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. 2022 Apr 11;114(4):609-617.
doi: 10.1093/jnci/djab215.

An Imaging Biomarker of Tumor-Infiltrating Lymphocytes to Risk-Stratify Patients With HPV-Associated Oropharyngeal Cancer

Germán Corredor  1   2 , Paula Toro  1 , Can Koyuncu  1 , Cheng Lu  1 , Christina Buzzy  1 , Kaustav Bera  1 , Pingfu Fu  3 , Mitra Mehrad  4 , Kim A Ely  4 , Mojgan Mokhtari  1 , Kailin Yang  5 , Deborah Chute  6 , David J Adelstein  7 , Lester D R Thompson  8 , Justin A Bishop  9 , Farhoud Faraji  10 , Wade Thorstad  11 , Patricia Castro  12 , Vlad Sandulache  13   14   15 , Shlomo A Koyfman  5 , James S Lewis  4 , Anant Madabhushi  1   2
Affiliations

An Imaging Biomarker of Tumor-Infiltrating Lymphocytes to Risk-Stratify Patients With HPV-Associated Oropharyngeal Cancer

Germán Corredor et al. J Natl Cancer Inst. .

Abstract

Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.

Methods: Association between OP-TIL and patient outcome was explored on whole slide hematoxylin and eosin images from 439 stage I HPV-associated OPSCC patients across 6 institutional cohorts. One institutional cohort (n = 94) was used to identify the most prognostic features and train a Cox regression model to predict risk of recurrence and death. Survival analysis was used to validate the algorithm as a biomarker of recurrence or death in the remaining 5 cohorts (n = 345). All statistical tests were 2-sided.

Results: OP-TIL separated stage I HPV-associated OPSCC patients with 30 or less pack-year smoking history into low-risk (2-year disease-free survival [DFS] = 94.2%; 5-year DFS = 88.4%) and high-risk (2-year DFS = 82.5%; 5-year DFS = 74.2%) groups (hazard ratio = 2.56, 95% confidence interval = 1.52 to 4.32; P < .001), even after adjusting for age, smoking status, T and N classification, and treatment modality on multivariate analysis for DFS (hazard ratio = 2.27, 95% confidence interval = 1.32 to 3.94; P = .003).

Conclusions: OP-TIL can identify stage I HPV-associated OPSCC patients likely to be poor candidates for treatment de-escalation. Following validation on previously completed multi-institutional clinical trials, OP-TIL has the potential to be a biomarker, beyond clinical stage and HPV status, that can be used clinically to optimize patient selection for de-escalation.

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Figures

Figure 1.
Figure 1.
Patient selection workflow for the datasets included in this study. D1 was employed for feature discovery and model training, and datasets D2-D6 were used for independent validation of the prognostic ability of the OP-TIL classifier. AJCC = American Joint Committee on Cancer.
Figure 2.
Figure 2.
Illustration of OP-TIL building blocks. A) Corresponds to a patient with higher risk of disease recurrence and B) corresponds to a patient who has a lower risk. TILs are represented with blue and non-TILs with green (non-TILs include different cells in the tumor microenvironment, such as cancer cells, macrophages, and fibroblasts, among others). HPV = human papillomavirus; OPSCC = oropharyngeal squamous cell carcinoma; TIL = tumor-infiltrating lymphocyte.
Figure 3.
Figure 3.
Kaplan-Meier plots for the DFS OP-TIL classifier applied to patients in the validation set (D2-D6) with overall stage I [AJCC 8th ed. (13)]. and with less than 30 pack-year of smoking history. Patients with less than 10- and 30 pack-year classified by OP-TIL as high risk (dashed line) are approximately 3 and 2 times, respectively, more likely to develop disease recurrence and/or die. P values were 2-sided and computed using the log-rank test. AJCC = American Joint Committee on Cancer; CI = confidence interval; DFS = disease-free survival; HG = high-risk group; HR = hazard ratio; LG = low-risk group.
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