Multiple imputation and clinico‐serological models to predict human papillomavirus status in oropharyngeal carcinoma: An alternative when tissue is unavailable

Abstract

In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico‐epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPVmi). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic‐HPVsero model incorporating a composite of 20 HPV serological antibodies (HPVsero) and 4 clinical factors (c‐index: 0.96) performed better than using HPVsero (c‐index: 0.92) or HPVmi (c‐index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic‐s1‐16E6; c‐index: 0.95). When defining HPV status by HPVsero, s1‐16E6, HPVmi or through p16 IHC, each of these definitions demonstrated improved overall and disease‐free survival in HPV‐positive OPSCC patients, when compared to HPV‐negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1‐16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.

Sensitivity and Specificity of Human Papillomavirus (HPV) 16 Early Antigen Serology for HPV-Driven Oropharyngeal Cancer: A Systematic Literature Review and Meta-Analysis

“…A total of 25 studies were included in the qualitative synthesis. A total of 23 studies, with study sizes ranging from 10 to 1053 individuals (total number of individuals = 3859), were included in the meta-analyses for HPV16 E6, E7 and E2 serology ( Figure 1 ) [ 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Nicotine dependence as a risk factor for upper aerodigestive tract (UADT) cancers: A mediation analysis

“…The HPV positivity was determined by p16 overexpression by immunohistochemistry (IHC) as the standard. For the subset where the IHC staining for p16 was not available (22%), HPV status was determined by either HPV DNA detection or serological antibodies (such as HPV16 E16) [25].…”

Clinical variables and magnetic resonance imaging‐based radiomics predict human papillomavirus status of oropharyngeal cancer

“…Clinical variables associated with HPV‐positive tumors are well known and include male gender, younger age, and less exposure to tobacco and alcohol 9 . These variables have been used to predict HPV status of head and neck cancer, including OPSCC 18‐21 …”

“…9 These variables have been used to predict HPV status of head and neck cancer, including OPSCC. [18][19][20][21] This study aims to assess and compare the ability of clinical variables, MR-based radiomic features, or a combination of these variables to predict HPV status of OPSCC.…”