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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

Objective To evaluate the therapeutic efficacy of a novel modular polymer platform in the treatment of head and neck squamous cell carcinoma (HNSCC). Design In vivo study. Setting Academic research laboratory. Subjects and Methods C3H/HeJ mice and SCID/beige mice were randomized to receive implantation of no polymer, plain polymer, plain polymer with local cisplatin injection, or cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive 4 Gy of external beam radiation for 4 days or no radiation. Tumor size was measured until the mice were humanely killed. At necropsy, the tumors were excised and weighed. Results There was a significant reduction in tumor growth using this novel polymer platform. The cisplatin-secreting polymer effectively reduced human head and neck tumor growth in SCID mice by 17-fold and SCC VII/SF tumors in C3H/HeJ mice by more than 16-fold compared with the control, plain polymer, and plain polymer + intratumoral cisplatin injection groups (P = .01 for both). We also observed a statistically significant lower tumor weight in mice treated with cisplatin polymer and concomitant radiation compared with the radiation alone and control groups. Conclusions We demonstrate the efficacy of a novel polymer platform in delivering cisplatin to a partially resected SCC in a murine model. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC.