and after a 24-week treatment with L-carnitine given at the dose of 2 g i.v. at the end of hemodialysis, or in dialysis solution, or per os twice daily. The aim of the study was to evaluate both the muscle morphology in dialyzed subjects and the modification provoked by the therapy. All patients manifested a significant, even if variable, degree of muscular atrophy which involved all types of muscle fibers. After the treatment there was an increase of about 7% in the diameter of type I and type IIa fibers, which can utilize carnitine for fatty acid oxidation to produce energy, and a reduction in the atrophic fibers. No noteworthy changes were documented in type IIb fibers, which depend on glycolysis for energy production.
