Can an inherited microRNA-disrupting variant, called the Kirsten rat sarcoma viral oncogene homolog (KRAS)–variant, predict cetuximab response in head and neck cancer?
In an analysis of a phase 3 randomized clinical trial of 891 patients with head and neck squamous cell carcinoma, the KRAS-variant predicted a significant, positive response to cetuximab. In addition, the KRAS-variant was found to interact with p16 status and was associated with significantly elevated transforming growth factor β1 levels in these patients.
The KRAS-variant appears to be an inherited biomarker of cetuximab response in patients with head and neck squamous cell carcinoma.
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.
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.
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.
clinicaltrials.gov Identifier: NCT00265941
Joanne B. Weidhaas, Jonathan Harris, Dörthe Schaue, Allen M. Chen, Robert Chin, Rita Axelrod, Adel K. El-Naggar, Anurag K. Singh, Thomas J. Galloway, David Raben, Dian Wang, Chance Matthiesen, Vilija N. Avizonis, Rafael R. Manon, Omar Yumen, Phuc Felix Nguyen-Tan, Andy Trotti, Heath Skinner, Qiang Zhang, Robert L. Ferris, David Sidransky, Christine H. Chung. The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell CancerA Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2017;3(4):483–491. doi:10.1001/jamaoncol.2016.5478