TP53 Mutational Status and Cetuximab Benefit in Rectal Cancer: 5-Year Results of the EXPERT-C Trial

Sclafani, Francesco; González, David; Cunningham, David; Wilson, Sanna Hulkki; Peckitt, Clare; Tabernero, Josep; Glimelius, Bengt; Cervantes, Andrés; Dewdney, Alice; Wotherspoon, Andrew; Brown, Gina; Tait, Diana; Oates, J.; Chau, Ian

doi:10.1093/jnci/dju121

Cited by 48 publications

(27 citation statements)

References 25 publications

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“…Although FcgRIIa-131H and FcgRIIIa-158V polymorphisms predicted favorable survival outcomes with cetuximab, they did not identify patients with a higher rate of tumor response during preoperative treatment or pathologic complete response at the time of surgery. In contrast, we have previously shown that the mutational status of KRAS (or RAS) maintained its predictive value for response of the primary tumor to cetuximab but did not significantly correlate with the potential, long-term beneficial effect of this drug (8,9). Interestingly, and consistently with the hypothesis of ADCC as an important mechanism of action of cetuximab against micrometastases, we found that carriers of 131R and/or 158F alleles had a significantly lower risk of distant failure than patients homozygous for 131H and/or 158V when cetuximab was added to the study sequential treatment.…”

Section: Discussionmentioning

confidence: 79%

“…Larger studies are needed to evaluate the role of ADCC in the adjuvant setting in relation to RAS mutations. Moreover, further investigation is necessary to assess whether enhanced ADCC may be the main mechanism underlying the increased beneficial effects of cetuximab previously observed in patients with TP53 wild-type tumors treated in this trial (9).…”

Section: Discussionmentioning

confidence: 98%

“…Mutational analyses of KRAS (exons 2-4), NRAS (exons 2-4), and TP53 (exons 4-9) were performed centrally on genomic DNA extracted from formalin-fixed, paraffinembedded tissue from pretreatment biopsy and/or primary resection samples as previously described (8,9,18).…”

Section: Tumor Molecular Analysesmentioning

confidence: 99%

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FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Clinical Cancer Research

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Purpose: FcgR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX AE cetuximab in high-risk, locally advanced rectal cancer.Experimental Design: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX ¼ 54, CAPOX-C ¼ 51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcgRIIa-131R (HR, 0.38; P ¼ 0.058) and FcgRIIIa-158F alleles (HR, 0.21; P ¼ 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P ¼ 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P ¼ 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P ¼ 0.017) and remained significant after adjusting for prognostic variables (P ¼ 0.003).Conclusion: This is the first study investigating FcgRIIa and FcgRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 98%

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FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Clinical Cancer Research

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“…Overall, cetuximab did not improve the primary outcome (ypCR), thus it was not felt to have contributed significantly to increased radiation-induced cytotoxicity. Given the role of TP53 wild-type status and a functional p53 tumor suppressor gene in radiosensitization [65,66], a retrospective analysis in EXPERT-C noted that TP53 wild-type status was a predictive biomarker in favor of cetuximabbased therapy, albeit not for ypCR, with 5-year DFS and OS of 93 vs. 89 and 68 vs. 65 %, respectively (p = 0.02 each), in favor of the cetuximab arm [67]. Another phase II study tested RT with capecitabine (500 mg/m 2 twice daily), irinotecan (40 mg/m 2 weekly) and cetuximab (400 mg/m 2 on day 1 followed by 250 mg/m 2 weekly) [26].…”

Section: Anti-epidermal Growth Factor Therapymentioning

confidence: 99%

Is There a Best Radiosensitizing Agent in the Treatment of Locally Advanced Rectal Cancer?

Coveler

Richard

Apisarnthanarax

et al. 2016

Curr Colorectal Cancer Rep

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Over the past several decades, the management of localized rectal cancer has evolved from surgery alone as the definitive treatment to incorporating both radiation and chemotherapy to improve rates of local control and disease-free survival. Several chemoradiation regimens have been tested with different mechanisms of action, efficacy, and toxicity. There is little debate that concurrent radiation and a fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine) is the current standard of care prior to total mesorectal excision (TME). Attempts to add additional chemotherapy, such as oxaliplatin or irinotecan, have not consistently improved results. Recent attention has been given to concurrent biologic therapies (vascular endothelial growth factor (VEGF)-, epidermal growth factor receptor (EGFR)-, Poly(ADP-ribose) polymerase (PARP)-inhibitors, etc.) which may improve the outcomes of multi-modality therapy; however, the evidence is limited to phase I/II trials. It is critical for oncologists to be aware of various radiosensitizing agents that have been investigated and which will provide the best chance of disease control. In this review, we describe the mechanisms of action and evidence supporting these regimens to determine if there is a best radiosensitizing agent. Furthermore, we describe the relevant studies investigating the recent use of biologic radiosensitizers and the future direction using those agents.

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“…Interestingly, a retrospective biomarker analysis on samples from patients with rectal cancer undergoing neoadjuvant chemoradiation, recently suggested P53 mutational status as an independent predictive biomarker for anti-EGFR monoclonal antibody cetuximab clinical benefit (Sclafani et al, 2014).…”

Section: Future Perspectivesmentioning

confidence: 99%

A perspective on the current treatment strategies for locally advanced rectal cancer

Avallone

Aloj

Aprile

et al. 2015

The International Journal of Biochemistry & Cell Biology

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TP53 Mutational Status and Cetuximab Benefit in Rectal Cancer: 5-Year Results of the EXPERT-C Trial

Cited by 48 publications

References 25 publications

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Is There a Best Radiosensitizing Agent in the Treatment of Locally Advanced Rectal Cancer?

A perspective on the current treatment strategies for locally advanced rectal cancer

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