Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation

PURPOSE We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. EXPERIMENTAL DESIGN DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). CONCLUSION rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule

Facteurs prédictifs de longue survie chez les patients Caucasiens atteints de cancer de l'estomac métastatique traité par une 2ème ligne de chimiothérapie

Lorsque cette étude a débutée, les données suggérant un bénéfice d'une deuxième ligne de chimiothérapie dans les cancers gastriques avancés étaient limitées. La proportion de patients recevant des traitements au-delà d'une première ligne était donc très variable, entre 14 - 75 % selon les institutions. Cette étude s'est intéressée à des patients Caucasiens souffrant d'un cancer de l'estomac, strictement métastatique, traités aux HUG avec une deuxième ligne de chimiothérapie. L'objectif était de déterminer des facteurs pronostiques clinico-pathologiques. En l'absence d'études randomisées, ces facteurs peuvent aider à sélectionner les patients candidats à une deuxième ligne de chimiothérapie. En analyse univariée, une survie sans progression de 26 semaines, un antécédent de chirurgie à visée curative et un CEA élevé étaient associés à la survie globale. En intégrant ces données à la littérature récente, notre étude soutient que la sensibilité à une chimiothérapie antérieure permet d'identifier des patients ayant une longue survie

Survival predictors for second-line chemotherapy in Caucasian patients with metastatic gastric cancer

There are very limited data suggesting a benefit for second-line chemotherapy in advanced gastric cancer. Therefore, the number of patients who receive further treatment after failure of first-line chemotherapy varies considerably, ranging from 14% to 75%. In the absence of a demonstrated survival benefit of second-line chemotherapy, appropriate selection of patients based on survival predictors is essential. However, no clinico-pathologic parameters are currently widely adopted in clinical practice. We looked exclusively at Caucasian patients with metastatic gastric cancer treated with second-line chemotherapy to see if we could establish prognostic factors for survival