The Prognostic Significance of Facial Nerve Involvement in Carcinomas of the Parotid Gland.

IMPORTANCE AND BACKGROUND: Facial nerve (FN) palsy and perineural invasion (PNI) are adverse features in carcinomas of the parotid gland. FN sacrifice at the time of surgery is associated with significant morbidity. The role of adjuvant radiotherapy in patients with high-risk features, including FN involvement, remains unclear. OBJECTIVE: Analyze the disease-free survival (DFS) and overall survival (OS) and the impact of tumor characteristics, including FN involvement, for patients treated with surgical resection for carcinoma of the parotid gland. DESIGN: This is a retrospective chart review. SETTING: University of Utah and Intermountain Healthcare, Utah. PARTICIPANTS: A total of 129 patients who were treated with primary surgery for nonmetastatic primary malignancies of the parotid gland from 1988 to 2006. INTERVENTIONS: Parotidectomy with or without adjuvant therapy. MAIN OUTCOME(S) AND MEASURES: Kaplan-Meier analysis was used to obtain 5-year estimates of DFS and OS. Recurrence risk factors, particularly the impact of FN involvement, were analyzed. RESULTS: Five-year DFS and OS rates were 79% and 78%, respectively. Thirty-two (28%) patients developed recurrent disease. Disease recurrence occurred in 64% of patients with both FN palsy and PNI, in 43% with FN palsy without PNI, in 27% with only PNI, and in 16% without either feature. CONCLUSIONS AND RELEVANCE: FN involvement, particularly FN palsy, is a predictor of increased risk of recurrence and death. Radiotherapy cannot substitute for FN sacrifice in high-risk patients.

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial.

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 ß1 (TGF-ß1). 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-ß1 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-ß1 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-ß1 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-ß1 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-ß1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-ß1-induced suppression of antitumor immunity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00265941.