Molecular and clinical determinants of survival following relapse after curative treatment of stage II-III colon cancer (CC): Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial.

3504 Background: We presented the prognostic (prog) impact of molecular markers (MM) on relapse free survival (RFS) of stage II-III CC (ASCO proc 2009, 27, abstr. 4002). We analyze now the impact of the 8 same MM on the overall survival (OS) after relapse of stage II-III CC in PETACC 3, an adjuvant trial with 3278 patients (pts). Methods: 1,564 blocks were prospectively collected, tumor (Tu) DNA extracted and 8 MM assessed as described previously. Markers prog value was analysed by Cox regression for OS, multivariate analysis (MA) and Kaplan-Meier estimates of median survival (MS). Time to recurrence (TTR) of ≤18m defined early relapse (ER), >18m late relapse (LR). Results: 392 out 990 relapsing pts were assayed for the 8 MM, 221 ER, 171 LR. The MA investigating prog factors impacting on OS after relapse is presented in the Table. BRAF, Tu site, and TTR were found to be major predictors of OS after relapse. MS (95%CI) according to BRAF was 7.5 m (4.8-11.2) vs. 25.2m (21.1-29.5) p=1.9e-11, according to Tu site 16.1 m (12.6-19.0) vs. 27.6 m (22.9-33.6) p=2.71e-06, according to TTR 17.9m (15.5-20.3) vs. 30.0 m (24.7-38.4) p=0.00032. Similar MS according to Tu site (16.2 m vs. 28.6 m, p=4.52e-14) and TTR (18.4 m vs. 30.5 m, p=2.18e-08) were observed in the full relapsing pts set (n=990). Conclusions: Whereas BRAF and Tu site had no prog value on RFS of stage II-III CC (Roth AD, doi: 10.1200/JCO.2009.23.3452), BRAF, Tu site, and TTR are strong determinants of CC OS after relapse and should imperatively be used to stratify studies in metastatic CC. The independent effects of Tu site and TTR might be indicative of additional non-yet-identified MM. HR (95% CI) P value TTR (ER/LR) 1.60 (1.23-2.09) 0.0005 Age 1.00 (0.99-1.01) 0.98 Sex 1.24 (0.95-1.62) 0.11 Tu grade 1.52 (1.02-2.25) 0.04 Stage 1.53 (1.00-2.36) 0.051 Tu site (right/left) 1.69 (1.29-2.21) 0.0002 Treatment group 1.09 (0.84-1.39) 0.52 Microsat. instabil. 0.51 (0.28-0.95) 0.034 Thymidilate synth. 0.99 (0.68-1.44) 0.95 SMAD4 1.21 (0.91-1.60) 0.18 p53 0.96 (0.73-1.26) 0.76 hTERT 1.37 (0.96-1.96) 0.09 18qLOH 0.86 (0.60-1.24) 0.43 BRAF mutation ± 3.61 (2.24-5.81) 1.24e-07 KRAS 1.13 (0.85-1.51) 0.40 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer