Abstract
Purpose
Breast cancer is a heterogeneous disease, characterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxanes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experience severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clinical parameters, such as toxicity or outcome.
Methods
The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015.
Results
We studied the literature in order to find any possible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population.
Conclusions
Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experimental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxicity and with resistant or responsive outcome, before the administration of taxanes.
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References
Foukakis T, Fornander T, Lekberg T, Hellborg H, Adolfsson J, Bergh J (2011) Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm, Sweden. Breast Cancer Res Treat 130:553–560
Henningsson A, Sparreboom A, Sandstrom M et al (2003) Population pharmacokinetic modeling of unbound and total plasma concentrations of paclitaxel in cancer patients. Eur J Cancer 39:1105–1114
Oshiro C, Marsh S, McLeod H, Carrillo M, Klein T, Altman R (2009) Taxane pathway. Pharmacogenet Genomics 19:979–983
Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671
Di Leo A, Gomez HL, Aziz Z et al (2008) Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26:5544–5552
Ten Tije AJ, Verweij J, Loos WJ, Sparreboom A (2003) Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 42:665–685
Gelderblom H, Verweij J, van Zomeren DM et al (2002) Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel. Clin Cancer Res 8:1237–1241
Gelderblom H, Verweij J, Nooter K, Sparreboom A (2001) Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer 37:1590–1598
Boulanger J, Boursiquot JN, Cournoyer G et al (2014) Management of hypersensitivity to platinum- and taxane-based chemotherapy: cepo review and clinical recommendations. Curr Oncol 21:e630–e641
De Iuliis F, Taglieri L, Salerno G, Lanza R, Scarpa S (2015) Taxane induced neuropathy in patients affected by breast cancer: literature review. Crit Rev Oncol Hematol. doi:10.1016/j.critrevonc.2015.04.011
Verschraegen CF, Sittisomwong T, Kudelka AP et al (2000) Docetaxel for patients with paclitaxel-resistant Mullerian carcinoma. J Clin Oncol 18:2733–2739
Van Zuylen L, Verweij J, Sparreboom A (2001) Role of formulation vehicles in taxane pharmacology. Invest New Drugs 19:125–141
McLeod HL, Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101–121
Williams JA, Ring BJ, Cantrell VE et al (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 30:883–891
Jover R, Bort R, Gomez-Lechon MJ, Castell JV (2001) Cytochrome P450 regulation by hepatocyte nuclear factor 4 in human hepatocytes: a study using adenovirus- mediated antisense targeting. Hepatology 33:668–675
Bort R, Gomez-Lechon MJ, Castell JV, Jover R (2004) Role of hepatocyte nuclear factor 3 g in the expression of human CYP2C genes. Arch Biochem Biophys 426:63–72
Engels FK, Ten Tije AJ, Baker SD et al (2004) Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel. Clin Pharmacol Ther 75:448–454
Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F (2002) Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos 30:438–445
Smith NF, Acharya MR, Desai N, Figg WD, Sparreboom A (2005) Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol Ther 4:815–818
Smith NF, Marsh S, Scott-Horton TJ et al (2007) Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharmacol Ther 81:76–82
Lagas JS, Vlaming ML, van Tellingen O et al (2006) Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clin Cancer Res 12:6125–6132
Huisman MT, Chhatta AA, van Tellingen O, Beijnen JH, Schinkel AH (2005) MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer 116:824–829
Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human ABCB1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33
Masuyama H, Suwaki N, Tateishi Y, Nakatsukasa H, Segawa T, Hiramatsu Y (2005) The pregnane X receptor regulates gene expression in a ligand- and promoter-selective fashion. Mol Endocrinol 19:1170–1180
Ferguson SS, Chen Y, LeCluyse EL, Negishi M, Goldstein JA (2005) Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Mol Pharmacol 68:747–757
Harmsen S, Meijerman I, Beijnen JH, Schellens JH (2009) Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol 64:35–43
Baker SD, Verweij J, Cusatis GA et al (2009) Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 85:155–163
Henningsson A, Marsh S, Loos WJ et al (2005) Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 11:8097–8104
Marsh S, Somlo G, Li X et al (2007) Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. Pharmacogenomics J 7:362–365
Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15:693–704
Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478
Bosch TM, Huitema AD, Doodeman VD et al (2006) Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res 12:5786–5793
Tran A, Jullien V, Alexandre J et al (2006) Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther 79:570–580
Yamaguchi H, Hishinuma T, Endo N et al (2006) Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancer. Int J Gynecol Cancer 16:979–985
Sissung TM, Mross K, Steinberg SM et al (2006) Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893–2896
Kim HS, Kim MK, Chung HH et al (2009) Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: a Korean population-based study. Gynecol Oncol 113:264–269
Gianni L, Kearns CM, Giani A et al (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180–190
Yamamoto N, TamuraT Murakami H et al (2005) Randomized pharmacokinetic and pharmacodynamic study of docetaxel: dosing based on body-surface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol. J Clin Oncol 23:1061–1069
Quattrochi LC, Guzelian PS (2001) Cyp3A regulation: from pharmacology to nuclear receptors. Drug Metab Dispos 29:615–622
Tham LS, Holford NH, Hor SY et al (2007) Lack of association of single-nucleotide polymorphisms in pregnane X receptor, hepatic nuclear factor 4alpha, and constitutive androstane receptor with docetaxel pharmacokinetics. Clin Cancer Res 13:7126–7132
Tsai SM, Lin CY, Wu SH et al (2009) Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms. Clin Chim Acta 404:160–165
Leskelä S, Jara C, Leandro-García LJ et al (2011) Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J 11:121–129
Kim KP, Ahn JH, Kim SB et al (2012) Prospective evaluation of the drug-metabolizing enzyme polymorphisms and toxicity profile of docetaxel in Korean patients with operable lymph node-positive breast cancer receiving adjuvant chemotherapy. Cancer Chemother Pharmacol 69:1221–1227
Bosó V, Herrero MJ, Santaballa A et al (2014) SNPs and taxane toxicity in breast cancer patients. Pharmacogenomics 15:1845–1858
Kiyotani K, Mushiroda T, Kubo M, Zembutsu H, Sugiyama Y, Nakamura Y (2008) Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leucopenia. Cancer Sci 99:967–972
Uchiyama T, Kanno H, Ishitani K et al (2012) An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel. Cancer Chemother Pharmacol 69:1617–1624
Awada Z, Haider S, Tfayli A et al (2013) Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS 17:353–367
Leandro-García LJ, Inglada-Pérez L, Pita G et al (2013) Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J Med Genet 50:599–605
Abraham JE, Guo Q, Dorling L et al (2014) Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel. Clin Cancer Res 20:2466–2475
Gréen H, Khan MS, Jakobsen-Falk I, Åvall-Lundqvist E, Peterson C (2011) Impact of CYP3A5*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer. J Pharm Sci 100:4205–4209
Puisset F, Chatelut E, Dalenc F et al (2004) Dexamethasone as a probe for docetaxel clearance. Cancer Chemother Pharmacol 54:265–272
O’Driscoll L, Clynes M (2006) Biomarkers and multiple drug resistance in breast cancer. Curr Cancer Drug Targets 6:365–384
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–9824
Rudek MA, Sparreboom A, Garrett-Mayer ES et al (2004) Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40:1170–1178
Baker SD, Li J, Ten Tije AJ et al (2005) Relationship of systemic exposure to unbound docetaxel and neutropenia. Clin Pharmacol Ther 77:43–53
Chang H, Rha SY, Jeung H et al (2009) Association of the ABCB1 gene polymorphisms 2677G>T/A and 3435C>T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann Oncol 20:272–277
Petros WP, Hopkins PJ, Spruill S et al (2005) Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol 23:6117–6125
Rizzo R, Spaggiari F, Indelli M et al (2010) Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients. Breast Cancer Res Treat 124:593–598
Krens SD, McLeod HL, Hertz DL (2013) Pharmacogenetics, enzyme probes and therapeutic drug monitoring as potential tools for individualizing taxane therapy. Pharmacogenomics 14:555–574
Baldwin RM, Owzar K, Zembutsu H et al (2012) A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res 18:5099–5109
Sergentanis TN, Economopoulos KP (2010) Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 122:459–469
Baker SD, Verweij J, Cusatis GA et al (2008) Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 85:155–163
Watson RG, McLeod HL (2011) Pharmacogenomic contribution to drug response. Cancer J 17:80–88
Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526
Gandara DR, Kawaguchi T, Crowley J et al (2009) Japanese–US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol 27:3540–3546
Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish randomised trial in ovarian cancer. J Clin Oncol 25:4528–4535
Tulsyan S, Chaturvedi P, Singh AK et al (2014) Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach. Gene 543:69–75
Gor PP, Su HI, Gray RJ et al (2010) Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res 12:R26
McGrogan BT, Gilmartin B, Carney DN, McCann A (2008) Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta 1785:96–132
Huzil JT, Chen K, Kurgan L, Tuszynski JA (2007) The roles of beta-tubulin mutations and isotype expression in acquired drug resistance. Cancer Inform 3:159–181
Monzo M, Rosell R, Sanchez JJ et al (1999) Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 17:1786–1793
Kelley MJ, Li S, Harpole DH (2001) Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer. J Natl Cancer Inst 93:1886–1888
Seve P, Dumontet C (2008) Is class III b-tubulin a predictive factor in patients receiving tubulin-binding agents? Lancet Oncol 9:168–175
Berrieman HK, Lind MJ, Cawkwell L (2004) Do beta-tubulin mutations have a role in resistance to chemotherapy? Lancet Oncol 5:158–164
Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124
Spink DC, Spink BC, Cao JQ et al (1998) Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells. Carcinogenesis 19:291–298
Sissung TM, Danesi R, Price DK et al (2008) Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. Mol Cancer Ther 7:19–26
McFadyen MC, Cruickshank ME, Miller ID et al (2001) Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer. Br J Cancer 85:242–246
Martinez VG, O’Connor R, Liang Y, Clynes M (2008) CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. Br J Cancer 98:564–570
Gehrmann M, Schmidt M, Brase JC, Roos P, Hengstler JG (2008) Prediction of paclitaxel resistance in breast cancer: is CYP1B1*3 a new factor of influence? Pharmacogenomics 9:969–974
Pusztai L (2007) Markers predicting clinical benefit in breast cancer from microtubule-targeting agents. Ann Oncol 18:5–20
Kroetz DL, Pauli-Magnus C, Hodges LM et al (2003) Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13:481–494
Sissung TM, Baum CE, Deeken J et al (2008) ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel. Clin Cancer Res 14:4543–4549
Green H, Soderkvist P, Rosenberg P, Horvath G, Peterson C (2006) Mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res 12:854–859
Lanni JS, Lowe SW, Licitra EJ, Liu JO, Jacks T (1997) P53-independent apoptosis induced by paclitaxel through an indirect mechanism. Proc Natl Acad Sci USA 94:9679–9683
Wahl AF, Donaldson KL, Fairchild C et al (1996) Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nat Med 2:72–79
Kandioler-Eckersberger D, Ludwig C, Rudas M et al (2000) P53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 6:50–56
Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245
Bartel F, Meye A, Wurl P et al (2001) Amplification of the MDM2 gene, but not expression of splice variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma. Int J Cancer 95:168–175
Bond GL, Hu W, Bond EE et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602
Chrisanthar R, Knappskog S, Løkkevik E et al (2011) Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel. PLoS One 6:e19249
Dong N, Yu J, Wang C et al (2012) Pharmacogenetic assessment of clinical outcome in patients with metastatic breast cancer treated with docetaxel plus capecitabine. J Cancer Res Clin Oncol 138:1197–1203
Hertz DL, Motsinger-Reif AA, Drobish A et al (2012) CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel. Breast Cancer Res Treat 134:401–410
Marmé F, Werft W, Walter A et al (2012) CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane- based neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res Treat 132:819–831
Lee SY, Im SA, Park YH et al (2014) Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy. Eur J Cancer 50:698–705
Rodriguez-Antona C (2010) Pharmacogenomics of paclitaxel. Pharmacogenomics 11:621–623
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De Iuliis, F., Salerno, G., Taglieri, L. et al. Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review. Cancer Chemother Pharmacol 76, 679–690 (2015). https://doi.org/10.1007/s00280-015-2818-4
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DOI: https://doi.org/10.1007/s00280-015-2818-4