Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: Investigation in the QUASAR2 study, systematic review, and meta-analysis

Dan Rosmarin, Claire Palles, David Church, Enric Domingo, Angela Jones, Elaine Johnstone, Haitao Wang, Sharon Love, Patrick Julier, Claire Scudder, George Nicholson, Anna Gonzalez-Neira, Miguel Martin, Daniel Sargent, Erin Green, Howard McLeod, Ulrich M. Zanger, Matthias Schwab, Michael Braun, Matthew SeymourLindsay Thompson, Benjamin Lacas, Valérie Boige, Nuria Ribelles, Shoaib Afzal, Henrik Enghusen, Søren Astrup Jensen, Marie Christine Etienne-Grimaldi, Gérard Milano, Mia Wadelius, Bengt Glimelius, Hans Garmo, Milena Gusella, Thierry Lecomte, Pierre Laurent-Puig, Eva Martinez-Balibrea, Rohini Sharma, Jesus Garcia-Foncillas, Zdenek Kleibl, Alain Morel, Jean Pierre Pignon, Rachel Midgley, David Kerr, Ian Tomlinson

Research output: Contribution to journalArticle

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Abstract

Purpose: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and*2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10-6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value - better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to*2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

Original languageEnglish (US)
Pages (from-to)1031-1039
Number of pages9
JournalJournal of Clinical Oncology
Volume32
Issue number10
DOIs
StatePublished - Apr 1 2014

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Genetic Markers
Fluorouracil
Meta-Analysis
Biomarkers
Odds Ratio
Colorectal Neoplasms
Alleles
Drug Therapy
Sensitivity and Specificity
Capecitabine
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens : Investigation in the QUASAR2 study, systematic review, and meta-analysis. / Rosmarin, Dan; Palles, Claire; Church, David; Domingo, Enric; Jones, Angela; Johnstone, Elaine; Wang, Haitao; Love, Sharon; Julier, Patrick; Scudder, Claire; Nicholson, George; Gonzalez-Neira, Anna; Martin, Miguel; Sargent, Daniel; Green, Erin; McLeod, Howard; Zanger, Ulrich M.; Schwab, Matthias; Braun, Michael; Seymour, Matthew; Thompson, Lindsay; Lacas, Benjamin; Boige, Valérie; Ribelles, Nuria; Afzal, Shoaib; Enghusen, Henrik; Jensen, Søren Astrup; Etienne-Grimaldi, Marie Christine; Milano, Gérard; Wadelius, Mia; Glimelius, Bengt; Garmo, Hans; Gusella, Milena; Lecomte, Thierry; Laurent-Puig, Pierre; Martinez-Balibrea, Eva; Sharma, Rohini; Garcia-Foncillas, Jesus; Kleibl, Zdenek; Morel, Alain; Pignon, Jean Pierre; Midgley, Rachel; Kerr, David; Tomlinson, Ian.

In: Journal of Clinical Oncology, Vol. 32, No. 10, 01.04.2014, p. 1031-1039.

Research output: Contribution to journalArticle

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', Journal of Clinical Oncology, vol. 32, no. 10, pp. 1031-1039. https://doi.org/10.1200/JCO.2013.51.1857
Rosmarin, Dan ; Palles, Claire ; Church, David ; Domingo, Enric ; Jones, Angela ; Johnstone, Elaine ; Wang, Haitao ; Love, Sharon ; Julier, Patrick ; Scudder, Claire ; Nicholson, George ; Gonzalez-Neira, Anna ; Martin, Miguel ; Sargent, Daniel ; Green, Erin ; McLeod, Howard ; Zanger, Ulrich M. ; Schwab, Matthias ; Braun, Michael ; Seymour, Matthew ; Thompson, Lindsay ; Lacas, Benjamin ; Boige, Valérie ; Ribelles, Nuria ; Afzal, Shoaib ; Enghusen, Henrik ; Jensen, Søren Astrup ; Etienne-Grimaldi, Marie Christine ; Milano, Gérard ; Wadelius, Mia ; Glimelius, Bengt ; Garmo, Hans ; Gusella, Milena ; Lecomte, Thierry ; Laurent-Puig, Pierre ; Martinez-Balibrea, Eva ; Sharma, Rohini ; Garcia-Foncillas, Jesus ; Kleibl, Zdenek ; Morel, Alain ; Pignon, Jean Pierre ; Midgley, Rachel ; Kerr, David ; Tomlinson, Ian. / Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens : Investigation in the QUASAR2 study, systematic review, and meta-analysis. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 10. pp. 1031-1039.
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abstract = "Purpose: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and*2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10-6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26{\%} sensitivity, 86{\%} specificity, and 49{\%} positive predictive value - better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to*2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.",
author = "Dan Rosmarin and Claire Palles and David Church and Enric Domingo and Angela Jones and Elaine Johnstone and Haitao Wang and Sharon Love and Patrick Julier and Claire Scudder and George Nicholson and Anna Gonzalez-Neira and Miguel Martin and Daniel Sargent and Erin Green and Howard McLeod and Zanger, {Ulrich M.} and Matthias Schwab and Michael Braun and Matthew Seymour and Lindsay Thompson and Benjamin Lacas and Val{\'e}rie Boige and Nuria Ribelles and Shoaib Afzal and Henrik Enghusen and Jensen, {S{\o}ren Astrup} and Etienne-Grimaldi, {Marie Christine} and G{\'e}rard Milano and Mia Wadelius and Bengt Glimelius and Hans Garmo and Milena Gusella and Thierry Lecomte and Pierre Laurent-Puig and Eva Martinez-Balibrea and Rohini Sharma and Jesus Garcia-Foncillas and Zdenek Kleibl and Alain Morel and Pignon, {Jean Pierre} and Rachel Midgley and David Kerr and Ian Tomlinson",
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T1 - Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens

T2 - Investigation in the QUASAR2 study, systematic review, and meta-analysis

AU - Rosmarin, Dan

AU - Palles, Claire

AU - Church, David

AU - Domingo, Enric

AU - Jones, Angela

AU - Johnstone, Elaine

AU - Wang, Haitao

AU - Love, Sharon

AU - Julier, Patrick

AU - Scudder, Claire

AU - Nicholson, George

AU - Gonzalez-Neira, Anna

AU - Martin, Miguel

AU - Sargent, Daniel

AU - Green, Erin

AU - McLeod, Howard

AU - Zanger, Ulrich M.

AU - Schwab, Matthias

AU - Braun, Michael

AU - Seymour, Matthew

AU - Thompson, Lindsay

AU - Lacas, Benjamin

AU - Boige, Valérie

AU - Ribelles, Nuria

AU - Afzal, Shoaib

AU - Enghusen, Henrik

AU - Jensen, Søren Astrup

AU - Etienne-Grimaldi, Marie Christine

AU - Milano, Gérard

AU - Wadelius, Mia

AU - Glimelius, Bengt

AU - Garmo, Hans

AU - Gusella, Milena

AU - Lecomte, Thierry

AU - Laurent-Puig, Pierre

AU - Martinez-Balibrea, Eva

AU - Sharma, Rohini

AU - Garcia-Foncillas, Jesus

AU - Kleibl, Zdenek

AU - Morel, Alain

AU - Pignon, Jean Pierre

AU - Midgley, Rachel

AU - Kerr, David

AU - Tomlinson, Ian

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Purpose: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and*2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10-6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value - better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to*2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

AB - Purpose: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and*2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10-6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value - better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to*2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

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