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Prognostic and predictive roles of cancer stem cell markers in head and neck squamous cell carcinoma patients receiving chemoradiotherapy with or without nimotuzumab

British Journal of Cancer volume 126, pages 1439–1449 (2022)Cite this article

Subjects

Abstract

Background

Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are needed to identify the patients most likely to benefit from these therapies. Here, we present predictive and prognostic associations of different cancer stem cell markers in HPV-negative locally advanced (LA) HNSCC patients.

Methods

Pretreatment tumour tissues of 404 HPV-negative LA-HNSCCs patients, a subset of—phase 3-randomised study comparing cisplatin-radiation(CRT) and nimotuzumab plus cisplatin-radiation(NCRT) were examined. The expression levels of CD44, CD44v6, CD98hc, ALDH1A1, SOX2 and OCT4A were evaluated using immunohistochemistry. Progression-free survival(PFS), loco-regional control(LRC),- and overall survival(OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.

Results

NCRT showed significantly improved OS with low membrane expression of CD44 compared to CRT [HR (95% CI) = 0.63 (0.46–0.88)]. Patients with low CD44v6 also showed better outcomes with NCRT [LRC: HR (95% CI) = 0.25 (0.10–0.62); OS: HR (95% CI) = 0.38 (0.19–0.74)]. No similar benefit with NCRT observed in patients with high CD44 or CD44v6 expression. Bootstrap resampling confirmed the predictive effect of CD44 (Interaction P = 0.015) and CD44v6 (Interaction P = 0.041) for OS. Multivariable Cox analysis revealed an independent negative prognostic role of CD98hc membrane expression for LRC [HR (95% CI) = 0.63(0.39–1.0)] and OS[HR (95% CI) = 0.62 (0.40–0.95)].

Conclusions

CD44 and CD44v6 are potential predictive biomarkers for NCRT response. CD98hc emerged as an independent negative prognostic biomarker.

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: Representative images of immunohistochemistry (IHC) staining in HPV-negative LA-HNSCC patients.
Fig. 3: Prognostic and predictive association of CD98hc and CD44, respectively, in HPV-negative LA-HNSCC patients.
Fig. 4: Predictive association of CD44 and CD44v6 in HPV-negative LA-HNSCC patients.

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Data availability

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

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Acknowledgements

We acknowledge all patients and investigators who contributed to the study. Additionally, we would like to thank Cactus Communications Pvt. Ltd., Mumbai, India for their assistance in English language editing.

Funding

Council of Scientific & Industrial Research, fellowship to Usha Patel, Grant/Award Number: 09/513(0099)/2014‐EMR‐I; Science and Engineering Research Board, Grant/Award Number: EMR/2015/001591; Tata Memorial Centre, Seed In Air grant, Grant/Award Number: TMC/SIA/2696.

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Authors and Affiliations

  1. Mahimkar Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Usha Patel, Subhakankha Manna, Vishwayani Shejwal & Manoj B. Mahimkar

  2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India

    Usha Patel, Sadhana Kannan, Swapnil U. Rane, Neha Mittal, Poonam Gera, Asawari Patil, Vanita Noronha, Amit Joshi, Vijay M. Patil, Kumar Prabhash & Manoj B. Mahimkar

  3. Biostatistician, Clinical Research Secretariat, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Sadhana Kannan

  4. Department of Pathology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Swapnil U. Rane & Asawari Patil

  5. Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India

    Neha Mittal

  6. Biorepository, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Poonam Gera

  7. Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India

    Vanita Noronha, Amit Joshi, Vijay M. Patil & Kumar Prabhash

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  1. Usha Patel
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Contributions

Methodology: UP, SM, VS and MBM; scoring of IHC slides: SR, NM, PG and AP; data curation and formal analysis: UP and SK; project administration: UP and MBM; writing—original draft: UP and MBM; writing—review and editing: UP, MBM, SR, NM and SK; conducting the trial: AJ, VN, VMP and KP; conceptualisation and supervision: MBM; funding acquisition and resources: MBM. All authors approved the final paper.

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Correspondence to Manoj B. Mahimkar.

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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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Patel, U., Kannan, S., Rane, S.U. et al. Prognostic and predictive roles of cancer stem cell markers in head and neck squamous cell carcinoma patients receiving chemoradiotherapy with or without nimotuzumab. Br J Cancer 126, 1439–1449 (2022). https://doi.org/10.1038/s41416-022-01730-9

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