Abstract
There is substantial evidence that circulating estrogens promote the proliferation of breast cancer. Consequently, adjuvant hormonal treatment strategies targeting estrogen action have been established. Such hormonal therapies include selective estrogen receptor modulators, such as tamoxifen, which interfere at the estrogen receptors directly, or non-steroidal aromatase inhibitors, such as anastrozole and letrozole, which inhibit estrogen synthesis through blocking the aromatase, a key enzyme of estrogen production. Despite considerable therapeutic success, in several cases, the use of these drugs is limited by side effects that have been described to significantly impair the adherence of patients to endocrine treatment. However, objective data concerning patient adherence and its clinical relevance are limited. One promising approach to check patient-reported adherence is drug monitoring in human plasma. Therefore, a liquid chromatography–tandem mass spectrometry method to determine the plasma concentrations of tamoxifen, anastrozole, and letrozole has been developed and fully validated according to guidelines for clinical and forensic toxicology. The validation criteria evaluated were selectivity, linearity, accuracy and precision, limit of quantification, recovery and matrix effects, sample stability, and carryover. The six-point calibration curves showed linearity over the range of concentrations from 25 to 500 ng/ml for tamoxifen, 5 to 200 ng/ml for anastrozole, and 10 to 300 ng/ml for letrozole. The intra- and inter-day precision and accuracies were always better than 15%. The validated procedure was successfully applied to a clinical study (Patient-Reported Outcomes in Breast Cancer Patients undergoing Endocrine Therapy, PRO-BETh). A major aim of PRO-BETh study is the comprehensive evaluation of adherence to treatment in pre- and post-menopausal women with breast cancer. Plasma samples of 310 breast cancer patients undergoing anti-estrogen therapy were analyzed. Eight samples did not contain a quantifiable amount of drug, strongly indicating non-adherence of the corresponding patients to adjuvant breast cancer treatment. Furthermore, plasma concentrations at the lower end of the observed plasma level distribution might represent a hint but not a confirmation for non-adherence in terms of non-daily and irregular intake of the prescribed drug.
Similar content being viewed by others
References
Hortobagyi GN, de la Garza SJ, Pritchard K, Amadori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O’Shaughnessy JA, Shen ZZ, Albain KS (2005) Clin Breast Cancer 6:391
Hiscox S, Davies EL, Barrett-Lee P (2009) Maturitas 63:275
Choueiri TK, Alemany CA, Bou-Jawde RM, Budd GT (2004) Clin Ther 26:1199
Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI (2008) Cancer Treat Rev 34:157
Hind D, Ward S, De NE, Simpson E, Carroll C, Wyld L (2007) Health Technol Assess 11:1
Musgrove EA, Sutherland RL (2009) Nat Rev Cancer 9:631
Robinson E, Kimmick GG, Muss HB (1996) Drugs Aging 8:329
Conte P, Frassoldati A (2007) Breast J 13:28
Perez EA (2007) Ann Oncol 18(Suppl 8):viii26
Demissie S, Silliman RA, Lash TL (2001) J Clin Oncol 19:322
Fink AK, Gurwitz J, Rakowski W, Guadagnoli E, Silliman RA (2004) J Clin Oncol 22:3309
Partridge AH, Wang PS, Winer EP, Avorn J (2003) J Clin Oncol 21:602
Partridge AH (2006) Ann Oncol 17:183
Ziller V, Kalder M, Albert US, Holzhauer W, Ziller M, Wagner U, Hadji P (2009) Ann Oncol 20:431
Chlebowski RT, Geller ML (2006) Oncology 71:1
Ruddy K, Mayer E, Partridge A (2009) CA Cancer J Clin 59:56
Hadji P (2010) Crit Rev Oncol Hematol 73:156
Larson ME, Richards TM (2009) Clin Med Res 7:134
Van Rossum AM, Bergshoeff AS, Fraaij PL, Hugen PW, Hartwig NG, Geelen SP, Wolfs TF, Weemaes CM, de Groot R, Burger DM (2002) Pediatr Infect Dis J 21:743
Hiemke C (2008) Eur J Clin Pharmacol 64:159
Touw DJ, Neef C, Thomson AH, Vinks AA (2005) Ther Drug Monit 27:10
Gjerde J, Kisanga ER, Hauglid M, Holm PI, Mellgren G, Lien EA (2005) J Chromatogr A 1082:6
Liu W, Zhang L, Chen S, Duan H, Chen X, Wei Z, Chen G (2009) Anal Chim Acta 631:47
Murphy C, Fotsis T, Pantzar P, Adlercreutz H, Martin F (1987) J Steroid Biochem 26:547
Teunissen SF, Rosing H, Koornstra RH, Linn SC, Schellens JH, Schinkel AH, Beijnen JH (2009) J Chromatogr B 877:2519
Zweigenbaum J, Heinig K, Steinborner S, Wachs T, Henion J (1999) Anal Chem 71:2294
de Voss D, Slee PH, Briggs RJ, Stevenson D (1998) Cancer Chemother Pharmacol 42:512
Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, Sandri MT, Barreca A, Costa A, Robertson C, Lien EA (1999) J Clin Oncol 17:2633
Dowsett M, Cuzick J, Howell A, Jackson I (2001) Br J Cancer 85:317
Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR (2003) J Chromatogr B 791:245
MacCallum J, Cummings J, Dixon JM, Miller WR (1996) J Chromatogr B 678:317
Apostolou C, Dotsikas Y, Kousoulos C, Loukas YL (2008) J Pharm Biomed Anal 48:853
Mendes GD, Hamamoto D, Ilha J, Pereira AS, De Nucci G (2007) J Chromatogr B 850:553
Rodriguez-Flores J, Contento Salcedo AM, Villasenor Llerena MJ, Munoz FL (2008) Electrophoresis 29:811
Ingle JN, Buzdar AU, Schaid DJ, Goetz MP, Batzler A, Robson ME, Northfelt DW, Olson JE, Perez EA, Desta Z, Weintraub RA, Williard CV, Flockhart DA, Weinshilboum RM (2010) Cancer Res 70:3278
Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE (1999) Clin Cancer Res 5:2338
Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M, Hornberger U (2001) Biopharm Drug Dispos 22:191
Peters FT, Drummer OH, Musshoff F (2007) Forensic Sci Int 165:216
Oberacher H, Krajete A, Parson W, Huber CG (2000) J Chromatogr A 893:23
Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Anal Chem 75:3019
Dadgar D, Burnett PE (1995) J Pharm Biomed Anal 14:23
Koster E (2005) The Peak August 2005:5
Oberacher H, Pavlic M, Libiseller K, Schubert B, Sulyok M, Schuhmacher R, Csaszar E, Kofeler HC (2009) J Mass Spectrom 44:485
Oberacher H, Pavlic M, Libiseller K, Schubert B, Sulyok M, Schuhmacher R, Csaszar E, Kofeler HC (2009) J Mass Spectrom 44:494
Pfister CU, Duval M, Godbillon J, Gosset G, Gygax D, Marfil F, Sioufi A, Winkler B (1994) J Pharm Sci 83:520
Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM (2002) Cancer 95:2006
Author information
Authors and Affiliations
Corresponding author
Additional information
Beate Beer and Birthe Schubert have contributed equally to this study.
Rights and permissions
About this article
Cite this article
Beer, B., Schubert, B., Oberguggenberger, A. et al. Development and validation of a liquid chromatography–tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 398, 1791–1800 (2010). https://doi.org/10.1007/s00216-010-4075-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00216-010-4075-z