576P - Pharmacogenetic profiling for toxicity of oxaliplatin and fluoropyrimidines. Final report from an ancillary protocol to the TOSCA (Three Or Six Col...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Complications of Treatment
Colon Cancer
Rectal Cancer
Presenter Francesco Graziano
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors F. Graziano1, A. Ruzzo2, F. Galli3, E. Giacomini2, I.C. Floriani4, F. Galli3, E. Rulli3, S. Lonardi5, M. Ronzoni6, B. Massidda7, V. Zagonel8, N. Pella9, C. Mucciarini10, R. Labianca11, E. Veltri12, P. Sozzi13, S. Barni14, V. Ricci15, A. Sobrero16, M. Magnani2
  • 1Dipartimento Di Oncologia, Azienda Ospedaliera "Ospedali Riuniti Marche Nord"-Presidio San Salvatore Muraglia, 61122 - Pesaro/IT
  • 2Dipartimento Di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”., Urbino/IT
  • 3Dipartimento Di Oncologia, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Milano/IT
  • 4Department Of Oncology, Mario Negri Institute, 20156 - Milano/IT
  • 5Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 6Irccs San Raffaele, Dipartimento di Oncologia, Milano/IT
  • 7Dipartimento Di Scienze Biomediche E Biotecnologie, 6Azienda Ospedaliera Universitaria di Cagliari, P.O. Monserrato, caglairi/IT
  • 8Department Of Oncology, IOV-IRCCS, 35138 - Padova/IT
  • 9Oncologia Medica, Azienda Ospedaliera Universitaria-Udine Sta Maria della Misericordia, Udine/IT
  • 10U.o. Medicina Oncologica, Ospedale Ramazzini, Carpi/IT
  • 11Director, Cancer Center, Azienda Ospedaliera Papa Giovanni XXIII, 24127 - Bergamo/IT
  • 12Oncology Department, S.M Goretti Hospital, Latina, 04100 - Latina/IT
  • 13Medical Oncology, Ospedale degli Infermi, IT-13900 - Biella/IT
  • 14Oncology, Azienda Ospedaliera Treviglio-Caravaggio, 24047 - Treviglio/IT
  • 15Oncologia Medica, IRCCS San Raffaele, 22000 - Milano/IT
  • 16Oncologia Medica, Azienda Ospedaliera Universitaria S. Martino di Genova, Genova/IT

Abstract

Aim

A number of germline polymorphisms have shown promising predictive role for chemotherapy related toxicity in colorectal cancer patients. However, large-scale validation trials are necessary before pharmacogenetic findings are incorporated into clinical practice. We investigated 17 polymorphisms in 11 genes for their association with toxicity of fluoropyrimidines and oxaliplatin (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2) in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy.

Methods

TOSCA is a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemoterapy. A planned sample of patients was accrued in the ancillary pharmacogenetic study. The primary endpoint was the evaluation of the relationship of genetic polymorphisms with occurrence of grade 3-4 CTCAE toxicity event (grade 2-4 for neurotoxicity).

Results

From July 2007 to October 2011, 531 patients were enrolled from 26 experimental centres (194 patients in 6-month FOLFOX-4 arm, 194 patients in 3-month FOLFOX-4 arm, 74 patients in 6-month XELOX arm, 69 patients in 3-month XELOX arm). Grade ≥3 neutropenia and grade >2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade > 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity.

Conclusions

In the studied population, we ruled out a strong predictive role of known genetic variants for toxicity. Future investigations should address novel polymorphisms emerging from genome-wide association studies.

Disclosure

All authors have declared no conflicts of interest.