Differences in T-cell infiltrates and survival between HPV+ and HPV- oropharyngeal squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Matlung SE
PROVIDER: S-EPMC5137981 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
2022-05-05 | PXD028618 | Pride
Project description:BackgroundHPV-related oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable prognosis, yet patients of color and low socioeconomic status (SES) continue to experience inferior outcomes. We aim to understand how the emergence of HPV has impacted race and SES survival disparities in OPSCC.MethodsA retrospective cohort of 18,362 OPSCC cases from 2010 to 2017 was assembled using the SEER (Surveillance, Epidemiology, and End Results) database. Cox proportional regression and Fine and Gray regression models were used to calculate hazard ratios (HRs) adjusting for race, SES, age, subsite, stage, and treatment.ResultsBlack patients had lower overall survival than patients of other races in HPV-positive and HPV-negative OPSCC (HR 1.31, 95% CI 1.13-1.53 and HR 1.23, 95% CI 1.09-1.39, respectively). Higher SES was associated with improved survival in all patients. Race had a diminished association with survival among high SES patients. Low SES Black patients had considerably worse survival than low SES patients of other races.ConclusionRace and SES interact variably across cohorts. High SES was protective of the negative effects of race, although there remains a disparity in outcomes among Black and non-Black patients, even in high SES populations. The persistence of survival disparities suggests that the HPV epidemic has not improved outcomes equally across all demographic groups.
| S-EPMC10166958 | biostudies-literature
Project description:High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.
| S-EPMC3668826 | biostudies-literature
Project description:Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) forms a distinct tumor entity with better survival clinical outcome. Numerous underlying molecular mechanisms have been postulated for differences in treatment response, but the impact of MEK/ERK signaling, a main driver of carcinogenesis in various cancers including OPSCC and key player mediating therapy resistance remains elusive. In a retrospective experimental cohort study, primary tumor samples from OPSCC patients (n = 124) were available on tissue microarrays (TMAs) and expression levels of phosphorylated ERK1/2 (pERK1/2) were detected by immunohistochemical staining. Correlations of pERK1/2 expression patterns with clinicopathological features and clinical outcome were evaluated by statistical analysis. A low pERK1/2 expression was strongly associated with HPV-related OPSCC, while primary tumors with high pERK1/2 staining showed a distinctly worse survival outcome and were associated with higher cellular differentiation. Co-activation of both ERK1/2 and AKT was a common event and was associated with unfavorable prognosis in our cohort. However, the combinatorial analysis of pAKT (Ser473) and pERK1/2 did not strengthen the predictive power of pERK1/2, suggesting that pERK1/2 plays a more significant function in OPSCC. In summary, our data provide a compelling experimental and statistical evidence that low levels of tumor cell intrinsic ERK1/2 activation contribute at least in part to the favorable outcome of HPV-related OPSCC. On the other hand, presented findings indicate that non-HPV-related OPSCC with elevated ERK phosphorylation are at high risk for treatment failure and might benefit from targeted therapy of MEK/ERK signaling.
| S-EPMC6520790 | biostudies-literature
Project description:Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical 'gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (FFPE) tissue at the expense of sensitivity and specificity. Recently, a novel RNA in situ hybridisation test (RNAscope) has been developed for the detection of HR-HPV in FFPE tissue; however, validation against the 'gold standard' has not been reported.A tissue microarray comprising FFPE cores from 79 OPSCC was tested using HR-HPV RNAscope. Analytical accuracy and prognostic capacity were established by comparison with the reference test; qRT-PCR for HR-HPV on matched fresh-frozen samples.High-risk HPV RNAscope had a sensitivity and specificity of 97 and 93%, respectively, against the reference test. Kaplan-Meier estimates of disease-specific survival (DSS, P=0.001) and overall survival (OS, P<0.001) by RNAscope were similar to the reference test (DSS, P=0.003, OS, P<0.001) and at least, not inferior to p16 immunohistochemistry +/- HR-HPV DNA-based tests.HR-HPV RNAscope demonstrates excellent analytical and prognostic performance against the 'gold standard'. These data suggest that the test could be developed to provide the 'clinical standard' for assigning a diagnosis of HPV-related OPSCC.
| S-EPMC3619267 | biostudies-other
Project description:Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV). HPV-positive OPSCC is considered a distinct molecular entity with a better prognosis than HPV-negative cases of OPSCC. However, the exact pathogenic mechanisms underlying the differences in clinical and molecular behavior between HPV-positive and HPV-negative OPSCC remain poorly understood. Epigenetic events play an important role in the development of cancer. Hypermethylation of DNA in promoter regions and global hypomethylation are 2 epigenetic changes that have been frequently observed in human cancers. It is suggested that heterogeneous epigenetic changes play a role in the clinical and biological differences between HPV-positive and HPV-negative tumors. Unraveling the differences in methylation profiles of HPV-associated OPSCC may provide for promising clinical applications and may pave the road for personalized cancer treatment. This systematic review aims to assess the current state of knowledge regarding differences in promoter hypermethylation and global methylation between HPV-positive and HPV-negative OPSCC.
| S-EPMC3962529 | biostudies-literature
Project description:BackgroundOutcomes of oropharyngeal squamous cell carcinoma (OPSCC) after development of distant metastases (DM) in the context of human papillomavirus (HPV) tumor status remain controversial in the literature.MethodsOPSCC patients with DM treated between June 2015 and March 2019 were included from a prospectively enrolled database. Characteristics of DM including sites, episodes, and timing of disease were analyzed in addition to survival after DM.ResultsSixty-nine HPV-positive and 18 HPV-negative OPSCC patients with DM were included. The 2-year survival after DM was higher for HPV-positive patients (54.0% vs. 11.3%, p < 0.001). HPV-positive patients did not demonstrate greater episodes or sites of DM. Multiple sites of DM, early development of DM, and Charlson comorbidity Index were independently associated with worse survival after DM.ConclusionsWhile multiple sites, early DM, and comorbidities were poor prognostic factors, OPSCC patients with distant progression can have substantial survival after DM, including M1 patients.
| S-EPMC8251991 | biostudies-literature
Project description:Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.
| S-EPMC7136454 | biostudies-literature
Project description:Objectives:We investigated how tonsillectomy during childhood may influence the distribution of human papillomavirus (HPV) positive cancer of the tonsils in adult life using p16 as a surrogate marker for HPV infection. Study Design:Retrospective observational study. Methods:A total of 280 patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) and known p16 status were eligible for this study. Each participant was called to obtain the childhood tonsillectomy history. Respondents were subgrouped by p16 status and the primary tumor location. Patient demographic and clinical information was analyzed for association with Fisher's exact and Wilcoxon rank sum tests. Location of tumor was modeled using univariate (UVA) and multivariate (MVA) logistic regression with associated odds ratios (OR) and 95% confidence intervals. Results:Of the 280 patients, 115 (41%) were respondents: 104 (90.4%) were p16 positive and 11 (9.6%) were p16 negative. For p16 positive patients, we observed a majority (93%) of intact tonsils in those with tonsil cancer, compared to 45% of intact tonsils in patients with p16 positive cancer elsewhere in the oropharynx (P?<?.001). MVA logistic regression showed that female gender (OR = 4.16, P = .0675), prior smoking history (OR = 2.6, P = .0367), and intact tonsils (OR = 15.2, P?<?.0001) were associated with tonsillar OPSCC. Conclusion:We found that patients with p16 positive OPSCC at a non-tonsil site were much more likely to have had prior tonsillectomy vs those with p16 positive OPSCC arising within the tonsil. Nevertheless, we do not advocate tonsillectomies as a public health policy to reduce HPV-related OPSCC. Level of Evidence:6.
| S-EPMC7178443 | biostudies-literature
Project description:Oropharyngeal cancers caused by human papillomaviruses (HPV) have a different epidemiology, prognosis, genetic mutational landscape, response to treatment, and outcome when compared to HPV-negative cancers. In this review, a summary of our current understanding of HPV in head and neck cancer and the important advances that have shown HPV to be an etiological agent are discussed. HPV-positive and HPV-negative tumors are compared discussing clinicopathological factors, prognosis, outcome following treatment, and the molecular and genetic differences. Currently, the standard of care for oropharyngeal cancer is both surgery and post-operative radiotherapy with or without cisplatin or concurrent chemo-radiotherapy. The latter is used more often, especially in cancers of tonsil and base of tongue. However, there is increased interest in trying to de-intensify treatment and in the development of new treatments to target the underlying different molecular pathways of HPV-positive cancers. The current clinical trials involving surgery, chemotherapy, and radiation therapy are discussed. The new targeted treatments are also summarized. Although there is currently is no evidence from prospective studies to support a change in the treatment algorithm, the treatment options for patients with HPV-positive disease are likely to change in the future.
| S-EPMC4837939 | biostudies-literature