7545 Background: Temozolomide (T) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (P) is able to down regulate the AGAT activity, so enhancing the antitumor activity of T. From previous phase I study the recommended doses of T were 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1, respectively, every 4 weeks. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination vs single agent T, in patients with advanced melanoma. Patients and Methods: From January 2000 to April 2002, 127 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the 2 arms. Patients with cerebral metastases were included. Patients received T 200mg/m2 /day po for 5 consecutive days every 4 weeks or T+P 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1. Results: Tumor responses (CR and PR) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.6 months in arm A and 5.8 months in arm B. The median survival (OS) was 14.6 months in arm A and 12.4 months in arm B. The difference between treatment arms regarding objective response rates, TTP, OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralias-myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. Conclusion: No clear benefit in terms of response rates, median time to progression or overall survival was shown with the combination of T+P. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Pfizer
Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood–brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.
The role of oncogenes in carcinoma of unknown primary site (CUP) has not yet been elucidated. In the present study the expression of the c-myc p62, ras p21 and c-erB-2 p185 oncoproteins were studied by a 3-step immunoperoxidase technique in 26 cases of CUP. Positive immunoreactivity was observed in 96% of the cases for c-myc, 92% for ras and in 65% for c-erb-2, with at least half of tumor cells labelled in 85%, 92% and 58% respectively. The degree of staining intensity was considered moderate or strong in more than half of the cases for all oncogene products. In conclusion, our results showed that patients with CUP have an extremely high overexpression of all three oncogenes studied. Nevertheless, the biological role of these overexpressed oncoproteins, their relationship with different histological or clinical parameters and their diagnostic or prognostic value need further evaluation.
The aim of this study was the evaluation of p53/MDM-2 protein overexpression in different subtypes of human sarcomas, and their correlation with proliferative activity and patient outcome. We selected 40 cases of human sarcomas comprising 6 malignant fibrous histiocytomas (MFH), 1 fibrosarcoma, 1 dermatofibrosarcoma protuberans, 5 liposarcomas, 9 leiomyosarcomas, 1 rhabdomyosarcoma, 3 synovial sarcomas, 2 osteosarcomas, 1 chondrosarcoma, 4 Ewing's sarcomas, 2 Kaposi's sarcomas, 1 malignant haemangiopericytoma, 1 phylloides cystosarcoma, 1 neuroblastoma, 1 chordoma and 1 unclassified sarcoma. All the immunohistochemical markers, which had been used for the characterization of these sarcomas were re-examined. Additionally, the Streptavidin-Biotin peroxidase method was performed on paraffin sections using the monoclonal antibodies: anti-p53 antibody DO7, anti-MDM-2 antibody IF2 and anti-Ki-67 antibody MIB-1. According to our results, p53 protein nuclear expression was detected in 20% (8/40) of the tumours (1 fibrosarcoma, 2 liposarcomas, 1 leiomyosarcoma, 1 rhabdomyosarcoma, 2 Ewing's sarcomas and 1 unclassified sarcoma). MDM-2 nuclear staining was determined in 7.5% (3/40) of the cases (1 MFH and 2 liposarcomas). A high proliferative index was demonstrated in 27.5% (11/40) of the tumours (2 MFH, 4 leiomyosarcomas, 1 rhabdomyosarcoma, 1 osteosarcoma, 2 Ewing's sarcomas and 1 unclassified sarcoma). p53 overexpression was associated with high tumour grade (p < 0.05) and MIB-1 expression was correlated with reduced survival (p < 0.05), but p53 overexpression was not significantly associated with either MIB-1 score or with overall survival of the patients. In conclusion, from this limited and heterogeneous sample of cases, we suggest that the p53/MDM-2 pathway is involved in the tumourigenesis of several sarcoma subtypes, but it is unclear if the overexpression of these genes may become prognostic marker for patients affected with these highly aggressive tumours.
7545 Background: Temozolomide (T) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (P) is able to down regulate the AGAT activity, so enhancing the antitumor activity of T. From previous phase I study the recommended doses of T were 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1, respectively, every 4 weeks. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination vs single agent T, in patients with advanced melanoma. Patients and Methods: From January 2000 to April 2002, 127 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the 2 arms. Patients with cerebral metastases were included. Patients received T 200mg/m2 /day po for 5 consecutive days every 4 weeks or T+P 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1. Results: Tumor responses (CR and PR) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.6 months in arm A and 5.8 months in arm B. The median survival (OS) was 14.6 months in arm A and 12.4 months in arm B. The difference between treatment arms regarding objective response rates, TTP, OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralias-myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. Conclusion: No clear benefit in terms of response rates, median time to progression or overall survival was shown with the combination of T+P. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Pfizer
Abstract Background: It has been shown that the HER2 and uPA/PAI-1 pathways independently affect the aggressive behavior of breast tumors. While HER2 positive patients have been shown to respond to trastuzumab, the role of uPA and PAI-1 in patients with advanced breast cancer (ABC) treated with trastuzumab is unclear, while the IGF-IR pathway appears to mediate resistance to trastuzumab.Material and Methods: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 138 patients with ABC treated with trastuzumab in the first-line. Clinical information was retrieved from medical records. The median age of the patients was 55 years, with 31% being premenopausal. HER2, IGF-IRa, IGF-IRb, uPA, PAI-1, Ki-67, ER, and PgR were assessed centrally by immunohistochemistry (IHC), while HER2 was also assessed centrally by FISH. All stains were examined by 2 independent pathologists, using the Allred 8-unit system for IGF-IRa and IGF-IRb, a combination of a proportion score from 0 to 5 and an intensity score on a scale of 0 to 3 (none, weak, moderate, strong). uPA protein expression was considered positive if >75% of the cells showed intense staining, with PAI-1 deemed positive when >6% of the cells showed mild staining. PFS and survival from the initiation of trastuzumab were estimated by the Kaplan-Meier method and compared using the log-rank test.Results: Trastuzumab alone or in combination with chemotherapy and/or hormonal therapy was given as first-line treatment in all patients. HER2 gene amplification was confirmed in 89 cases, while in 49 patients HER2 was found to be non-amplified (HER2 negative patients). As expected, survival of HER2 positive patients was found to be significantly longer (50.7 months vs. 30.5 months, p<0.0001), with no significant differences found in PFS (14.0 months vs. 9.2 months, p=0.124). IGF-IRa, IGF-IRb, uPA, or PAI-1 positive patients were not found to have significantly different PFS or survival in either HER2 positive or negative patients.Discussion: Protein expression of IGF-IRa, IGF-IRb, uPA, or PAI-1 assessed by IHC was not found to be associated with significantly different survival in patients with advanced breast cancer treated with trastuzumab in the current analysis. Studies are ongoing to include patients receiving second-line treatment with trastuzumab and evaluation of PI3K mutations. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2036.
