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Poster Display session 2

2196 - FUSAFE individual patient data meta-analysis (MA) to assess the performance of dihydropyrimidine dehydrogenase (DPD) gene polymorphisms for predicting grade 4-5 fluoropyrimidine (FP) toxicity

Date

29 Sep 2019

Session

Poster Display session 2

Topics

Tumour Site

Colon and Rectal Cancer

Presenters

Marie-Christine Etienne-Grimaldi

Citation

Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246

Authors

M. Etienne-Grimaldi1, N. Cozic2, J. BOYER3, V. Boige4, R.B. Diasio5, J. Taieb6, D. Meulendijks7, C. Palles8, U. Zanger9, M. Deenen10, C. Largiader11, M. Boisdron-Celle12, A. Marinaki13, B. Jennings14, E. Gross15, F. Thomas16, M. Loriot17, G. Le Teuff2, J. Pignon2

Author affiliations

  • 1 Oncopharmacology Laboratory, Centre Antoine Lacassagne, 06189 - Nice/FR
  • 2 Biostatistics And Epidemiology Unit, Gustave Roussy, Villejuif/FR
  • 3 Biochemistry Laboratory, CHU de Nîmes, Nîmes/FR
  • 4 Digestive Oncology Department, Gustave Roussy, 94805 - Villejuif/FR
  • 5 Cancer Center, Mayo Clinic, MN55905 - Rochester/US
  • 6 Department Of Gastroenterology And Digestive Oncology, Hopital European George Pompidou, 75015 - Paris/FR
  • 7 Pharmacology Department, Medicines Evaluation Board, 3531 AH - Utrecht/NL
  • 8 Institute Of Cancer And Genomic Sciences, The University of Birmingham - Medical School, B15 2TT - Birmingham/GB
  • 9 Clinical Pharmacology Department, Dr Margarete Fischer-Bosch Institute, Stuttgart/DE
  • 10 Clinical Pharmacy Department, Catharina Hospital, Eindhoven/NL
  • 11 Institute Of Clinical Chemistry, Inselspital Bern University Hospital, Bern/CH
  • 12 Oncopharmacology Department, ICO Paul Papin, Angers/FR
  • 13 Purine Research Laboratory, St Thomas' Hospital, London/GB
  • 14 Molecular Genetics Department, Norwich Medical School, University of East Anglia, Norwich/GB
  • 15 Gynecology Department, LMU University Hospital, Munich/DE
  • 16 Laboratoire De Biologie Médicale Oncologique, Institut Claudius Regaud, Toulouse/FR
  • 17 Clinical Biochemistry Department, Hopital Européen Georges Pompidou, Paris/FR

Resources

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Abstract 2196

Background

Despite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox.

Methods

Eligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index.

Results

From the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p<.0001) improved the model (M2). Further adding HapB3 did not improve the model (p=.24, M3). M3-adjusted OR (95%CI) was 10.0 (6.9-14.7) for the 3 variants *2A/D949V/*13 and 2.1 (1.4-3.0) for HapB3. Similar results were observed on colorectal pts only, or when excluding bolus administration alone.Table:

569P

ModelAUC (area under the curve)SensitivitySpecificityPositive predictive valueNegative predictive value
M10.72569.7%65.4%15.1%96.1%
M20.75075.5%62.8%15.2%96.7%
M30.75276.4%61.9%15.0%96.8%

Conclusions

This is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Centre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator).

Funding

French Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer.

Disclosure

V. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.

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