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

Peter Y F Zeng; Matthew J Cecchini; John W Barrett; Matthew Shammas-Toma; Loris De Cecco; Mara S Serafini; Stefano Cavalieri; Lisa Licitra; Frank Hoebers; Ruud H Brakenhoff; C René Leemans; Kathrin Scheckenbach; Tito Poli; Xiaowei Wang; Xinyi Liu; Francisco Laxague; Eitan Prisman; Catherine Poh; Pinaki Bose; Joseph C Dort; Mushfiq H Shaikh; Sarah E B Ryan; Alice Dawson; Mohammed I Khan; Christopher J Howlett; William Stecho; Paul Plantinga; Sabrina Daniela da Silva; Michael Hier; Halema Khan; Danielle MacNeil; Adrian Mendez; John Yoo; Kevin Fung; Pencilla Lang; Eric Winquist; David A Palma; Hedyeh Ziai; Antonio L Amelio; Shawn S-C Li; Paul C Boutros; Joe S Mymryk; Anthony C Nichols

doi:10.1016/j.ebiom.2022.104373

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

EBioMedicine. 2022 Dec:86:104373. doi: 10.1016/j.ebiom.2022.104373. Epub 2022 Nov 25.

Authors

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.

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.

MeSH terms

Biomarkers
Head and Neck Neoplasms*
Human Papillomavirus Viruses
Humans
Neoplasm Recurrence, Local
Oropharyngeal Neoplasms* / therapy
Papillomaviridae
Papillomavirus Infections* / complications
Prognosis
Retrospective Studies
Squamous Cell Carcinoma of Head and Neck

Substances

Biomarkers

Grants and funding

R01 DE026471/DE/NIDCR NIH HHS/United States