DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer

Chiara Cremolini, Marzia Del Re, Carlotta Antoniotti, Sara Lonardi, Francesca Bergamo, Fotios Loupakis, Beatrice Borelli, Federica Marmorino, Valentina Citi, Enrico Cortesi, Roberto Moretto, Monica Ronzoni, Gianluca Tomasello, Alberto Zaniboni, Patrizia Racca, Angela Buonadonna, Giacomo Allegrini, Vincenzo Ricci, Samantha Di Donato, Vittorina Zagonel, Luca Boni, Alfredo Falcone, Romano Danesi, Chiara Cremolini, Marzia Del Re, Carlotta Antoniotti, Sara Lonardi, Francesca Bergamo, Fotios Loupakis, Beatrice Borelli, Federica Marmorino, Valentina Citi, Enrico Cortesi, Roberto Moretto, Monica Ronzoni, Gianluca Tomasello, Alberto Zaniboni, Patrizia Racca, Angela Buonadonna, Giacomo Allegrini, Vincenzo Ricci, Samantha Di Donato, Vittorina Zagonel, Luca Boni, Alfredo Falcone, Romano Danesi

Abstract

Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing DPYD c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the DPYD c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned DPYD and UGT1A1 variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments' safety through a "genotype-guided" approach.

Keywords: 5-fluorouracil; DPYD; UGT1A1; irinotecan; toxicity.

Conflict of interest statement

CONFLICTS OF INTEREST All authors declare no potential competing interests.

References

    1. Cremolini C, Schirripa M, Antoniotti C, Moretto R, Salvatore L, Masi G, Falcone A, Loupakis F. First-line chemotherapy for mCRC-a review and evidence-based algorithm. Nat Rev Clin Oncol. 2015;12:607–619.
    1. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crinò L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, et al. Gruppo Oncologico Nord Ovest Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:1670–1676.
    1. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371:1609–1618.
    1. Bendell J, Tan B, Reeves JA, Xiong H, Somer B, Lenz HJ, Hochster H, Scappaticci F, Sommer N, Day B, Hurwitz H. Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) J Clin Oncol. 2016;34 Abstract 492.
    1. Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan S, Lasserre S, Hermann F, Waterkamp D, Adam R. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26:702–708.
    1. Schmoll H, Garlipp B, Junghanss C, Leithaeuser M, Vogel A, Schaefers M, Kaiser U, Hoeffkes HG, Florschutz A, Russel J, Kanzler S, Edelmann T, Forstbauer H, et al. CHARTA: FOLFOX+bevacizumab +/− irinotecan in advanced colorectal cancer (CRC)-Final results of the randomized phase II trial AIO (KRK 0209) J Clin Oncol. 2017;35 Abstract 658.
    1. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–1422.
    1. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology — Colon Cancer; Version 1.2017. 2017 NCCN .
    1. Stein BN, Petrelli NJ, Douglass HO, Driscoll DL, Arcangeli G, Meropol NJ. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75:11–17.
    1. van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer. 2004;40:939–950.
    1. Gupta E, Lestingi TM, Mick R, Ramirez J, Vokes EE, Ratain MJ. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 1994;54:3723–3725.
    1. Amstutz U, Froehlich TK, Largiader CR. Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity. Pharmacogenomics. 2011;12:1321–1336.
    1. Liu X, Cheng D, Kuang Q, Liu G, Xu W. Association of UGT1A1*28 polymorphisms with irinotecan-induced toxicities in colorectal cancer: a meta-analysis in Caucasians. Pharmacogenomics J. 2014;14:120–129.
    1. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A. 1998;95:8170–8174.
    1. National Center for Biotechnology Information Database of single nucleotide polymorphisms (dbSNP)
    1. Meulendijks D, Cats A, Beijnen JH, Schellens JH. Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity - Ready for clinical practice? Cancer Treat Rev. 2016;50:23–34.
    1. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther. 2013;94:640–645.
    1. Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, Genazzani AA. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics. 2013;14:1255–1272.
    1. 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, et al. 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. 2015;16:1639–1650.
    1. Boige V, Vincent M, Alexandre P, Tejpar S, Landolfi S, Le Malicot K, Greil R, Cuyle PJ, Yilmaz M, Faroux R, Matzdorff A, Salazar R, Lepage C, et al. DPYD Genotyping to Predict Adverse Events Following Treatment With Flourouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial. JAMA Oncol. 2016.
    1. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382–1388.
    1. Li M, Wang Z, Guo J, Liu J, Li C, Liu L, Shi H, Liu L, Li H, Xie C, Zhang X, Sun W, Fang S, Bi X. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther. 2014;7:1653–1661.
    1. Campbell JM, Stephenson MD, Bateman E, Peters MD, Keefe DM, Bowen JM. Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J. 2017;17:21–28.
    1. Lee AM, Shi Q, Pavey E, Alberts SR, Sargent DJ, Sinicrope FA, Berenberg JL, Goldberg RM, Diasio RB. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147) Natl Cancer Inst. 2014;106:106.
    1. Deenen MJ, Meulendijks D. Recommendation on testing for dihydropyrimidine dehydrogenase deficiency in the ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2017;28:184.
    1. Danesi R, Del Re M, Ciccolini J, Schellens JH, Schwab M, van Schaik RH, van Kuilenburg AB. Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck? Ann Oncol. 2017;28:183.
    1. AIOM-SIF Working Group Recommendations for pharmacogenetic analyses. 2015
    1. Deenen MJ, Meulendijks D, Cats A, Sechterberger MK, Severens JL, Boot H, Smits PH, Rosing H, Mandigers CM, Soesan M, Beijnen JH, Schellens JH. Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol. 2016;34:227–234.
    1. Innocenti F, Schilsky RL, Ramirez J, Janisch L, Undevia S, House LK, Das S, Wu K, Turcich M, Marsh R, Karrison T, Maitland ML, Salgia R, Ratain MJ. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014;32:2328–2334.
    1. O'Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol. 2006;24:4534–4538.
    1. Innocenti F, Vokes EE, Ratain MJ. Irinogenetics: what is the right star? J Clin Oncol. 2006;24:2221–2224.
    1. Launay M, Dahan L, Duval M, Rodallec A, Milano G, Duluc M, Lacarelle B, Ciccolini J, Seitz JF. Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer. Br J Clin Pharmacol. 2016;81:124–130.
    1. 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. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res. 2011;17:3455–3468.
    1. 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, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol. 2014;32:1031–1039.
    1. Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, German 5-FU Toxicity Study Group Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008;26:2131–2138.
    1. National Cancer Institute-Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 2006

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