AMSTERDAM – TP53 mutational status was a strong, independent predictor of cetuximab benefit in high-risk, locally advanced rectal cancer in the phase II EXPERT-C trial.
For TP53 wildtype patients, adding cetuximab (Erbitux) to neoadjuvant chemoradiotherapy resulted in a significant 24.3% improvement in 5-year progression-free survival from 65% to 89.3% (hazard ratio, 0.23; P = .02) and a 25.2% increase in overall survival from 67.5% to 92.7% (HR, 0.16; P = .02).
In contrast, TP53-mutant patients experienced no benefit with neoadjuvant cetuximab in either progression-free (60.9% vs. 52.3%; HR, 1.21; P = .59) or overall survival (67.1% vs. 67.3%; HR, 0.97; P = .94), Dr. Francesco Sclafani reported at the multidisciplinary European cancer congresses.
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Dr. Francesco Sclafani
In a multivariable analysis, a statistically significant interaction was found between TP53 status and cetuximab effect for progression-free and overall survival, even after investigators adjusted for prognostic variables and KRAS status.
"TP53 mutational status was not prognostic, but emerged as an independent predictive factor for cetuximab benefit," he said. "The benefit from cetuximab in TP53 wildtype patients was independent of RAS and did not appear to be related to its radiosensitizing effect."
TP53 is a tumor-suppressor gene located in chromosome 17p, and mutations in this gene occur in about half of colorectal cancers. Functional p53 may predict response to radiotherapy, and preclinical evidence suggests p53 also has a role in modulating response to anti–epidermal growth factor therapies.
Neoadjuvant chemoradiotherapy (CRT) or short-course radiotherapy followed by total mesorectal excision (TME) is a standard treatment for locally advanced rectal cancer. Alternative multimodality strategies have in most cases failed to demonstrate a significant advantage over standard CRT, and there is a lack of validated prognostic or predictive biomarkers to guide optimal treatment selection. Thus, TP53 status could prove useful, if the current results are validated, said Dr. Sclafani of the Royal Marsden NHS Foundation Trust, London.
EXPERT-C compared neoadjuvant capecitabine (Xeloda) plus oxaliplatin (Eloxatin) and preoperative radiotherapy, with or without cetuximab, followed by TME in patients with high-risk rectal cancer. As previously reported, the addition of cetuximab did not improve the primary endpoint of complete response, but improved radiologic response and overall survival in patients with wildtype KRAS/BRAF status (J. Clin. Oncol. 2012;30:1620-7).
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Dr. Eric van Cutsem
For the biomarker analysis, TP53 status was analyzed in 144 patients (47 patients with biopsy only, 42 with surgical specimens only, and 55 with paired specimens). Of these, 75 patients (52%) had a TP53 mutation. Median follow-up was 65 months.
The EXPERT-C marker study is an interesting, hypothesis-generating study, but is a retrospective analysis without an adequate sample size for validation of biomarkers and had a relatively high degree of discordance between the initial biopsy before neoadjuvant treatment and the biopsy in surgery, said Dr. Eric Van Cutsem of the University Hospitals Leuven (Belgium), who was invited to discuss the results.
"It’s clearly not practice changing, but it may be the basis for further translational studies," he said.
Dr. Sclafani reported having no relevant financial disclosures.