The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer
| Autor: | Joanne B. Weidhaas, Thomas J. Galloway, Qiang Zhang, Christine H. Chung, Rafael R. Manon, Andy Trotti, David Sidransky, David Raben, Jonathan Harris, Rita Axelrod, Dörthe Schaue, Dian Wang, Chance Matthiesen, Robert Chin, Allen M. Chen, Anurag K. Singh, Vilija N. Avizonis, Robert L. Ferris, Phuc Felix Nguyen-Tan, Omar Yumen, Heath D. Skinner, Adel K. El-Naggar |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Oncology Cancer Research medicine.medical_treatment Cetuximab Kaplan-Meier Estimate medicine.disease_cause 0302 clinical medicine Medicine Cancer Tumor Hazard ratio Chemoradiotherapy Middle Aged Head and Neck Neoplasms 030220 oncology & carcinogenesis Public Health and Health Services Carcinoma Squamous Cell Female KRAS medicine.drug Adult medicine.medical_specialty Clinical Trials and Supportive Activities Oncology and Carcinogenesis Antineoplastic Agents Disease-Free Survival Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Rare Diseases Clinical Research Internal medicine Genetics Biomarkers Tumor Carcinoma Humans neoplasms Aged Proportional Hazards Models Squamous Cell Carcinoma of Head and Neck business.industry Proportional hazards model medicine.disease Head and neck squamous-cell carcinoma digestive system diseases Radiation therapy 030104 developmental biology Squamous Cell Cisplatin business Biomarkers |
| Zdroj: | JAMA oncology, vol 3, iss 4 |
| ISSN: | 2374-2437 |
| Popis: | Importance There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment. Objectives To examine whether the Kirsten rat sarcoma viral oncogene homolog ( KRAS ) – variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS -variant with p16 status and blood-based transforming growth factor β1 (TGF-β1). Design, Setting, and Participants A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS -variant. Genomic DNA was tested for the KRAS -variant in a CLIA-certified laboratory. Correlation of the KRAS -variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model. Main Outcomes and Measures The correlation of KRAS -variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested. Results Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS -variant testing, and 376 had plasma samples for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS -variant. Overall, for patients with the KRAS -variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS -variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS -variant treated without cetuximab had worse PFS than patients without the KRAS -variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS -variant, p16 status, and treatment for OS (HR, for KRAS -variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS -variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS -variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS -variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS -variant had significantly elevated TGF-β1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects. Conclusions and Relevance Patients with the KRAS- variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS -variant and p16 status. Elevated TGF-β1 levels in patients with the KRAS -variant suggests that cetuximab may help these patients by overcoming TGF-β1–induced suppression of antitumor immunity. Trial Registration clinicaltrials.gov Identifier:NCT00265941 |
| Databáze: | OpenAIRE |
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