In a retrospective analysis of the randomized phase II EXPERT-C trial, TP53 emerged as a strong, independent predictive biomarker for the benefit of cetuximab (Eribitux) in MRI-defined high-risk, locally advanced rectal cancer, according to Francesco Sclafani, MD, of The Royal Marsden NHS Foundation Trust in the United Kingdom, who presented the data at the European Cancer Congress in Amsterdam.1
Among patients with TP53 wild-type tumors, the addition of cetuximab to neoadjuvant chemotherapy and chemoradiotherapy significantly improved 5-year progression-free survival by 24% and 5-year overall survival by 25%, Dr. Sclafani reported.
Independent Predictive Factor
“TP53 mutational status was not prognostic but emerged as an independent predictive factor for cetuximab benefit,” Dr. Sclafani said. “The benefit from cetuximab in patients with TP53 wild-type tumors was independent of RAS and did not appear to be related to its radiosensitizing effect,” he said.
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 largely failed to provide a significant advantage over standard chemoradiotherapy, and there are no validated prognostic or predictive biomarkers to guide optimal treatment selection. If the current study results can be validated, TP53 status could prove to be a valuable biomarker, Dr. Sclafani suggested.
The European multicenter EXPERT-C trial evaluated the benefit of cetuximab when given in association with neoadjuvant capecitabine/oxaliplatin followed by chemoradiotherapy prior to total mesorectal excision in MRI-defined high-risk patients. In the KRAS/BRAF wild-type population, no significant improvement in progression-free survival or overall survival was observed in patients with the addition of cetuximab after a median follow-up of 64 months.
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 group of patients treated without cetuximab, no differences in progression-free survival (hazard ratio [HR] = 1.23; P = .59) or overall survival (HR = .97; P = .94) were observed between patients with TP53 wild-type tumors and those with TP53 mutant tumors. Five-year progression-free survival was 61% to 65%, and overall survival was approximately 67%, regardless of TP53 status.
In contrast, for patients receiving cetuximab, TP53 status was important, as patients with TP53 wild-type tumors 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 patients with TP53-mutant tumors, regardless of treatment (cetuximab or not), the survival rate rose to 92.7% for patients with TP53 wild-type tumors assigned to cetuximab, compared to 67.5% for patients with TP53 wild-type tumors treated without cetuximab (HR = 0.16; P = .02). The test for interaction was significant (P = .036), and the multivariate analysis of treatment by TP53 interaction carried a P value of .038, he reported.
The benefit—an overall 84% reduction in risk—was observed in all patients with TP53 wild-type tumors, 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 patients with TP53 wild-type tumors 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 patients with TP53 wild-type tumors had numerically higher response rates to capecitabine/oxaliplatin plus cetuximab, vs capecitabine/oxaliplatin alone. ■
Disclosure: Dr. Sclafani reported no potential conflicts of interest.
1. Sclafani F, Gonzalez D, Cunningham D, et al: TP53 status may predict benefit from cetuximab in high-risk, locally advanced rectal cancer: Results of the EXPERT-C trial. 2013 European Cancer Congress. Abstract 7. Presented September 29, 2013.
Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, the formal discussant of the late-breaking abstract, noted there is strong rationale for studying TP53 status in relation to rectal cancer outcomes, but he felt the findings of EXPERT-C could not yet be ...