- © 2010 by American Society of Clinical Oncology
ABCC2 and Clinical Outcome of Tamoxifen Therapy
To the Editor:
The study by Kiyotani et al1 is another important contribution to the field of tamoxifen (TAM) pharmacogenomics in favor of CYP2D6 genetic testing for the improvement of TAM response in postmenopausal Japanese patients with breast cancer. In addition, for the first time, the authors identified a significant association between the rs3740065 G allele (intron 29, IVS29+154A>G) of the ABC efflux drug transporter ABCC2 (multidrug related protein [MRP2]) and longer recurrence-free survival compared with individuals carrying the A allele in their study population of 282 patients. Because TAM-resistant MCF-7 cells express higher levels of ABCC2 than nonresistant MCF-7 cells,2 it has been suggested that ABCC2 induction could play a role in TAM resistance. On these grounds, Kiyotani et al1 speculated that the rs3740065 variant may be associated with increased ABCC2 expression and enhanced transport activity, thereby lowering the exposure of breast cancer cells to endoxifen, the active metabolite of TAM.3 However, in their study, the G allele was associated with longer recurrence-free survival, which would rather indicate a lower expression of ABCC2 and, hence, reduced transporter activity in breast cancer cells, resulting in higher intracellular endoxifen levels.
Recently, a systematic DNA sequencing study that included 236 healthy individuals of Japanese ethnic background showed that a common promoter variant in ABCC2 (−1774delG) is in strong linkage disequilibrium with rs3740065.4 Moreover, functional studies revealed that the −1774delG variation decreased ABCC2 promoter activity by 36% and that the promoter carrying the −1774delG allele had a defect in chenodeoxycholic acid–induced induction of promoter activity.5 Finally, a haplotype containing the −1774delG polymorphism showed a strong association with cholestatic or mixed-type hepatitis.5
We, therefore, propose that it is the −1774delG variant that can explain the findings of an association between ABCC2 and TAM outcome reported by Kiyotani et al.1 Unfortunately, the authors did not include the −1774delG variant in their investigation. Therefore, the issue of ABCC2 variants that predict clinical outcome must await more specific studies.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Hiltrud Brauch, AstraZeneca; Matthias Schwab, Roche Molecular Diagnostics Research Funding: Hiltrud Brauch, Roche Molecular Diagnostics; Matthias Schwab, Roche Molecular Diagnostics Expert Testimony: None Other Remuneration: None
