# Search for Mutations Connected With Non‐Response to Anti‐EGFR Therapy in mCRC in the Morphologically Defined Regions of Primary Tumours

## TL;DR

This study shows that analyzing specific tumor regions can reveal mutations linked to poor response to anti-EGFR therapy in colorectal cancer.

## Contribution

The study introduces a method to connect tumor morphology with mutation patterns to predict therapy response in CRC.

## Key findings

- Mutations in BRAF and KRAS were uniquely found in non-responders and linked to specific tumor morphologies.
- Morphology-based mutation analysis provided more detailed insights than whole-tumor analysis.
- Serrated and mucinous morphologies were associated with BRAF mutations, while mucinous and desmoplastic morphologies were linked to KRAS mutations.

## Abstract

Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti‐EGFR therapy, as compared to whole‐tissue analysis.

We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild‐type metastatic colorectal cancer (CRC) patients receiving anti‐EGFR therapy. Deep next‐generation sequencing was performed on whole‐tumour sections and six morphology‐defined tumour regions.

Mutations in genes linked to anti‐EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non‐responder group, with substantial variability across morphological sub‐regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub‐regions provided more details than that of the whole‐tumour profile.

Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.