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Open Access 01-06-2019 | Breast Cancer | Brief report

Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients

Authors: Chara Stavraka, Athanasios Pouptsis, Leroy Okonta, Karen DeSouza, Philip Charlton, Matthaios Kapiris, Anthony Marinaki, Eleni Karapanagiotou, Dionysis Papadatos-Pastos, Janine Mansi

Published in: Breast Cancer Research and Treatment | Issue 2/2019

Abstract

Purpose

Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London.

Methods

We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity.

Results

Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar–plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity.

Conclusions

Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 68(6):394–424. https://doi.org/10.3322/caac.21492 CrossRef

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743. https://doi.org/10.1056/NEJMoa064320 CrossRef

Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, Maroun J, Walde D, Weaver C, Harrison E, Burger HU, Osterwalder B, Wong AO, Wong R (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19(8):2282–2292. https://doi.org/10.1200/jco.2001.19.8.2282 CrossRef

Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, Bugat R, Findlay M, Frings S, Jahn M, McKendrick J, Osterwalder B, Perez-Manga G, Rosso R, Rougier P, Schmiegel WH, Seitz JF, Thompson P, Vieitez JM, Weitzel C, Harper P (2001) Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19(21):4097–4106. https://doi.org/10.1200/jco.2001.19.21.4097 CrossRef

Mikhail SE, Sun JF, Marshall JL (2010) Safety of capecitabine: a review. Expert Opin Drug Saf 9(5):831–841. https://doi.org/10.1517/14740338.2010.511610 CrossRefPubMed

Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16(4):215–237. https://doi.org/10.2165/00003088-198916040-00002 CrossRefPubMed

Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338. https://doi.org/10.1038/nrc1074 CrossRef

van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H, De Abreu RA, Maring JG, Vreken P, van Gennip AH (2000) Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 6(12):4705–4712PubMed

Milano G, Etienne MC, Pierrefite V, Barberi-Heyob M, Deporte-Fety R, Renée N (1999) Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity. Br J Cancer 79(3–4):627–630. https://doi.org/10.1038/sj.bjc.6690098 CrossRefPubMedPubMedCentral

10.

Heggie GD, Sommadossi JP, Cross DS, Huster WJ, Diasio RB (1987) Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47(8):2203–2206PubMed

11.

Mattison LK, Fourie J, Desmond RA, Modak A, Saif MW, Diasio RB (2006) Increased prevalence of dihydropyrimidine dehydrogenase deficiency in african-americans compared with caucasians. Clin Cancer Res 12:5491–5495CrossRefPubMed

12.

Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Renee N, Schneider M, Demard F, Milano G (1994) Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 12(11):2248–2253. https://doi.org/10.1200/jco.1994.12.11.2248 CrossRefPubMed

13.

Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiader CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z, Kleiblova P, Schwab M, Zanger UM, Palles C, Tomlinson I, Gross E, van Kuilenburg AB, Punt CJ, Koopman M, Beijnen JH, Cats A, Schellens JH (2015) Clinical relevance of DPYD variants c.1679T> G, c.1236G> A/HapB3, and c.1601G> A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 16(16):1639–1650. https://doi.org/10.1016/s1470-2045(15)00286-7 CrossRefPubMed

14.

Amstutz U, Offer SM, Sistonen J, Joerger M, Diasio RB, Largiadèr CR (2015) Polymorphisms in MIR27A associated with early-onset toxicity in fluoropyrimidine-based chemotherapy. Clin Cancer Res 21(9):2038–2044CrossRef

15.

Offer SM, Butterfield GL, Jerde CR, Fossum CC, Wegner NJ, Diasio RB (2014) microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites. Mol Cancer Ther 13(3):742–751. https://doi.org/10.1158/1535-7163.MCT-13-0878 CrossRefPubMedPubMedCentral

16.

Zhang X, Li L, Fourie J, Davie JR, Guarcello V, Diasio RB (2006) The role of Sp1 and Sp3 in the constitutive DPYD gene expression. Biochimica et biophysica acta 1759(5):247–256. https://doi.org/10.1016/j.bbaexp.2006.05.001 CrossRefPubMed

17.

Madi A, Fisher D, Maughan TS, Colley JP, Meade AM, Maynard J, Humphreys V, Wasan H, Adams RA, Idziaszczyk S, Harris R, Kaplan RS, Cheadle JP (2018) Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. Eur J Cancer 102:31–39. https://doi.org/10.1016/j.ejca.2018.07.009 CrossRef

18.

Lee AM, Shi Q, Pavey E, Alberts SR, Sargent DJ, Sinicrope FA, Berenberg JL, Goldberg RM, Diasio RB (2014) DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst 106 (12). https://doi.org/10.1093/jnci/dju298

19.

Pellicer M, Garcia-Gonzalez X, Garcia MI, Blanco C, Garcia-Alfonso P, Robles L, Gravalos C, Rueda D, Martinez J, Pachon V, Longo F, Martinez V, Iglesias I, Salvador S, Sanjurjo M, Lopez-Fernandez LA (2017) Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity. Pharmacogenomics 18(13):1215–1223. https://doi.org/10.2217/pgs-2017-0118 CrossRefPubMed

20.

Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A, Guchelaar HJ, Smits PH, Beijnen JH, Punt CJ, Schellens JH, Cats A (2011) Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 17(10):3455–3468. https://doi.org/10.1158/1078-0432.Ccr-10-2209 CrossRefPubMed

21.

Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, Wang H, Love S, Julier P, Scudder C, Nicholson G, Gonzalez-Neira A, Martin M, Sargent D, Green E, McLeod H, Zanger UM, Schwab M, Braun M, Seymour M, Thompson L, Lacas B, Boige V, Ribelles N, Afzal S, Enghusen H, Jensen SA, Etienne-Grimaldi MC, Milano G, Wadelius M, Glimelius B, Garmo H, Gusella M, Lecomte T, Laurent-Puig P, Martinez-Balibrea E, Sharma R, Garcia-Foncillas J, Kleibl Z, Morel A, Pignon JP, Midgley R, Kerr D, Tomlinson I (2014) Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 32(10):1031–1039. https://doi.org/10.1200/jco.2013.51.1857 CrossRefPubMedPubMedCentral

22.

van Kuilenburg AB, Dobritzsch D, Meinsma R, Haasjes J, Waterham HR, Nowaczyk MJ, Maropoulos GD, Hein G, Kalhoff H, Kirk JM, Baaske H, Aukett A, Duley JA, Ward KP, Lindqvist Y, van Gennip AH (2002) Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J 364(Pt 1):157–163CrossRefPubMedPubMedCentral

23.

Vreken P, Van Kuilenburg AB, Meinsma R, Smit GP, Bakker HD, De Abreu RA, van Gennip AH (1996) A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis 19(5):645–654CrossRefPubMed

24.

Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M (2018) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther 103(2):210–216. https://doi.org/10.1002/cpt.911 CrossRefPubMed

25.

Henricks LM, Lunenburg CA, Meulendijks D, Gelderblom H, Cats A, Swen JJ, Schellens JH, Guchelaar HJ (2015) Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score. Pharmacogenomics 16(11):1277–1286. https://doi.org/10.2217/pgs.15.70 CrossRefPubMed

26.

Offer SM, Wegner NJ, Fossum C, Wang K, Diasio RB (2013) Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity. Cancer Res 73(6):1958–1968. https://doi.org/10.1158/0008-5472.Can-12-3858 CrossRefPubMedPubMedCentral

27.

Deenen MJ, Meulendijks D, Cats A, Sechterberger MK, Severens JL, Boot H, Smits PH, Rosing H, Mandigers CM, Soesan M, Beijnen JH, Schellens JH (2016) Upfront genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol 34(3):227–234. https://doi.org/10.1200/jco.2015.63.1325 CrossRefPubMed

28.

Henricks LM, Lunenburg C, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers C, Rosing H, Beijnen JH, Werkhoven EV, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM (2018) DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. https://doi.org/10.1016/s1470-2045(18)30686-7 CrossRefPubMed

29.

Henricks LM, Opdam FL, Beijnen JH, Cats A, Schellens JHM (2017) DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update. Ann Oncol 28(12):2915–2922. https://doi.org/10.1093/annonc/mdx411 CrossRefPubMed

30.

Lunenburg C, Henricks LM, Guchelaar HJ, Swen JJ, Deenen MJ, Schellens JHM, Gelderblom H (2016) Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: ready for prime time. Eur J Cancer 54:40–48. https://doi.org/10.1016/j.ejca.2015.11.008 CrossRefPubMed

31.

Ruzzo A, Graziano F, Galli F, Galli F, Rulli E, Lonardi S, Ronzoni M, Massidda B, Zagonel V, Pella N, Mucciarini C, Labianca R, Ionta MT, Bagaloni I, Veltri E, Sozzi P, Barni S, Ricci V, Foltran L, Nicolini M, Biondi E, Bramati A, Turci D, Lazzarelli S, Verusio C, Bergamo F, Sobrero A, Frontini L, Menghi M, Magnani M (2017) Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. Br J Cancer 117(9):1269–1277. https://doi.org/10.1038/bjc.2017.289 CrossRefPubMedPubMedCentral

32.

Henricks LM, Lunenburg C, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers C, Rosing H, Beijnen JH, van Werkhoven E, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM (2018) A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy. Eur J Cancer 107:60–67. https://doi.org/10.1016/j.ejca.2018.11.010 CrossRefPubMed

33.

De Souza K, Papadatos-Pastos D, Karapanagiotou L, Sandri I, Marinaki A, Mansi J (2015) DPYD genotyping as a potential cost-effective predictive biomarker of capecitabine toxicity in breast cancer. Clin Oncol 27(6):e12. https://doi.org/10.1016/j.clon.2015.01.021 CrossRef

34.

Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, Maisey N, Ross P, Sanderson JD, Marinaki AM (2013) Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 108(12):2505–2515. https://doi.org/10.1038/bjc.2013.262 CrossRefPubMedPubMedCentral

35.

Loganayagam A, Arenas-Hernandez M, Fairbanks L, Ross P, Sanderson JD, Marinaki AM (2010) The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients. Cancer Chemother Pharmacol 65(2):403–406. https://doi.org/10.1007/s00280-009-1147-x CrossRefPubMed

36.

van Staveren MC, Guchelaar HJ, van Kuilenburg AB, Gelderblom H, Maring JG (2013) Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J 13(5):389–395. https://doi.org/10.1038/tpj.2013.25 CrossRefPubMed

Title: Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients
Authors: Chara Stavraka
Athanasios Pouptsis
Leroy Okonta
Karen DeSouza
Philip Charlton
Matthaios Kapiris
Anthony Marinaki
Eleni Karapanagiotou
Dionysis Papadatos-Pastos
Janine Mansi
Publication date: 01-06-2019
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 2/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05144-9

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