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

## TL;DR

This study shows that a specific genetic profile in stage III colon cancer patients can predict better outcomes with anti-EGFR treatment, while others may be harmed.

## Contribution

The study applies molecular negative hyperselection to stage III colon cancer, identifying a subgroup that benefits from anti-EGFR therapy in the adjuvant setting.

## Key findings

- Hyperselected patients had improved 5-year relapse-free and overall survival compared to gene-altered patients.
- Adding cetuximab to FOLFOX improved relapse-free survival in hyperselected patients with distal tumors.
- Cetuximab was detrimental to relapse-free and overall survival in gene-altered patients.

## Abstract

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.

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).

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.

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.

•Molecular negative hyperselection is prognostic for RFS and OS in resected stage III pMMR/MSS colon cancer (CC).•The addition of cetuximab to adjuvant FOLFOX improves RFS in patients with hyperselected stage III pMMR/MSS CC.•RFS with adjuvant cetuximab + FOLFOX is further improved in hyperselected patients with distal primary tumor location.•Adjuvant cetuximab + FOLFOX is associated with a detrimental effect on RFS and OS in patients with gene altered CC.

Molecular negative hyperselection is prognostic for RFS and OS in resected stage III pMMR/MSS colon cancer (CC).

The addition of cetuximab to adjuvant FOLFOX improves RFS in patients with hyperselected stage III pMMR/MSS CC.

RFS with adjuvant cetuximab + FOLFOX is further improved in hyperselected patients with distal primary tumor location.

Adjuvant cetuximab + FOLFOX is associated with a detrimental effect on RFS and OS in patients with gene altered CC.