Table 1. Literature in support of an association of DPYD variance and toxicity from fluoropyrimidine exposure
Meta-analysis publish date Which Meta-analysis (or meta-analyses) included this study Individual study publish date Citation Study design Patient population Total (n) Observation arm description Comparator arm description Interventions Event(s) Event count in observation arm Total (n) in observation arm Percent incidence of Events in observation arm (in decimal form) Event count in comparator arm Total (n) in comparator arm Percent incidence of Events in comparator arm (in decimal form) Total number of Events Measurement type Meaurement value Statistitical measurement type Statistitical measurement value Statistitical measurement value Statistitical measurement value
                                               
10/22/2015, 09/03/2020 PMID: 26603945, PMID: 32899374 Friday, October 19, 2018 PMID: 30348537 Multicenter 5-FU adults (>18 years) with cancer (solid tumor) 1181 c.1679T>G (rs55886062, DPYD*13, I560S) DPYD wild-type 5-FU or CAPE Overall toxiciy 0 1103 (grade >3) 0 260 1018 (grade >3) 0.26              
    Safety analysis GI toxicity 94 0.09              
      Hematological toxicity 77 0.07              
      Hand-foot syndrome 36 0.04              
      Cardiac toxicity 10 0.01              
      c.2846A>T (rs67376798, D949V) Overall toxiciy 9 0.53                  
      GI toxicity 4 0.24                  
      Hematological toxicity 4 0.24                  
      Hand-foot syndrome 1 0.06                  
      DPYD*2A (rs3918290, c.1905+1G>A, IVS14+1G>A) Overall toxiciy 5 0.31                  
      GI toxicity 2 0.13                  
      Hematological toxicity 2 0.13                  
      c.1236G>A (rs56038477, E412E, Hap B3) Overall toxiciy 23 0.45                  
      GI toxicity 12 0.24                  
      Hematological toxicity 8 0.16                  
      Cardiac toxicity 1 0.02                  
                                               
    11/28/2018. PMID: 30485432 Matched pair analysis 5-FU adults (>18 years) with cancer (solid tumor) 1,692 DPYD*2A (rs3918290, c.1905+1G>A, IVS14+1G>A) DPYD wild-type 5-FU Overall toxiciy 66 86 (grade >3) 0.77 372 1606 (grade >3) 0.23       Hazard ratio (95% CI) 0.82    
    GI toxicity 33 0.38 150 0.09          
    Hematological toxicity 48 0.56 158 0.10          
    Hand-foot syndrome 0 0.00 84 0.05          
                                               
    Friday, November 19, 2021 PMID: 34797200 Retrospective cohort 5-FU adults (>18 years) with cancer (solid tumor) 228 DPYD Variant(s)   5-FU or CAPE Overall toxiciy 63 63 (grade >3) 0.28                    
      GI toxicity 11 0.05                    
      Hematological toxicity 26 0.11                    
      Hand-foot syndrome 7 0.03                    
                                               
8/09/2013, 03/03/2014, 09/03/2020 PMID: 23930673, PMID: 24590654, PMID: 32899374 Monday, November 16, 2015 PMID: 26573078 Safety analysis 5-FU adults (>18 years) with cancer (solid tumor) 2,038 DPYD*2A (rs3918290, c.1905+1G>A, IVS14+1G>A) DPYD wild-type 5-FU Overall toxiciy 35 1613 (grade >3) 0.73   48 (grade >3)                
    Cost analysis GI toxicity 23 0.56 373 0.23              
      Hematological toxicity 27 0.66 159 0.10              
      Hand-foot syndrome N/A N/A 86 0.05              
                                               
    Monday, November 15, 2021 PMID: 34780066 Prospective observational 5-FU adults (>18 years) with cancer (solid tumor) 503 DPYD*2A (rs3918290, c.1905+1G>A, IVS14+1G>A)   5-FU or CAPE Hand-foot syndrome 15 283 (grade >3) 0.03             Hazard ratio (95% CI) 2 (recheck)    
      Neutropenia 178 0.36                
      Diarrhea 102 0.20                
      Infection 90 0.18                
      Oral mucositis 46 0.09                
      Fatigue 38 0.08                
      Vomiting 28 0.06                
      Abdominal pain 13 0.03                
                                               
    Wednesday, February 6, 2019 PMID: 30723313 Comprehensive analysis 5-FU adults (>18 years) with cancer (solid tumor) 1254 DPYD Variant(s)   5-FU Hematological toxicity (fever, leucopenia, neutropenia, febrile neutropenia, anemia, Thrombocytopenia) 584 982 (grade >3) 0.47         Odds Ratio (95% CI) 1.1        
      GI Toxicity (nausea/vomiting, diarrhea, stomatitis) 878 0.70         Odds Ratio (95% CI) 1.86        
      Hand-foot syndrome 113 0.09                    
                                               
09/29/21. PMID: 34506675 Thursday, December 21, 2017 PMID: 29487697 Mulicenter 5-FU adults (>18 years) with cancer (solid tumor) 443 FOLFIRI FOLFOXIRI 5-FU/Leucovorin/​Irinotecan with bevacizumab (FOLFIRI) or 5-FU/leucovorin/​oxaliplatin/​irinotecan with bevacizumab (FOLFOXIRI) Overall Toxicity 82 217 (grade >3) 0.38 143 226 (grade >3) 0.63              
    Randomized GI Toxicity 41 0.19 61 0.27              
    Phase III Trial Hematological Toxicity 52 0.24 118 0.52              
                                               
  PMID: 34506675, PMID: 35207713 Thursday, January 21, 2016 PMID: 26794347 Secondary Analysis 5-FU adults (>18 years) with cancer (solid tumor) 1,545 FOLFOX4 FOLFOX4 with Cetuximab 5-FU / leucovorin /oxaliplatin (FOLFOX4) or 5-FU / leucovorin /oxaliplatin / cetuximab Overall Toxicity 49 380 (grade >3)  0.129 50 385 (grade >3)  0.130   Odds Ratio (95% CI) 1.1        
9/29/2021, 02/06/2022   Randomized Hematologic Toxicity 78 610 (grade>3)  0.128 75 569 (grade >3)  0.132   Odds Ratio (95% CI) 0.9        
      GI Toxicity 27 203 (grade >3)  0.133 47 365 (grade >3)  0.129   Odds Ratio (95% CI) 2        
                                               
    Monday, January 19, 2015 PMID: 25601966 Noninferiority Phase II Trial CAPE adults (>18 years) with cancer (solid tumor) 192 DPYD Variant(s) N/A CAPE Hand Foot Syndrome ? 99 (grade >3) ? N/A N/A N/A              
    Randomized              
    Pharmacogenetic Analysis              
                                               
    01/2015. PMID: 24647007 Randomized CAPE adults (>18 years) with cancer (solid tumor) 968 DPYD Variant(s) N/A CAPE with/without bevacizumab Overall Toxicity 353 968 (grade >3) 0.34 N/A N/A N/A              
    Phase III GI Toxicity 147 0.013              
Friday, October 22, 2015 PMID: 26603945,   Hand Foot Syndrome 247 0.24              
      Hematologic Toxicity 26 0.02              
                                               
10/22/2015, 09/29/21, 08/09/2013, 02/06/2022, 09/03/2020, 12/28/2014 PMID: 26603945, PMID: 34506675, PMID: 23930673, PMID: 35207713, PMID: 32899374, PMID: 25614737 Sunday, May 15, 2011 PMID: 21498394 Case-cohort analysis CAPE adults (>18 years) with cancer (solid tumor) 568 DPYD Variant(s) N/A CAPE/​Oxaliplatin/​bevacizumab with/without cetuximab GI Toxicity 139 869 (grade >3) 0.24 N/A N/A N/A              
  Hand Foot Syndrome 245 0.43              
  Hematologic Toxicity 485 0.85              
                                               
    Tuesday, February 12, 2019 PMID: 30746637  Retrospective observational CAPE adults (>18 years) with cancer (solid tumor) 66 DPYD Variant(s)  CAPE    Overall toxicity  14  61 (grade >3)  0.23                    
      GI toxicity  5 0.08                    
       Palmar-plantar erythrodysesthesia  9 0.15                    
                                               
3/3/2014, 09/29/21, 08/09/2013 PMID: 24590654, PMID: 34506675, PMID: 23930673 Monday, April 12, 2010 PMID: 20385995 exploratory study Metastatic colorectal cancer  349 LV5FU2 (FU/leucovorin)   FOLFOX or FOLFIRI   GI Toxicity 14  67 (grade >3)  0.08             Hazard Raio 0.69    
                    Hematologic Toxicity 6    0.04                    
                                               
10/22/2015, 08/09/2013, 09/29/2021 PMID: 26603945, PMID: 23930673, PMID: 34506675 11/22/2006 PMID: 17121937 Prospective Study Advanced carcinomas 487 DPYD Variant(s) 5-FU regimen FA/LV5FU2, FOLFIRI, FOLFOX, epirubicin/​cyclophosphamide, cisplatin or carboplatin GI Toxicity 27 38 (Grade >3) 0.71                    
Hematologic Toxicity 8 0.21                    
Hand-Foot Syndrome 7 0.184                    
Cardiac Toxicity 3 0.079                    
                                               
10/22/2015, 09/03/2020, 09/29/2021 PMID: 26603945, PMID: 32899374, PMID: 34506675 Wednesday, November 7, 2014 PMID: 25381393 Study Cohort Colon Cancer 2594 DYPD*2A   FOLFOX or FOLFIRI with Cetuximab Overall Toxicity 1581 2564 (Grade >3) 0.617                    
GI Toxicity 526 0.205                    
Constitutional Symptoms (i.e. fatigue) 122 0.048                    
Hematologic Toxicity 343 0.133                    
Pain 20 0.008                    
Febrile Neutropenia 42 0.016                    
                                               
10/22/2015, 09/29/2021 PMID: 26603945, PMID: 34506675 Friday, June 13, 2014 PMID: 24923815 Observational study Advanced carcinomas 500 DPYD Variant(s)   5FU or CAPE Hematologic Toxicity 41 500 (grade >3) 0.08                    
  GI Toxicity 36 0.07                    
  Febrile Neutropenia 12 0.02                    
  Located Infection 8 0.02                    
  Hand-Foot Syndrome 9 0.02                    
                                               
10/22/2015, 09/29/2021 PMID: 26603945, PMID: 34506675 Tuesday, June 04, 2013 PMID: 23736036 retrospective study Solid Cancer 430 DPYD Variant(s)   5FU or CAPE Overall Toxicity 104 430 (grade >3) 0.24                    
  GI Toxicity 83 0.2                    
  Hematologic Toxicity 43 0.1                    
                                               
3/3/2014, 08/09/2013, 09/03/2020, 09/29/2021 PMID: 24590654, PMID: 23930673, PMID: 32899374, PMID: 34506675 9/21/2016 PMID: 18299612 Prospective Clinical Trial Solid Cancer 683 DPYD Variant(s)   5FU GI Toxicity 111 683 (grade >3) 0.162                    
  Hematologic Toxicity 32 0.047                    
                                               
Monday, March 3, 2014 PMID: 24590654 Wednesday, September 8, 2004 PMID: 15355920 Experimental Design Colorectal Cancer 90 DPYD Variant(s)   5FU GI Toxicity 13 90 (grade >3) 0.14                    
  Hematologic Toxicity 7 0.06                    
  Hand-Foot Syndrome 1 0.01                    
  Angor 1 0.01                    
  Neuropathy 9 0.1                    
                                               
3/3/2014, 08/09/2013, 09/29/2021 PMID: 24590654, PMID: 23930673, PMID: 34506675 Monday, September 25, 2006 PMID: 17000685 Experimental Design Breast Cancer 105 DPYD Variant(s)   CAPE Overall Toxicity 18 105 (grade >#) 0.179                    
  GI Toxicity 14 0.135                    
  Hematologic Toxicity 6 0.061                    
  Hand-Foot Syndrome 5 0.052                    
                                               
Monday, March 3, 2014 PMID: 24590654 Friday, February 1, 2008 PMID: 18245544 Experimental Design Colorectal Cancer 54 DPYD Variant(s)   CAPE GI Toxicity 7 54 (grade >3) 0.04                    
  Hand-Foot Syndrome 9 0.05                    
  Fatigue 2 0.01                    
                                               
Monday, March 3, 2014 PMID: 24590654 Thursday, March 31, 2011 PMID: 21325291 Experimental Design Breast and Colorectal Cancer 130 DPYD Variant(s)   CAPE Hand-Foot Syndrome 41 130 (grade >3) 0.32                    
                                               
2/6/2022 PMID: 35207713 06/2017. PMID: 28347776 Observational Colorectal Cancer 301 DPYD Variant(s)   CAPE Overall Toxicity 133 301 (grade >2) 0.442                    
Descriptive   GI Toxicity 57 0.189                    
Cross-sectional   Hematologic Toxicity 32 0.106                    
ambispective   Dermatology Toxicity 20 0.066                    
    Hepatoxicity 21 0.07                    
    Hand-Foot Syndrome 24 0.08                    
    Asthenia 16 0.053                    
    Neuropathy 11 0.037                    
                                               
2/06/2022, 09/03/2020 PMID: 35207713, PMID: 32899374 3/12/2019 PMID: 30858516 Case-Control Solid Cancer 1827 DPYD*2A   5FU Overall Toxicity 12 146 (grade >3) 0.26                    
  GI Toxicity 39 0.85                    
  Hematologic Toxicity 22 0.48                    
  Neutropenia 23 0.5                    
                                               
Wednesday, August 09, 2013 PMID: 23930673 Tuesday, May 8, 2007 PMID: 17064846 Prospective Study Colorectal Cancer 252 DPYD Variant(s)   5FU GI Toxicity 168 252 (grade >3) 0.667                    
  Hematologic Toxicity 12 0.048                    
  Neutropenia 47 0.19                    
  Hand-Foot Syndrome 168 0.667                    
                                               
Wednesday, August 09, 2013 PMID: 23930673 Wednesday, June 17, 2009 PMID: 19530960 Prospective Study Solid Cancer 111 DPYD Variant(s)   5FU Overall Toxicity 6 111 (grade >3) 0.06                    
  GI Toxicity 3 0.03                    
  Hematologic Toxicity 3 0.03                    
  Infection 6 0.06                    
                                               
8/09/2013, 09/29/2021 PMID: 23930673, PMID: 34506675 Monday, May 20, 2010 PMID: 20507294 Prospective Study Solid Cancer 1219 DPYD*2   5FU or CAPE GI Toxicity 18 31 (grade >3) 0.58                    
  Neutropenia 13 0.42                    
                                               
Wednesday, August 09, 2013 PMID: 23930673 Wednesday, March 16, 2011 PMID: 21410976 Phase II Rectal Cancer 85 DPYD Variant(s)   UFT with Leucovorin GI Toxicity 25 85 (grade >3) 0.3                    
  Hematologic Toxicity 3 0.03                    
  Cerebrovascular Event 2 0.02                    
  Epistaxis 1 0.01                    
  Pneumopathy 1 0.01                    
  Subocclusive Syndrome 1 0.01                    
                                               
9/3/2020, 09/29/2021 PMID: 32899374, PMID: 34506675 Monday, May 8, 2017 PMID: 28481884 Prospective Observational Study Breast Cancer 243 DPYD Variant(s)   CAPE GI Toxicity 14 243 (grade >3) 0.058                    
  Hematologic Toxicity 20 0.085                    
  Hand-Foot Syndrome 23 0.095                    
  Nausea 4 0.017                    
  Vomiting 4 0.017                    
  Neurotoxicity 2 0.008                    
  Cutaneous Toxicity 4 0.017                    
  Asthenia 17 0.07                    
                                               
Thursday, September 3, 2020, 09/29/2021 PMID: 32899374, PMID: 34506675 Tuesday, June 16, 2020 PMID: 32546132 Cross-sectional study Colorectal Cancer 88 DPYD Variant(s)   5FU GI Toxicity 33 88 (grade >3) 0.514                    
  Nausea 25 0.357                    
  Vomiting 37 0.485                    
  Peripheral neuropathy 2 0.01                    
                                               
Thursday, September 3, 2020 PMID: 32899374 Wednesday, December 1, 2000 PMID: 11156223 Clinical Solid Cancer 14 DPYD Variant(s)   5FU GI Toxicity 10 14 (grade >3) 0.714                    
  Hematologic Toxicity 3 0.214                    
  Malaise 2 0.143                    
  Dermatological 2 0.143                    
  Neurological 1 0.071                    
  Alopecia 1 0.071                    
  Hand-Foot Syndrome 1 0.071                    
                                               
Thursday, September 3, 2020, 09/29/2021 PMID: 32899374, PMID: 34506675 Friday, February 13, 2015 PMID: 25677447 Prospective Study GI & Colorectal Cancer 140 c.2846A>T (rs67376798, D949V)   CAPE GI Toxicity 6 140 (grade >3) 0.043                    
  Nausea 3 0.0214                    
  Hand-Foot Syndrome 2 0.0143                    
                                               
9/29/2021, PMID: 34506675 Saturday, February 11, 2017 PMID: 28395758 Multicenter prospective cohort study Colorectal Cancer 1142 DPYD Variant(s)   5FU GI Toxicity 3 26 (grade >4) 0.12                    
                  Hematologic Toxicity 20   0.769                    
                  Anorexia 1   0.0385                    
                    Febrile aplasia 1   0.0385                    
                                               
9/29/2021, PMID: 34506675 Thursday, August 24, 2017 PMID: 29065426 Phase III Colorectal Cancer 508 DPYD Variant(s)   FOLFOX-4 or XELOX GI Toxicity 30 508 (grade >3) 0.155                    
                  Hematologic Toxicity 14   0.078                    
                  Neutopenia 130   0.67                    
                    Asthenia 8   0.041                    
                    Nausea 8   0.041                    
                    Vomiting 3   0.016                    
                    Skin Toxicity 1   0.005                    
                                               
9/29/2021, PMID: 34506675 Thursday, December 13, 2018 PMID: 30551678 Retrospective Study Colorectal Cancer 85 DPYD Variant(s)   5FU GI Toxicity 1 85 (grade >3) 0.012                    
                  Hematologic Toxicity 24   0.283                    
                  Hand-Foot Syndrome 4   0.047                    
                    Hair and Skin Toxicity 2   0.024                    
                                               
9/29/2021, PMID: 34506675 3/17/2015 PMID: 25782327 Clinical Colorectal Cancer 64 DPYD Variant(s)   COI-B or COI-E GI Toxicity 20 23 (grade >3) 0.31                    
                  Neutropenia 3   0.05                    
                  Asthenia 2   0.03                    
                                               
9/29/2021, PMID: 34506675 6/23/2015 PMID: 26099996 Prospective Solid Cancer 603 DPYD Variant(s)   5FU GI Toxicity 49 603 (grade >3) 0.081                    
                  Hematologic Toxicity 59   0.098                    
                  Nausea/Vomiting 9   0.015                    
                    Hepatic Toxicity 9   0.015                    
                                               
    Monday, June 7, 2010 PMID: 20530282 Prospective Colorectal Cancer 520 DPYD Variant(s)   IFL, IROX, FOLFOX GI Toxicity 401 520 (GRADE >3) 0.35                    
                  Dehydration 60   0.05                    
                  Hematologic Toxicity 190   0.16                    
                    Vomiting 131   0.11                    
                    Febrile Neutropenia 103   0.09                    
                    Paresthesia 92   0.08                    
                                               
    Saturday, March 26, 2016 PMID: 26658227 Cohort Colon Cancer 1228 DPYD Variant(s)   FOLFOX with or without cetuximab Overall Toxicity 638 1228 (grade >3) 0.327                    
                  GI Toxicity 203   0.166                    
                  Hematologic Toxicity 126   0.103                    
                    Pain 66   0.054                    
                    Fatigue 63   0.052                    
                    Nausea/Vomiting 57   0.047                    
                                               
    03/2013. PMID: 23603345 Clinical Colon or Breast Cancer 1407 DPYD Variant(s)   5FU or CAPE Hand-Foot Syndrome 9 / 49, 49 (grade >3) 0.18                    
                  Myelosupression 9 / 46,   0.2                    
                                             
                                               

 

MetaCensus: a blockchain meta-analysis network to improve scientific consensus and clinical decision support in pharmacogenomics