Molecular Diagnostics

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).

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Fig. 1: Flow diagram of the study.
Fig. 2: Prognostic value of HIF1α and pEGFRY1068.
Fig. 3: Forest plots showing predictive association of the studied biomarkers.
Fig. 4: HIF1α showing qualitative interaction.
Fig. 5: Kaplan–Meier curves stratified by biomarker status and treatment.

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Acknowledgements

We acknowledge all the participating patients.

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Affiliations

Authors

Contributions

Methodology: U.P., M.P. and T.S.; scoring of IHC slides: P.G., N.M., S.R. and A.P.; data curation and formal analysis: U.P. and S.K.; project administration: U.P., M.P. and M.B.M.; writing—original draft: U.P. and M.B.M.; writing—review and editing: S.K., M.P. and T.S.; conducing the trial: A.J., V.N., V.M.P. and K.P.; conceptualisation and supervision: M.B.M.; funding acquisition and resources: M.B.M. All authors approved the final paper.

Corresponding author

Correspondence to Manoj B. Mahimkar.

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Ethics approval and consent to participate

This study was approved by the institutional ethics committee of Tata Memorial Center (IEC approval 50 of 2011) and was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent.

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Not applicable.

Data availability

All data generated or analysed during this study are included in this published article (and its supplementary information file). However, if required, we can submit the clinical outcomes/follow-up and biomarker data.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the Department of Science & Technology—Science and Engineering Research Board (EMR/2015/001591), Tata Memorial Centre, Seed In Air grant (TMC/SIA/2696) and Council of Scientific & Industrial Research for fellowship (to U.P.).

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Patel, U., Pandey, M., Kannan, S. et al. Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01064-4

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