Dataset Information

Variations in HPV function are associated with survival in squamous cell carcinoma.

ABSTRACT: Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV- tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.

SUBMITTER: Gleber-Netto FO

PROVIDER: S-EPMC6485353 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Variations in HPV function are associated with survival in squamous cell carcinoma.

Gleber-Netto Frederico O FO Rao Xiayu X Guo Theresa T Xi Yuanxin Y Gao Meng M Shen Li L Erikson Kelly K Kalu Nene N NN Ren Shuling S Xu Guorong G Fisch Kathleen M KM Akagi Keiko K Seiwert Tanguy T Gillison Maura M Frederick Mitchell J MJ Johnson Faye M FM Wang Jing J Myers Jeffrey N JN Califano Joseph J Skinner Heath D HD Pickering Curtis R CR

JCI insight 20190110 1

Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patien ...[more]

PMID: 30626753

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Project description:Purpose:This study aimed to compare the swallowing function in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma treated with de-intensified chemoradiation therapy (6 weeks, 60?Gy) versus those receiving standard-of-care chemoradiation therapy (7 weeks, 70?Gy). Methods and materials:A retrospective review was conducted of 78 patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with modified barium swallow studies pretreatment and 6 to 8 weeks posttreatment. The swallowing function was objectively scored for penetration, aspiration, and pharyngeal residue. Forty patients received de-intensified chemoradiation therapy (60?Gy image guided radiation therapy with weekly cisplatin 30?mg/m2) and 38 patients received standard-of-care chemoradiation therapy (70?Gy image guided radiation therapy with chemotherapy of the medical oncologist's choosing). Univariate and multivariate analyses were performed to detect differences between the cohorts with regard to laryngeal penetration, aspiration, and pharyngeal residue. A multivariate logistic regression was used to determine the overall effect of treatment on the swallowing function. Patient-reported swallowing outcomes in de-intensified cohort were assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Module for Head and Neck Cancer and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaires. Results:Patients treated with de-intensified chemoradiation therapy were associated with a suggestion of lower risk of developing overall swallowing dysfunction (odds ratio [OR], 0.62; P?=?.07), laryngeal penetration (OR, 0.63; P?=?.12), and pharyngeal residue (OR, 0.61; P?=?.08). The mean pre- and 2-year post-European Organisation for Research and Treatment of Cancer Quality of Life scores pertaining to swallowing (1-4 scale, higher worse) in the de-intensified cohort were 1.4 and 1.2 for liquids; 1.2 and 1.1 for purees; 1.5 and 1.7 for solids, 1.0 and 1.3 for choked when swallowing; and 9.0 and 10.8 for composite score, respectively. The mean pre- and 2-year post-Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events swallowing difficulty scores (1-5 scale, with higher scores being worse) were 1.5 and 1.8, respectively. Conclusions:Compared with 7 weeks of 70?Gy, 6 weeks of 60?Gy de-intensified chemoradiation therapy appears to better preserve the baseline swallowing function (per objective modified barium swallow assessment). Patients treated with de-intensified chemoradiation therapy reported minimal changes in swallowing function.

Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.

Dataset Information

Variations in HPV function are associated with survival in squamous cell carcinoma.

Publications

Variations in HPV function are associated with survival in squamous cell carcinoma.

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