Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues

Abstract

We studied the relationship between response of breast cancer to docetaxel (DOC) or cylophosphamide ؉ epirubucin (CE) treatment and CYP3A4 mRNA expression in breast tumors. CYP3A4 inactivates DOC but not E, which is a predominant effector in CE treatment. Twenty patients with locally advanced breast tumors and 18 patients with locally recurrent tumors underwent tumor biopsy before chemotherapy, and CYP3A4 mRNA expression levels in tumor tissues were assayed by real-time quantitative polymerase chain reaction. Twenty-three patients were treated with DOC (60 mg/m 2 q3w) and 15 patients were treated with CE (C 600 mg/m 2 and E 60 mg/m 2 q3w). Patients with low CYP3A4 mRNA levels (n ‫؍‬ 14) exhibited a significantly (p < 0.01) higher response rate (71%) to DOC treatment than those (n ‫؍‬ 9) with high CYP3A4 mRNA levels (response rate, 11%). Positive predictive value, negative predictive value and diagnostic accuracy of CYP3A4 mRNA levels in the prediction of response to DOC were 71, 89, and 78%, respectively. However, no significant association was observed between CYP3A4 mRNA expression and response to CE treatment. These results suggest that intratumoral CYP3A4 mRNA levels might be useful as a predictor of response to DOC treatment, but not to CE treatment, in breast cancer patients. The increased inactivation of DOC by CYP3A4 in tumor tissues may play some role in the acquisition of resistance to DOC.

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

“…This finding confirms previous results testing C-1311 under non-cellular conditions [16] . Namely, this compound was not metabolized by CYP3A4, which is the P450 isoenzyme with the highest abundance in the human liver and which contributes to the oxidative metabolism of more than 60% of all clinically used drugs, including antitumor agents such as cyclophosphamide [32] , ifosfamide [33] , paclitaxel [34] , tamoxifen [35,36] and doxorubicin [37] . The resistance of C-1311 to the action of other cytochrome P450 enzymes was shown previously with human recombinant enzymes from the CYP1A, CYP2C and CYP2D families [16] .…”

Cytochrome P450 pharmacogenetics and cancer

“…The model of predictive value in terms of survival, time to treatment failure and tumour growth showed that the tumour phenotype was indeed related to the therapeutic response to 5-fluorouracil (Tanaka et al, 2004). Miyoshi et al (2002Miyoshi et al ( , 2005 showed that a low CYP3A4 expression in breast tumours, as determined at mRNA and protein level, resulted in a better response to docetaxel, which is inactivated by CYP3A4. Similarly, Dhaini et al (2003) showed that a high CYP3A expression in osteosarcoma tumours from 18 patients predicted metastasis and poor prognosis.…”

“…Furthermore, Yamamoto et al (2005) phenotyped CYP3A4 in patients with advanced nonsmall-cell lung cancer by measuring urinary 6-beta-OHF after cortisol administration and found that an individualized dosing method, based on CYP3A4 phenotyping, decreased the pharmacokinetic variability of docetaxel when compared to body-surface area-based dosing (Yamamoto et al, 2005). In addition, CYP3A4 expression in breast tumour tissue has been shown to predict therapeutic response to docetaxel (Miyoshi et al, 2002(Miyoshi et al, , 2005. Similarly to docetaxel, irinotecan is inactivated by CYP3A4 and induction of CYP3A4 in patients receiving irinotecan results in a significant decrease in the formation of the toxic metabolite of this drug (Friedman et al, 1999;Mathijssen et al, 2002).…”

Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): trends and problems

“…Its potential as a clinical diagnostic assay (Bustin & Dorudi 1998) is also being realised, and its use has been reported for the identification of micrometastases or minimal residual disease in colorectal cancer (Bustin et al 1999), neuroblastoma (Cheung & Cheung 2001), prostate cancer (Gelmini et al 2001) and leukaemia (Buonamici et al 2002). It has been used to distinguish different types of lymphoma (Bijwaard et al 2001), for the analysis of cellular immune responses in the peripheral blood (Hempel et al 2002), the detection of bacterial (Goerke et al 2001) and viral (Greijer et al 2002) RNA in clinical samples and for monitoring the response of human cancer to drugs (Miyoshi et al 2002). Other clinically relevant applications include its use for the detection of gene amplification in breast cancer (Bieche et al 1999), for the analysis of tissue-specific gene expression and for cytokine mRNA profiling (Stordeur et al 2002).…”