E Mrozek1, J Kolesar2, D Young3, J Allen4, M Villalona-Calero5, C L Shapiro6. 1. Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing; Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus. Electronic address: ewa.mrozek@osumc.edu. 2. School of Pharmacy, University of Wisconsin, Madison. 3. Center for Biostatistics, Comprehensive Cancer Center, The Ohio State University, Columbus. 4. Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus; Clinical Trials Office, Comprehensive Cancer Center, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA. 5. Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing. 6. Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing; Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus.
Abstract
BACKGROUND: Preclinical studies show that mitomycin-C (MMC) followed by irinotecan (CPT-11) is synergistic. Therefore, we evaluated the toxicity and efficacy of sequentially administered low-dose MMC and CPT-11 in patients (pts) with pretreated metastatic breast cancer (MBC). Secondary objective was to evaluate the correlation between MMC-induced topoisomerase I (TOPO I) expression and NAD(P)H:quinone oxireductase 1 (NQO1) genotypes in peripheral blood mononuclear cells (PBMC) and efficacy or toxicity of the regimen. DESIGN: Thirty-two pts received MMC i.v. 6 mg/m(2) day 1 and CPT-11 i.v. 125 mg/m(2) days 2 and 8 every 28 days for maximum of six cycles. TOPO I expression and NQO1 reductase genotyping in 23 of 32 (72%) pts were assayed by PCR. RESULTS: The median time to progression (TTP) was 4.7 months (95% confidence interval 4.0-5.4 months). TOPO I expression was increased 5- to 10-fold and 20- to 30-fold in PBMC at 24 and 168 h, respectively. There was no relationship between these markers and efficacy or toxicity of the regimen. CONCLUSIONS: Sequential low-dose MMC and CPT-11 was active and tolerable by pretreated MBC pts. Future trials should focus on less pretreated MBC pts and sequential tumor biopsies to test the hypothesis that increased intratumoral expression of TOPO I is related to efficacy.
BACKGROUND: Preclinical studies show that mitomycin-C (MMC) followed by irinotecan (CPT-11) is synergistic. Therefore, we evaluated the toxicity and efficacy of sequentially administered low-dose MMC and CPT-11 in patients (pts) with pretreated metastatic breast cancer (MBC). Secondary objective was to evaluate the correlation between MMC-induced topoisomerase I (TOPO I) expression and NAD(P)H:quinone oxireductase 1 (NQO1) genotypes in peripheral blood mononuclear cells (PBMC) and efficacy or toxicity of the regimen. DESIGN: Thirty-two pts received MMC i.v. 6 mg/m(2) day 1 and CPT-11 i.v. 125 mg/m(2) days 2 and 8 every 28 days for maximum of six cycles. TOPO I expression and NQO1 reductase genotyping in 23 of 32 (72%) pts were assayed by PCR. RESULTS: The median time to progression (TTP) was 4.7 months (95% confidence interval 4.0-5.4 months). TOPO I expression was increased 5- to 10-fold and 20- to 30-fold in PBMC at 24 and 168 h, respectively. There was no relationship between these markers and efficacy or toxicity of the regimen. CONCLUSIONS: Sequential low-dose MMC and CPT-11 was active and tolerable by pretreated MBCpts. Future trials should focus on less pretreated MBCpts and sequential tumor biopsies to test the hypothesis that increased intratumoral expression of TOPO I is related to efficacy.