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RESEARCH PRODUCT

The impact of TP53 mutation on high-risk rectal cancer patients treated within the EXPERT-C trial, a randomized phase II study of neoadjuvant oxaliplatin/capecitabine (CAPOX) and chemoradiation (CRT) with or without cetuximab.

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e14088 Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.