Phase II study of gemcitabine and carboplatin in metastatic breast cancers with prior exposure to anthracyclines and taxanes.

BACKGROUND: Patients with metastatic breast cancer (MBC) are usually exposed to both anthracyclines and taxanes during neoadjuvant or adjuvant treatment of primary breast cancer or during initial therapy of MBC. We investigate the combination of gemcitabine and carboplatin in MBC with prior exposure to both anthracyclines and taxanes. PATIENTS AND METHODS: MBC patients previously treated with anthracyclines and taxanes were enrolled in a single tertiary center phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) I.V on days 1 and 8) and carboplatin (AUC 5 I.V on day 1) administered every 3 weeks. Results 41 patients were recruited. Objective response rate was 39% including 1 complete response (2%) and 15 partial responses (37%). Twelve patients (29%) had stable disease. Median time to progression was 4.6 months (95% CI 3.3-5.9 months) and median overall survival 10.5 months (95% CI 7.6-13.4 months). Grade 3 & 4 hematological toxicities included neutropenia (58%), febrile neutropenia (15%), anemia (12%) and thrombocytopenia (49%), including 7% who required platelet transfusions. Non-hematological toxicity was rarely severe. 56% of patients required at least one dose reduction; the mean relative dose intensity for gemcitabine and carboplatin were 0.82 (range 0.5-1.0) and 0.95 (range 0.75-1.00) respectively, with no difference in dose intensity between responders and non-responders. CONCLUSION: Gemcitabine combined with carboplatin has promising efficacy in MBC with prior treatment with anthracyclines and taxanes but has significant haematological toxicities requiring dose modifications. The regimen may be modified to gemcitabine 800 mg/m(2) days 1 and 8 to improve tolerability.

Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer.

OBJECTIVE: Tumor gene expression signatures have been used to classify, prognosticate, and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short-term and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures. METHODS: Using a set of 47 breast cancer patients, we obtained paired prechemotherapy and postchemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), postchemotherapy tumor (T2), and chemotherapy-induced relative change signatures (TDelta) to predict pathological response and progression-free survival (PFS). The signatures were validated in two independent test sets with paired prechemotherapy and postchemotherapy tumor samples, comprising of 18-20 patients each. RESULTS: T2 and TDelta were superior to T1 signatures in predicting for PFS (area under the curve of receiver operating characteristic 0.770 and 0.660 vs. 0.530) and pathological response (area under the curve of receiver operating characteristic 0.631 and 0.462 vs. 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2, but not T1, signatures remained as significant independent predictors. CONCLUSION: Postchemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.

A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers.

PURPOSE: The aims were to determine the maximum tolerable dose (MTD) of docetaxel with CYP3A inhibition by ketoconazole, and to correlate the pharmacokinetics of docetaxel with midazolam phenotyping of CYP3A activity. METHODS: Forty-one patients with refractory metastatic cancers were treated with an escalating dose of intravenous docetaxel once in every 3 week of 10 mg/m(2), concurrently with oral ketoconazole 200 mg twice daily for 3 days starting 2 days before the administration of docetaxel. Midazolam phenotyping test with ketoconazole modulation was performed before the first cycle of docetaxel. Docetaxel and midazolam pharmacokinetics were compared to our previous study of docetaxel treatment without ketoconazole modulation. RESULTS: Neutropenia was the dose-limiting toxicity. The maximum tolerated dose was 70 mg with mean AUC at 70 mg similar to 75 mg/m(2) of docetaxel without ketoconazole. The plasma clearances of docetaxel and midazolam were reduced by 1.7- and 6-fold, respectively. The variability of midazolam AUC was reduced from 157 to 67%, but variability of docetaxel clearance was not reduced by CYP3A inhibition. Docetaxel clearance correlated with renal function and maximum concentration of ketoconazole, but not midazolam clearance or other variables of hepatic function. CONCLUSION: Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.

Lack of somatic ErbB2 tyrosine kinase domain mutations in hepatocellular carcinoma.

AIM: Small molecules targeting the epidermal growth factor receptor (EGFR) intracellular tyrosine kinase domain have shown promising activity in cancer therapeutics. Recent reports suggest activity of erlotinib, an ErbB1 inhibitor, and lapatinib, a dual inhibitor of ErbB1 and ErbB2, in hepatocellular carcinoma (HCC). Activating ErbB1 somatic mutations may predict treatment responses. METHOD AND RESULTS: We have previously reported ErbB1 tyrosine kinase domain mutations to be rare or absent in HCC, but data on the frequency of ErbB2 tyrosine kinase domain mutations in HCC is currently limited, apart from reports of a missense mutation identified in 11% of a small Caucasian sample. We studied exons 18-23 of the ErbB2 gene from tumor DNA of 100 Asian human HCC and found no exonic mutations of potential significance. CONCLUSION: Alternative mechanisms may be responsible for the observed therapeutic efficacy of ErbB1 and ErbB2 tyrosine kinase inhibitors.

Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies.

PURPOSE: To determine the safety and tolerability of ABT-869 at escalating doses and its effects on biomarkers relevant for antiangiogenic activity in patients with solid malignancies. PATIENTS AND METHODS: Patients with solid malignancies refractory to or for which no standard effective therapy exists were enrolled onto escalating-dose cohorts and treated with oral ABT-869 once daily continuously. RESULTS: Thirty-three patients were studied at doses of 10 mg/d, 0.1 mg/kg/d, 0.25 mg/kg/d, and 0.3 mg/kg/d. Dose-limiting toxicities in the first cycle (21 days) included grade 3 fatigue in a patient at 10 mg/d, grade 3 proteinuria and grade 3 hypertension in two separate patients at 0.25 mg/kg/d, and grade 3 hypertension and grade 3 proteinuria in two separate patients at 0.3 mg/kg/d, which was the maximum-tolerated dose. Other significant treatment-related adverse events included asthenia, hand and foot blisters, and myalgia. Oral clearance of ABT-869 was linear, with a mean of 2.7 +/- 1.2 L/h and half-life of 18.4 +/- 5.7 hours, with no evidence of drug accumulation at day 15. Two patients with lung cancer and one patient with colon cancer achieved partial response. Stable disease for more than four cycles was observed in 16 patients (48%). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed dose-dependent reduced tumor vascular permeability that correlated with drug exposure. By day 15 of treatment, circulating endothelial cells were significantly reduced (P = .007), whereas plasma vascular endothelial growth factor was increased (P = .004). CONCLUSION: ABT-869 by continuous once-daily dosing was tolerable at doses

Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity.

OBJECTIVES: Doxorubicin is a cytotoxic drug with potential for severe myelosuppression that is highly variable and poorly predictable. METHODS: We correlated CBR1 and CBR3 genotypes with the pharmacokinetics and pharmacodynamics of doxorubicin in 101 Southeast Asian breast cancer patients receiving first-line doxorubicin. RESULTS: A common CBR3 11G>A variant was associated with lower doxorubicinol area under the concentration-time curve (AUC)/doxorubicin AUC metabolite ratio (P=0.009, GG vs. AA; trend test, P=0.004), lower CBR3 expression in breast tumor tissue (P=0.001, GG vs. AA), greater tumor reduction (P=0.015, GG vs. AA), and greater percentage reduction of leukocyte and platelet counts at nadir (trend test, P < or = 0.03). Chinese and Malays had higher frequency of the CBR3 11G>A variant than Indians (P < or = 0.002). Another variant CBR3 730G>A was associated with higher doxorubicinol AUC (P=0.009, GG vs. AA) and CBR3 expression in breast tumor tissue (P=0.001, GG vs AA). CONCLUSION: Polymorphisms in CBR3 may explain interindividual and interethnic variability of doxorubicin pharmacokinetics and pharmacodynamics.

Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.

The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan-induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90-min intravenous infusion of 375 mg/m(2) once every 3 weeks (n = 45). Genotypic-phenotypic correlates showed a non-significant influence of UGT1A1*28 and ABCG2 c.421C>A polymorphisms on the pharmacokinetics of SN-38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN-38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC < or = 500/microL) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3-fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN-38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study.

Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients.

OBJECTIVE: To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients. EXPERIMENTAL DESIGN: Irinotecan was administered over 90 min either at 100 mg/m on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m once every three weeks (N=43). Plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecinG were analysed after the first dose of the first cycle and the influence of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on the disposition of irinotecan and its metabolites were evaluated. RESULTS: Pharmacokinetic parameters were obtained from 71 cancer patients. Genotypic-phenotypic correlates showed the clearance of irinotecan to be 3-fold lower in patients carrying the *15 haplotype than cancer patients with the reference genotype *1a/*1a (9.57+/-3.15 vs. 28.86+/-10.97 l/h/m; P=0.001). The area under the plasma concentration-time curve from zero to infinity and normalized by dose and body surface area (AUC0-nf/dose/BSA) were significantly higher in patients harbouring the *15 haplotype than patients with the reference genotype for irinotecan (39.27+/-15.17 vs. 17.32+/-6.30 h/m; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28+/-0.53 vs. 0.69+/-0.32 h/m; P=0.021). The exposure levels to 7-ethyl-10-hydroxycamptothecinG also showed a statistically significant trend among the SLCO1B1 haplotype pairs, being approximately 10-fold lower in patients with *15 haplotype than with patients harbouring the reference genotype (3.57+/-1.95 vs. 12.0+/-6.09 h/m; P=0.016). CONCLUSION: These findings suggest that (1) SLCO1B1 haplotypes may have a significant influence on the disposition of irinotecan and its metabolites in Asian cancer patients, and (2) patients with SLCO1B1*15 haplotype may be susceptible to increased sensitivity to irinotecan, which may manifest itself either by increased efficacy or toxicity or both owing to the increased exposure levels to 7-ethyl-10-hydroxycamptothecin.