. 2022 Dec:86:104373.

doi: 10.1016/j.ebiom.2022.104373. Epub 2022 Nov 25.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

Peter Y F Zeng¹, Matthew J Cecchini², John W Barrett³, Matthew Shammas-Toma³, Loris De Cecco⁴, Mara S Serafini⁴, Stefano Cavalieri⁵, Lisa Licitra⁵, Frank Hoebers⁶, Ruud H Brakenhoff⁷, C René Leemans⁷, Kathrin Scheckenbach⁸, Tito Poli⁹, Xiaowei Wang¹⁰, Xinyi Liu¹⁰, Francisco Laxague³, Eitan Prisman¹¹, Catherine Poh¹², Pinaki Bose¹³, Joseph C Dort¹³, Mushfiq H Shaikh³, Sarah E B Ryan³, Alice Dawson³, Mohammed I Khan³, Christopher J Howlett², William Stecho², Paul Plantinga², Sabrina Daniela da Silva¹⁴, Michael Hier¹⁴, Halema Khan³, Danielle MacNeil¹⁵, Adrian Mendez¹⁵, John Yoo¹⁵, Kevin Fung¹⁵, Pencilla Lang¹⁶, Eric Winquist¹⁵, David A Palma¹⁵, Hedyeh Ziai¹⁷, Antonio L Amelio¹⁸, Shawn S-C Li¹⁹, Paul C Boutros²⁰, Joe S Mymryk²¹, Anthony C Nichols²²

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
² Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
³ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
⁴ Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy.
⁵ Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
⁶ Department of Radiation Oncology (MAASTRO), Research Institute GROW, Maastricht University, Maastricht, the Netherlands.
⁷ Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology/Head and Neck Surgery, Cancer Center Amsterdam, the Netherlands.
⁸ Department of Otolaryngology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
⁹ Unit of Maxillofacial Surgery, Department of Medicine and Surgery, University of Parma-University Hospital of Parma, Parma, Italy.
¹⁰ Department of Pharmacology and Regenerative Medicine, The University of Illinois at Chicago, Chicago, IL, USA.
¹¹ Division of Otolaryngology- Head and Neck Surgery, Department of Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada.
¹² Division of Otolaryngology- Head and Neck Surgery, Department of Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
¹⁴ Department of Otolaryngology Head and Neck Surgery, McGill University, Montreal, Quebec, Canada.
¹⁵ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada.
¹⁶ Department of Oncology, University of Western Ontario, London, Ontario, Canada.
¹⁷ Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁹ Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
²⁰ Department of Human Genetics, University of California, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA.
²¹ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
²² Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada. Electronic address: anthony.nichols@lhsc.on.ca.

PMID: 36442320
PMCID: PMC9706534
DOI: 10.1016/j.ebiom.2022.104373

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

Peter Y F Zeng et al. EBioMedicine. 2022 Dec.

. 2022 Dec:86:104373.

doi: 10.1016/j.ebiom.2022.104373. Epub 2022 Nov 25.

Authors

Affiliations

¹ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
² Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada.
³ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
⁴ Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy.
⁵ Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
⁶ Department of Radiation Oncology (MAASTRO), Research Institute GROW, Maastricht University, Maastricht, the Netherlands.
⁷ Amsterdam UMC, Vrije Universiteit Amsterdam, Otolaryngology/Head and Neck Surgery, Cancer Center Amsterdam, the Netherlands.
⁸ Department of Otolaryngology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
⁹ Unit of Maxillofacial Surgery, Department of Medicine and Surgery, University of Parma-University Hospital of Parma, Parma, Italy.
¹⁰ Department of Pharmacology and Regenerative Medicine, The University of Illinois at Chicago, Chicago, IL, USA.
¹¹ Division of Otolaryngology- Head and Neck Surgery, Department of Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada.
¹² Division of Otolaryngology- Head and Neck Surgery, Department of Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ Division of Otolaryngology - Head and Neck Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
¹⁴ Department of Otolaryngology Head and Neck Surgery, McGill University, Montreal, Quebec, Canada.
¹⁵ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada.
¹⁶ Department of Oncology, University of Western Ontario, London, Ontario, Canada.
¹⁷ Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁹ Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
²⁰ Department of Human Genetics, University of California, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA.
²¹ Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada; Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
²² Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada. Electronic address: anthony.nichols@lhsc.on.ca.

PMID: 36442320
PMCID: PMC9706534
DOI: 10.1016/j.ebiom.2022.104373

Abstract

Background: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV⁺) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV⁺ OPSCC patients.

Methods: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes.

Findings: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10^-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation.

Interpretation: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV⁺ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned.

Funding: CIHR, European Union, and the NIH.

Keywords: Biomarkers; Cancer immunology; De-escalation; HPV; Head and neck squamous cell carcinoma; Transcriptomics.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests PYFZ, JWB, PCB, JSM and ACN have a US patent pending for the UWO3 score. All other authors declare no conflict of interest.

Figures

**Fig. 1**
**UWO3 immune group is a strong predictor of survival outcomes across six independent cohorts.** Patients from the immune desert and mixed group show inferior disease free survival and overall survival compared to the immune rich patients (**A–D**). Hazard ratio (HR) are based on the univariate Cox model and were combined using a Mantel-Haenszel fixed-effect model. Heterogeneity between studies was analyzed with χ2 and I² statistics. ∗Hazard ratio for overall survival in the JHU cohort excluded from the analysis due to only one event in the cohort. Pooled Kaplan–Meier analyses of disease-free survival (E) and overall survival (F) of HPV+ HNSCC patients show that UWO3 immune groups are associated with distinct survival outcomes. LHSC samples are not included in the meta-analysis or pooled analysis. P values from two-sided log rank tests and Cox proportional regression model.

**Fig. 2**
**UWO3 immune class outperforms clinical factors in predicting disease-free survival.** (A) Brier prediction score analysis shows lower error rate, thus higher prediction accuracy of disease-free survival for the UWO3 immune class than major clinical factors combined (AJCC8 stage, age, sex, smoking status). Integration of UWO3 immune group with other clinical factors further decreased prediction error rate. (B) Relative importance of each risk parameter to survival risk using the Pearson χ² test for clinical parameters plus UWO3 immune group shows that immune group is the most important factor. AJCC: American Joint Committee on Cancer.

**Fig. 3**
**UWO3 immune classification has implications with respect to aggressive radiation de-intensification**. The UWO3 score preferentially identifies patients who recur following aggressive radiation de-escalation from 70 Gy to 30 Gy in the Mayo Clinic MC1273 trial (NCT01932697) and the Memorial Sloan Kettering (MSK, NCT00606294) 30ROC trial. Recurrence is defined as patients who have developed locoregional or metastatic disease as of last follow-up. Odds ratio and P-value are from logistic regression with UWO3 as a continuous variable and stratified for cohort.

**Fig. 4**
**UWO3 immune classification of HPV⁺ HNSCC has implications for treatment de-intensification and immunotherapy.** CI: confidence interval; DFS: disease-free survival; OS: overall survival.

See this image and copyright information in PMC

References

1. Menezes F.D.S., Fernandes G.A., Antunes J.L.F., Villa L.L., Toporcov T.N. Global incidence trends in head and neck cancer for HPV-related and -unrelated subsites: a systematic review of population-based studies. Oral Oncol. 2021;115 - PubMed
1. Cramer J.D., Burtness B., Le Q.T., Ferris R.L. The changing therapeutic landscape of head and neck cancer. Nat Rev Clin Oncol. 2019;16:669–683. - PubMed
1. Ang K.K., Harris J., Wheeler R., et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. - PMC - PubMed
1. Gillison M.L., Chaturvedi A.K., Anderson W.F., Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3235–3242. - PMC - PubMed
1. Nichols A.C., Finkelstein D.M., Faquin W.C., et al. Bcl2 and human papilloma virus 16 as predictors of outcome following concurrent chemoradiation for advanced oropharyngeal cancer. Clin Cancer Res. 2010;16(7):2138–2146. - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

Affiliations

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical