Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Abstract

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients. Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models. Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008). Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT. Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

“…A number of additional anti-EGFR antibodies have been recently developed and clinically tested, such as Panitumumab [ 142 , 143 , 144 ], Nimotuzumab [ 145 , 146 , 147 ], and Sym004 [ 148 , 149 ]. The anti-EGFR antibody Panitumumab was shown moderate activity as a single agent in HNSCC patients, previously treated with platinum-based drugs [ 142 ].…”

“…The anti-EGFR antibody Panitumumab was shown moderate activity as a single agent in HNSCC patients, previously treated with platinum-based drugs [ 142 ]. The benefits of adding Nimotuzumab to combination therapy with cisplatin and radiotherapy have been reported in some HNSCC patients [ 146 ], and high HIF1α (hypoxia-inducible factor 1-alpha) expression may indicate likely benefit for such treatments [ 145 ]. Sym004 has been in development for at least 10 years, and represents a mix of two chimeric monoclonal antibodies [ 150 ].…”

Molekulare Prädiktion für die Radio(chemo)therapie von Kopf-Hals-Plattenepithelkarzinomen

“…In der multivariaten Analyse konnte HIF1-α als unabhängiger negativer prognostischer Parameter erfasst werden. Eine hohe HIF1-α-Expression war mit einem kürzeren progressionsfreien Überleben, einer niedrigeren lokoregionären Kontrolle und einem kürzerem Gesamtüberleben im Vergleich zu der Standardtherapiegruppe (Bestrahlung und Cisplatin) verbunden [21]. » HIF1-α ist ein negativer prognostischer Parameter Die Quantifizierung von Hypoxie wurde initial durch die direkte Bestimmung des Sauerstoffpartialdruckes mittels invasiver Einbringung von Feinnadelelektroden in den Tumor durchgeführt [20].…”

Correlation of transcriptionally active human papillomavirus status with the clinical and molecular profiles of head and neck squamous cell carcinomas

“…However, accumulating reports suggest a negative correlation between HPV‐positive status and EGFR expression as reviewed by Mirghani et al 11 Furthermore, HNSCCs are characterized by a hypoxic tumor microenvironment, which decreases the therapeutic efficacy of radio‐chemotherapy 12 . The expression of hypoxia‐inducible factor 1α (HIF1α), which is a major effector of the cellular hypoxic response, is frequently overexpressed in HNSCCs 13 . Additionally, HIF1α is an independent negative prognostic factor for HPV‐negative HNSCCs 13 .…”

“…The expression of hypoxia‐inducible factor 1α (HIF1α), which is a major effector of the cellular hypoxic response, is frequently overexpressed in HNSCCs 13 . Additionally, HIF1α is an independent negative prognostic factor for HPV‐negative HNSCCs 13 . The levels of hypoxia are similar between HPV‐positive and HPV‐negative HNSCCs 14,15 .…”