Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents

doi:10.1016/j.oraloncology.2016.09.005

Oral Oncology

Volume 62, November 2016, Pages 20-27

https://doi.org/10.1016/j.oraloncology.2016.09.005 Get rights and content

Highlights

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HNSCC survival was poorer among cases in Brazil than in the US and Europe.
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HPV+/p16+ OPSCC predicted lower mortality in all 3 regions (US, Europe, Brazil).
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HPV was not prognostic among non-OP HNSCC (OC, larynx, and HP).
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Effect of HPV/p16 was significantly different in OPSCC & non-OP HNSCC.

Abstract

Objectives

To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers.

Methods

Data from 1362 head and neck SCC (HNSCC) diagnosed 2002–2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n = 388), U.S. (CHANCE study, n = 472), and Europe (ARCAGE study, n = 502). Tumors were centrally tested for p16^INK4a and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models.

Results

There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58 years and median follow-up of 3.1 years (IQR = 1.4–5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16+/HPV16+) compared to 333 HPV-unrelated (p16- and/or HPV16-) cases (HR = 0.25, 95%CI = 0.18–0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p ⩽ 0.01) and after adjustment, remained significantly reduced (aHR = 0.34, 95%CI = 0.24–0.49). Among non-OP HNSCC, neither p16 (aHR = 0.83, 95%CI = 0.60–1.14), HPV16 DNA (aHR = 1.20, 95%CI = 0.89–1.63), or p16+/HPV16+ (aHR = 0.59, 95%CI = 0.32–1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction = 0.02).

Conclusion

HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC.

Introduction

Head and neck squamous cell carcinoma cancer (HNSCC) has an estimated global annual burden of more than 500,000 incident cases and 300,000 deaths [1]. The incidence of HNSCC caused by human papillomavirus (HPV) is increasing in many high-income countries, but not in other areas [2]. Questions remain regarding the role of geographic differences in HPV associated HNSCC [3].

Several recent studies suggest HPV-related biomarkers have utility in predicting HNSCC survival [4], [5], [6], [7], [8], [9], [10]. Due to the improved survival in these cases, different staging for HPV-related oropharyngeal cancers has even been proposed [11], [12], and several HPV-OPSCC de-escalation trials are being conducted [13], [14]. However, recurrence remains an issue for HPV-related OPSCC patients, and it is unclear which patients may benefit from de-escalated therapy or de-intensified follow-up. Many questions remain, including whether HPV-related biomarkers also have utility in identifying better survival among non-oropharyngeal HNSCC. In addition, given the global geographic variation in the role of HPV, it is not known whether these biomarkers have consistent prognostic utility across different regions. We therefore performed a large international study to rigorously evaluate the ability of biological and behavioral markers to predict HNSCC survival.

Section snippets

Study population and design

This analysis is based on cases derived from case-control studies of HNSCCs in three distinct regions [15]. Studies included: the Brazilian Head and Neck Genome Project (GENCAPO; Southern Brazil – São Paulo) [16], the Carolina Head and Neck Cancer Study (CHANCE, North Carolina, U.S.A.) [17] and the Alcohol Related Cancers and Genetic Susceptibility in Europe study (ARCAGE) [18]. Data from ARCAGE included cases from Germany (36%, n = 181), Italy (52%, n = 259), and U.K (12%, n = 62). All cases were

Characteristics of cases

There were 1362 incident HNSCCs included in this analysis, all diagnosed between 2002 and 2011. This included cases from the U.S. (n = 472), Europe (n = 502), and Brazil (n = 388). There were 517 oropharyngeal, 397 laryngeal, 382 oral cavity, and 66 hypopharyngeal SCC. Cases were primarily male (81%), ever smokers (91%), ever drinkers (90%) and had a median age at diagnosis of 58 years (Table 1).

There were many similarities in the characteristics of cases in each of the three regions. In each region,

Discussion

This is one of the first large studies to examine the prognostic utility of HPV biomarkers among HNSCC across continents, using centralized testing and controlling for other risk factors. While the proportion of OPSCC caused by HPV varied widely by region, HPV-related OPSCC cases had similar survival benefits across these different continents. Tumor p16 and HPV16 DNA positivity both were strong biomarkers for improved survival among OPSCC, but their prognostic utility was not as clear among

Conflict of interest

None declared.

Financial support

This work was support by FAPESP, National Cancer Institute, European Framework Programs, French Health Ministry, and Italian AIRC.

Acknowledgements

The work was supported by FAPESP (GENCAPO: # 04/12054-9, 10/51168-0), NCI (CHANCE: R01- CA90731), the European Framework Programs, French Health Ministry, and Italian AIRC (ARCAGE), as follows.

ARCAGE study was supported by the grant from European Commission’s 5th (contract QLK1-2001-00182) and 7th (contract FP7-HEALTH-2011–282562) Framework Programs, the French Social Affairs and Health Ministry, the Italian Association for Research on Cancer (AIRC) IG 2013N.14220 and Fondazione Veronesi.

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A total of 121,550 patients were included. Of this cohort, 87,575 (72.1%) were tested for HPV, with the oropharynx (55,049/64,158; 85.8%) displaying the highest rates of testing and the sinonasal tract (1519/2853; 53.2%) displaying the lowest testing rates. Of the 86,136 with a definitive result, 46,878 (54.4%) were HPV-positive, with the oropharynx (40,313/54,205; 74.4%) displaying the highest rates of HPV-positivity and the oral cavity (1818/11,505; 15.8%) displaying the lowest. HPV-positive malignancy was associated with significantly improved adjusted overall survival in the oropharynx (HR = 0.42 [95% CI: 0.43–0.47]), oral cavity (HR = 0.86 [95% CI: 0.79–0.95]), sinonasal tract (HR = 0.63 [95% CI: 0.48–0.83]), larynx (HR = 0.78 [95% CI: 0.71–0.87]), and hypopharynx (HR = 0.56 [95% CI: 0.48–0.66]), but not the nasopharynx (HR = 0.93 [95% CI: 0.77–1.14]).
HPV testing rates were significantly lower in non-oropharyngeal subsites. This is relevant as HPV-associated disease displayed significantly improved overall survival in both the oropharynx and four of five non-oropharyngeal subsites. While validation with prospective studies is necessary, these findings may warrant HPV testing in all HNSCC subsites.
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Citation Excerpt :
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Patients were identified from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS in black versus white patients with sequential adjustment sets.
A total of 157 HPV-associated OPSCC patients were identified. Of these, 93% were white and 7% were black. Black patients with HPV-associated OPSCC were more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients had worse OS in the unadjusted analysis (HR 4.9, 95% CI 2.2–11.1, p < 0.0001). The racial disparity in OS slightly decreased when sequentially adjusting for demographic, clinical, and SES variables. However, HR for black race remained statistically elevated in the final adjustment set which controlled for age, sex, stage, smoking, alcohol use, and individual-level household income, insurance, and education level (HR 3.4, 95% CI 1.1–10.1, p = 0.028).
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¹: These authors contributed equally to this paper.

View full text

Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents

Highlights

Abstract

Objectives

Methods

Results

Conclusion

Introduction

Section snippets

Study population and design

Characteristics of cases

Discussion

Conflict of interest

Financial support

Acknowledgements

Ann Oncol

Lancet Oncol

Oral Oncol

Radiother Oncol

Eur J Cancer

Clinics (Sao Paulo)

Oral Oncol

Global cancer statistics, 2012

CA Cancer J Clin

Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers

J Clin Oncol

Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions

Int J Epidemiol

Human papillomavirus and survival of patients with oropharyngeal cancer

N Engl J Med

Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial

J Clin Oncol

Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection

Cancer Causes Control

Prognostic biomarkers of survival in oropharyngeal squamous cell carcinoma: systematic review and meta-analysis

Head Neck