ECC 2013: TP53 Status Predicts Benefit From Neoadjuvant Cetuximab in Rectal Cancer
In a retrospective analysis of the randomized phase II EXPERT-C trial presented at the European Cancer Congress 2013 (Abstract LBA7), TP53 emerged as a strong, independent predictive biomarker for the benefit of cetuximab (Erbitux) in high-risk, locally advanced rectal cancer, according to Francesco Sclafani, MD, of The Royal Marsden NHS Foundation Trust in the United Kingdom.
Among TP53 wild-type patients, neoadjuvant cetuximab significantly improved 5-year progression-free survival by 24% and 5-year overall survival by 25%, Dr. Sclafani reported.
“TP53 mutational status was not prognostic but emerged as an independent predictive factor for cetuximab benefit,” he said. “The benefit from cetuximab in TP53 wild-type patients was independent of RAS and did not appear to be related to its radiosensitizing effect.”
After neoadjuvant chemoradiotherapy or short-course radiotherapy and surgery, systemic relapses occur in 25% to 30% of locally advanced rectal cancer cases. Alternative multimodality strategies have typically failed to provide a significant advantage over standard chemoradiotherapy, and there are no validated prognostic or predictive biomarkers to guide optimal treatment selection. Based on the findings of this study, if validated, TP53 status could prove valuable, Dr. Sclafani suggested.
The European multicenter EXPERT-C trial evaluated the benefit of capecitabine plus oxaliplatin, with or without cetuximab as a component of chemoradiotherapy, before total mesorectal excision in high-risk patients. In the overall population, no significant improvement in progression-free survival or overall survival was observed with the addition of cetuximab after a median follow-up of 64 months.
Rationale for Determining TP53 Status
TP53 is a tumor-suppressor gene involved in the control of cell proliferation and response to DNA damage, and mutations in TP53 occur in about 50% of colorectal cancers. Preclinical evidence has suggested an association between p53 function and the activity of agents targeting the epidermal growth factor receptor.
The EXPERT-C investigators retrospectively analyzed 144 samples for TP53 mutations (exons 4–9) and their association with outcomes, identifying TP53 mutations (primarily missense) in 75 (52.1%) patients.
After a median follow-up of 65 months, in the capecitabine plus oxaliplatin–only arm (no cetuximab) no differences in progression-free survival (hazard ratio [HR] = 1.23; P = .59) or overall survival (HR = .97; P = .94) were observed between TP53 mutant patients and wild-type patients. Five-year progression-free survival was 61% to 65%, and overall survival was approximately 67%, regardless of TP53 status.
Wild-Type TP53 Patients Benefit From Cetuximab
In contrast, for patients receiving cetuximab, TP53 status was important, as TP53 wild-type patients on this treatment arm had a statistically significant improvement in progression-free survival and overall survival, Dr. Sclafani reported.
While 5-year overall survival was 67% in TP53 mutant patients, regardless of treatment (cetuximab or not), the survival rate rose to 92.7% for TP53 wild-type patients assigned to cetuximab, compared to 67.5% for wild-type patients receiving only capecitabine plus oxaliplatin (HR = 0.16; P = .02). The multivariate analysis of treatment by TP53 interaction carried a P value of .038, he reported.
The benefit—an 85% reduction in risk—was observed in all TP53 wild-type patients, including KRAS wild-type or mutant, KRAS/NRAS wild-type or mutant, KRAS/NRAS/BRAF wild-type or mutant, or KRAS/NRAS/BRAF/PIK3CA wild-type or mutant.
Similarly, 5-year progression-free survival in TP53 wild-type patients was significantly increased with the addition of cetuximab, from 65.0% to 89.3% (HR = 0.23; P = .02).
Tumor response after neoadjuvant chemotherapy or chemoradiotherapy, however, did not differ significantly according to TP53 status or treatment assignment, though TP53 wild-type patients had numerically higher response rates to capecitabine and oxaliplatin plus cetuximab vs capecitabine plus oxaliplatin alone.
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