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

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 DortMushfiq 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 x 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. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.

Original language	English
Article number	104373
Number of pages	13
Journal	EBioMedicine
Volume	86
Early online date	25 Nov 2022
DOIs	https://doi.org/10.1016/j.ebiom.2022.104373
Publication status	Published - 1 Dec 2022

Keywords

Head and neck squamous cell carcinoma
Transcriptomics
Biomarkers
Cancer immunology
HPV
De-escalation
SQUAMOUS-CELL CARCINOMA
HUMAN-PAPILLOMAVIRUS
NECK-CANCER
POSITIVE HEAD
SURVIVAL
CHEMORADIATION
EPIDEMIOLOGY
PREDICTORS
EXPRESSION
CONCURRENT

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Zeng, P. Y. F., Cecchini, M. J., Barrett, J. W., Shammas-Toma, M., De Cecco, L., Serafini, M. S., Cavalieri, S., Licitra, L., Hoebers, F., Brakenhoff, R. H., Leemans, C. R., Scheckenbach, K., Poli, T., Wang, X., Liu, X., Laxague, F., Prisman, E., Poh, C., Bose, P., ... Nichols, A. C. (2022). Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification. EBioMedicine, 86, Article 104373. https://doi.org/10.1016/j.ebiom.2022.104373

@article{9f716aac08e648c58994505ddae1f084,

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

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 x 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. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.",

keywords = "Head and neck squamous cell carcinoma, Transcriptomics, Biomarkers, Cancer immunology, HPV, De-escalation, SQUAMOUS-CELL CARCINOMA, HUMAN-PAPILLOMAVIRUS, NECK-CANCER, POSITIVE HEAD, SURVIVAL, CHEMORADIATION, EPIDEMIOLOGY, PREDICTORS, EXPRESSION, CONCURRENT",

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

year = "2022",

month = dec,

day = "1",

doi = "10.1016/j.ebiom.2022.104373",

language = "English",

volume = "86",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

Zeng, PYF, Cecchini, MJ, Barrett, JW, Shammas-Toma, M, De Cecco, L, Serafini, MS, Cavalieri, S, Licitra, L, Hoebers, F, Brakenhoff, RH, Leemans, CR, Scheckenbach, K, Poli, T, Wang, X, Liu, X, Laxague, F, Prisman, E, Poh, C, Bose, P, Dort, JC, Shaikh, MH, Ryan, SEB, Dawson, A, Khan, MI, Howlett, CJ, Stecho, W, Plantinga, P, Daniela da Silva, S, Hier, M, Khan, H, MacNeil, D, Mendez, A, Yoo, J, Fung, K, Lang, P, Winquist, E, Palma, DA, Ziai, H, Amelio, AL, Li, SS-C, Boutros, PC, Mymryk, JS & Nichols, AC 2022, 'Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification', EBioMedicine, vol. 86, 104373. https://doi.org/10.1016/j.ebiom.2022.104373

TY - JOUR

T1 - Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification

AU - Zeng, Peter Y F

AU - Cecchini, Matthew J

AU - Barrett, John W

AU - Shammas-Toma, Matthew

AU - De Cecco, Loris

AU - Serafini, Mara S

AU - Cavalieri, Stefano

AU - Licitra, Lisa

AU - Hoebers, Frank

AU - Brakenhoff, Ruud H

AU - Leemans, C René

AU - Scheckenbach, Kathrin

AU - Poli, Tito

AU - Wang, Xiaowei

AU - Liu, Xinyi

AU - Laxague, Francisco

AU - Prisman, Eitan

AU - Poh, Catherine

AU - Bose, Pinaki

AU - Dort, Joseph C

AU - Shaikh, Mushfiq H

AU - Ryan, Sarah E B

AU - Dawson, Alice

AU - Khan, Mohammed I

AU - Howlett, Christopher J

AU - Stecho, William

AU - Plantinga, Paul

AU - Daniela da Silva, Sabrina

AU - Hier, Michael

AU - Khan, Halema

AU - MacNeil, Danielle

AU - Mendez, Adrian

AU - Yoo, John

AU - Fung, Kevin

AU - Lang, Pencilla

AU - Winquist, Eric

AU - Palma, David A

AU - Ziai, Hedyeh

AU - Amelio, Antonio L

AU - Li, Shawn S-C

AU - Boutros, Paul C

AU - Mymryk, Joe S

AU - Nichols, Anthony C

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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 x 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. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.

AB - 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 x 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. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.

KW - Head and neck squamous cell carcinoma

KW - Transcriptomics

KW - Biomarkers

KW - Cancer immunology

KW - HPV

KW - De-escalation

KW - SQUAMOUS-CELL CARCINOMA

KW - HUMAN-PAPILLOMAVIRUS

KW - NECK-CANCER

KW - POSITIVE HEAD

KW - SURVIVAL

KW - CHEMORADIATION

KW - EPIDEMIOLOGY

KW - PREDICTORS

KW - EXPRESSION

KW - CONCURRENT

U2 - 10.1016/j.ebiom.2022.104373

DO - 10.1016/j.ebiom.2022.104373

M3 - Article

C2 - 36442320

SN - 2352-3964

VL - 86

JO - EBioMedicine

JF - EBioMedicine

M1 - 104373

ER -

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

Abstract

Keywords

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