Negative hyperselection of patients with stage III colon cancer receiving anti-EGFR-based adjuvant treatment.

BACKGROUND

The paradigm of molecular negative hyperselection, beyond RAS and BRAF, identifies metastatic colorectal cancer (mCRC) patients with the greatest benefit from anti-epidermal growth factor receptor (anti-EGFR) agents. We hypothesize that applying this model to stage III colon cancer (CC) might identify a subgroup deriving benefit from anti-EGFRs in the adjuvant setting.

PATIENTS AND

METHODS

We used a 'simplified PRESSING panel' grouping genomic alterations related to anti-EGFR primary resistance in mCRC, to select the proficient mismatch repair or microsatellite stable (pMMR/MSS) population of the randomized phase III PETACC-8 clinical trial, testing adjuvant FOLFOX ± cetuximab in resectable stage III CC. Patients without any tumor alterations in RAS/BRAF, or the simplified PRESSING panel were defined as 'hyperselected' (HS), whereas those with at least one such alteration were considered 'gene altered' (GA).

RESULTS

Of 1421 eligible patients, 536 (37.7%) were HS and 885 (62.2%) GA. HS patients were more frequently male, with distal tumor of lower stage and grade. HS patients showed improved 5-year relapse-free survival (RFS) (81% versus 68%) and overall survival (OS) (89% versus 77%) as compared with GA patients. A statistically significant interaction was observed for RFS between molecular profile and treatment (P = 0.05). Among HS patients, adding cetuximab to FOLFOX yielded a 5-year RFS of 83% versus 78% with FOLFOX alone [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.55-1.19, P = 0.28]. Adding distal tumor location further improved the HR to 0.72 (P for interaction = 0.03). No significant interaction for OS was observed. In GA patients, the addition of cetuximab to FOLFOX was detrimental for RFS and OS.

CONCLUSIONS

HS was prognostic for RFS and OS in patients with resected stage III pMMR/MSS CC and associated with a trend toward improved RFS with the addition of cetuximab to adjuvant FOLFOX. Conversely, cetuximab seems detrimental in patients with GA tumors. These data may help to improve patient selection in future adjuvant clinical trials testing anti-EGFR therapies.