Germline variants and clinical outcomes of high-risk stage II and stage III colon cancer patients treated with oxaliplatin and fluoropyrimidines adjuvant.

Presentazione sul tema: "Germline variants and clinical outcomes of high-risk stage II and stage III colon cancer patients treated with oxaliplatin and fluoropyrimidines adjuvant."— Transcript della presentazione:

1 Germline variants and clinical outcomes of high-risk stage II and stage III colon cancer patients treated with oxaliplatin and fluoropyrimidines adjuvant chemotherapy: a pharmacogenetic ancillary study to TOSCA trial. Ruzzo A1, Galli Fabio2, Galli Francesca2, Rulli E2, Lonardi S3, Zagonel V3, Ronzoni M4, Ionta MT5, Pella N6, Mucciarini C7, Labianca R8, Veltri E9, Sozzi P10, Barni S11, Nicolini M12, Biondi E13, Bramati A14, Turci D15, Buscaglia M16, Magnani M1, Graziano F17 1 Università degli Studi di Urbino, 2 IRCCS Milano, 3 IOV-IRCCS - Padova, 4 Ospedale San Raffaele - Milano, 5 Azienda Ospedaliera Universitaria - Cagliari, 6 Azienda Ospedaliera Universitaria - Udine, 7 Ospedala B. Ramazzini – Carpi, 8 Ospedale Papa Giovanni XXIII – Bergamo, 9 Ospedale di Gaeta ASL Latina – Gaeta, 10 Ospedale degli Infermi di Biella, 11 Ospedale Treviglio - Caravaggio – Treviglio, 12 Ospedale Cervesi – Cattolica, 13 Ospedale F. Renzetti – Lanciano, 14 Azienda Oapedaliera Fatebenefratelli – Milano, 15 AUSL Ospedale Ravenna – Ravenna, 16 Ospedale Policlinico San Martino – Genova, 17 Azienda Ospedaliera Ospedali Riuniti Marche Nord - Pesaro A03 Background Material and methods Conclusions Bibliography Functional germline variants (SNPs) may characterize sub-populations of cancer patients who gain different benefits from chemotherapy. We investigated 17 SNPs in 11 genes with putative impact on sensitivity to fluoropyrimidines and oxaliplatin (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2).  TOSCA was 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 FOLFOX-4 or XELOX adjuvant chemoterapy, sponsored by GISCAD (Italian Group For The Study Of Gastrointestinal Cancer) and supported by AIFA. Patients who signed the informed consent were prospectively accrued in this ancillary study. Molecular assessments were performed at University of Urbino. The primary and secondary endpoints were progression free survival (PFS) and overall survival (OS), respectively. Univariate and multivariate Cox proportional hazard models were used. XRCC1 rs25487 G>A produced remarkable differences in PFS and OS in the studied population. Additional functional germline variants involved in the DNA repair pathways may engage a clinical impact according to the duration of the adjuvant chemotherapy program. These findings may impact on the overall chemotherapy treatment strategy of colon cancer patients. Additional prospective studies are warranted for confirming this associations and after adjustment for tumor-related prognostic factors. Lonardi S et al.: Ann Oncol. 2016;27: Ruzzo A et al.: Sci Rep. 2014;4:6828. Acknowledgments This work was supported by FanoAteneo, Diatheva srl and POR MARCHE FESR 2007–2013. Overall N=512 Age at diagnosis – Median (Q1 – Q3) 64.0 (57.4 – 70.7) Female sex – (%) 218 (42.6) Tumor site – (%) Right colon 198 (38.7) Left colon 293 (57.2) Multiple site 21 (4.1) Clinical stage – (%) II 185 (36.1) III low risk 212 (41.4) III high risk 115 (22.5) Results From July 2007 to October 2011, 524 patients were enrolled in this study. Eight patients were excluded from analysis due to major violation and 4 never started treatment. Baseline characteristics are reported in Table and 188 patients were treated with FOLFOX-4, 68 and 71 with XELOX in 6-month and in 3-month arm, respectively. Allele frequencies of all SNPs were consistent with Hardy-Weinberg equilibrium. During a median follow-up of 74.5 months, 82 (16%) progression and 71 (14%) deaths were observed. Progression or deaths occurred in 106 (21%) patients. The XRCC1 rs25487 G>A shortened significantly PFS (adjusted HR[AA vs GG] 2.02; 95%CI ; p=0.015) and OS (adjusted HR[AA vs GG] 3.07; 95%CI ; p=0.001). Interactions between SNPs and treatment duration were detected. In detail, 3-month treatment was correlated with a shorter PFS for patients with G allele in XPD rs13181 T>G and for patients with CC genotype (vs TC+TT) in ERCC1 rs11675 T>C. A better PFS and OS were identified in patients treated for 3 months with GG genotype for ABCC2 rs A>G. Finally, the GG genotype in ABCC2 rs G>A increased OS in patients treated with 3 months treatment (Figure 1).  Table 1. Demographic and clinical-pathological characteristics Figure 1. Subgroup analysis according to treatment duration