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Prognostic Implications of HPV in Oropharyngeal Cancer

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Douglas R Lowy
Douglas R Lowy
Douglas R Lowy
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Karl Munger at Tufts University school of Medicine, Boston MA
Karl Munger
  • Tufts University school of Medicine, Boston MA
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Abstract

Identification of human papillomavirus (HPV) as the etiologic agent of cervical cancer has led to its identification in other cancers, with oropharyngeal squamous-cell carcinoma the most common of these.1,2 In this issue of the Journal, Ang and colleagues3 report findings from their study (ClinicalTrials.gov number, NCT00047008) that contribute to the growing body of evidence that HPV-positive oropharyngeal squamous-cell carcinoma represents a distinct clinicopathological entity associated with a better prognosis than HPV-negative oropharyngeal squamous-cell carcinoma.4,5 In a randomized trial of patients with oropharyngeal squamous-cell carcinoma, the overall survival was substantially better among patients with HPV-positive cancer than among patients . . .
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10.1056/nejme1003607 nejm.org
1
The
new england journal
of
me dicine
editorial
Prognostic Implications of HPV in Oropharyngeal Cancer
Douglas R. Lowy, M.D., and Karl Munger, Ph.D.
Identification of human papillomavirus (HPV) as
the etiologic agent of cervical cancer has led to
its identification in other cancers, with oropha-
ryngeal squamous-cell carcinoma t he most com-
mon of these.
1,2
In this issue of the Journal, Ang
and colleagues
3
report findings from their study
(ClinicalTrials.gov number, NCT00047008) that
contribute to the growing body of evidence that
HPV-positive oropharyngeal squamous-cell carci-
noma represents a distinct clinicopathological
entity associated with a better prognosis than
HPV-negative oropharyngeal squamous-cell carci-
noma.
4,5
In a randomized trial of patients with
oropha r y nge a l squa mous- cel l car cinom a, t he over-
all survival was substantially better among pa-
tients with HPV-positive cancer than among pa-
tients with HPV-negative cancer. The size of the
sample — 323 patients with oropharyngeal
squamous-cell c arcinoma and known HPV status,
of whom 64% had HPV-positive tumors — en-
abled the authors to control for many variables
and to conclude that HPV status was a critical
independent prognostic determinant.
The two classes of oropharyngeal squamous-
cell carcinoma appear to have distinct causes.
HPV-positive cases are associated with sex-related
risk factors that have also been linked to cervical
cancer and an increased likelihood of orogenital
activity, whereas tobacco and alcohol consump-
tion are the key risk factors for HPV-negative
cases. Epidemiologic studies suggest little inter-
action between the two sets of risk factors, sug-
gesting that HPV-positive cancer and HPV-nega-
t iv e c anc er ma y e ach h av e a di st i nc t p at hoge ne si s.
However, the data reported by Ang and col-
leagues suggest that smoking has an adverse
effect on prognosis in both HPV-positive and
HPV-negative cases. The incidence of oropharyn-
geal squamous-cell carcinoma is increasing in
industrialized countries, because the substantial
rise in HPV-positive cases is greater than the de-
crease in HPV-negative cases, which has paral-
leled decreases in other cancers associated with
tobacco use.
Clea r-cut molecula r dif ferences between HPV-
positive and HPV-negative oropharyngeal squa-
mous-cell carcinoma have been identified.
5,6
Nearly all HPV-positive cases express the viral
E6 and E7 oncoproteins. Each of these proteins
subverts a variety of cellular regulatory mecha-
nisms that are predominantly antiproliferative,
of which the best known are the p53 and retino-
blastoma (pRb) tumor suppressors.
7
The gene en-
coding p53, which is inactivated at the protein
level by E6, remains the wild type in almost all
HPV-posit ive tumors, whereas it is frequently mu-
tated in HPV-negative tumors. In HPV-positive
cases, the pRb protein is inactivated by E7; in
HPV-negative cases, the p16 tumor suppressor, a
component of the pRb tumor-suppressor net-
work, is frequently inactivated. Most HPV-posi-
tive tumors, including HPV-positive oropharyngeal
squamous-cell carcinoma, express p16, although
its tumor-suppressor activity is lost because that
function is mediated by pRb, which is inactivated
by E7. Other molecular differences between HPV-
positive and HPV-negative oropharyngeal squa-
mous-cell carcinoma have also been described.
8
The viral proteins E6 and E7 may render the
HPV-positive tumors more immunogenic than the
HPV-negative tumors. Serologic assays can detect
anti-E6 or anti-E7 antibodies in many patients
with HPV-positive tumors. A higher proportion
of patients with HPV-positive tumors have par-
tial or complete responses to therapy, even after
adjustment for differences in tumor stage. In ad-
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on June 9, 2010 . For personal use only. No other uses without permission.
The
new england journal
of
me dicine
10.1056/nejme1003607 nejm.org
2
dition, patients with HPV-positive orophar yngeal
squamous-cell carcinoma are younger, often have
less-advanced disease, and are less likely to have
serious concomitant disease than patients with
HPV-negative cancer. However, Ang and col-
leagues estimate that these factors account for
only about one tenth of the prognostic differ-
ence between the t wo groups.
Given this background, how might we under-
stand the relative contributions of differences in
inherent malignancy, immunogenicity, and treat-
ment response to the prognosis for patients with
HPV-positive oropharyngeal squamous-cell carci-
noma? It is plausible that HPV-positive cancer is
inherently less malignant than HPV-negative
cancer. Consistent with this speculation, when
surgery is the only treatment provided for oro-
pharyngeal squamous-cell carcinoma, patients
with p16-positive tumors have a better progno-
sis than those with p16-negative tumors, after
adjustment for tumor stage.
9
Mechanistically,
although expression of the HPV E6 and E7 onco-
genes markedly dampens the activity of certain
tumor suppressors, these suppressor pathways
are often inactivated to a greater degree in HPV-
negative tumors, by genetic or epigenetic mech-
anisms. For example, HPV E6 expression causes
accelerated degradation of the p53 protein, re-
sulting in a dramatic reduction of p53 levels. In
contrast, p53 mutation in an HPV-negative tu-
mor may result in the synthesis of a p53 protein
that not only is inactive as a tumor suppressor
but also can bind and inactivate any remaining
wild-type p53 in a tumor cell and that may be
associated with a gain of oncogenic activity.
Other differences in gene expression may also
contribute to a more severe, malignant pheno-
type in HPV-negative tumors than in HPV-posi-
tive ones.
8
The immunogenicity of viral proteins could
partially restrict the malignant behavior of HPV-
positive cancers. The presence of antibodies
against E6 and E7 or tumor-inf iltrating lympho-
cytes may be associated with a better progno-
sis.
10,11
Murine models suggest that treatment
might enhance the immunogenicity of HPV-pos-
itive tumors, thus contributing to the superior
treatment response.
12
However, the extent to
which the clinical outcome is attributable to the
immune response is unclear.
Biologic and immunologic properties of HPV-
positive tumors may contribute to their better
response to treatment with radiation and chemo-
therapy. Critical factors may include differences
in the degree to which various growth-regulatory
pathways are altered in HPV-positive tumors as
compared with HPV-negative tumors, together
with the mechanisms by which the pathways
have been perturbed. For example, since the p53
and pRb pathways are merely rendered dormant
by expression of the HPV E6 and E7 oncogenes,
these pathways can be reactivated under condi-
tions that reduce this expression.
13
Laboratory
evidence suggests that treatment of HPV-posit ive
cells with standard chemotherapeutic agents
causes down-regulation of HPV E6 and E7 ex-
pression and reactivation of tumor-suppressor
pathways, including that of p53.
14
On the other
hand, mutant p53, frequently present in HPV-
negative tumors, is associated with treatment
resistance.
The conclusion that HPV-positive and HPV-
negative oropharyngeal squamous-cell carcino-
mas are distinct entities implies that their treat-
ment or prevention might benefit from different
approaches. For example, in HPV-positive can-
cers, efforts to inhibit the expression or activity
of E6 and E7 might result in effective treat-
ment.
13
For HPV-negative cancers, the targeting
of pathogenetically relevant biomarkers associ-
ated with a poor prognosis, such as BCL2, might
improve the therapeutic response.
15
For preven-
tion, risk reduction through modification of ex-
posure to the various etiologic factors is one
approach, and the development of screening
methods is another. Vaccination against HPV
also may be a way to prevent HPV-positive oro-
pharyngeal squamous-cell carcinoma.
6
Approxi-
mately 90% of HPV-positive cancers contain
HPV type 16, and another 5% have HPV type 18.
Both HPV types are targeted by the t wo preven-
tive HPV vaccines approved by the Food and
Drug Administration. Vaccination, if performed
before exposure to the virus, might prevent a
large number of HPV-positive cases of oropha-
ryngeal squamous-cell carcinoma. The vaccines
can prevent persistent genita l infection with these
types of HPV and the consequent precancerous
lesions, but it is not known whether they can
prevent oropharyngeal HPV infection.
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the full text of this article at NEJM.org.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on June 9, 2010 . For personal use only. No other uses without permission.
10.1056/nejme1003607 nejm.org
3
editorial
From the Laboratory of Cellular Oncolog y, Center for Cancer
Research, National Institutes of Health, Bethesda, MD (D.R.L.);
and the Division of Infectious Diseases, Brigham and Women’s
Hospital, Department of Medicine, Harvard Medical School,
Boston (K.M.).
This article (10.1056/NEJMe1003607) was published on June 7,
2010, at NEJM.org.
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... Obwohl die Expression der HPV E6 und E7-Onkogene die Aktivität bestimmter Tumorsuppressoren, wie p53 und des Retinoblastoma, deutlich dämpfen, werden diese Suppressorwege bei HPV-negativen Tumoren oft durch genetische oder epigenetische Mechanismen in noch größerem Maße inaktiviert. Dadurch kann eine auf die Zellen toxisch wirkende Radiochemotherapie bei HPV-positiven Tumoren besser anschlagen als bei HPV-negativen Tumoren mit gänzlich zerstörten Tumorsuppressorgenen(Douglas et al., 2010). Außerdem konnte gezeigt werden, dass viele HPV-positive Patienten Anti-E6-und Anti-E7-Antikörper besitzen, welche die Tumorgenese über das Immunsystem beeinflussen. ...
... Eine Radiochemotherapie könnte die Immunantwort gegen HPV-positive Tumoren stimuliert und daher die bessere Prognose dieser Therapien begründen. Des Weiteren wird gemutmaßt, dass durch eine Chemotherapie die E6-und E7-Expression herunterreguliert wird und dadurch die zellulären Regulationsmechanismen wieder eingreifen können(Douglas et al., 2010).Nichtsdestotrotz gibt es unter den Patienten mit HPV-positivem Kopf-Hals-Tumor eine nicht unerhebliche Anzahl an Patienten, die entweder gar nicht oder nur unzureichend auf eine Radiooder Radiochemotherapie ansprechen(Thibodeau et al., 2015). Die molekularen Mechanismen, die hinter diesem Phänomen stehen, sind bis heute kaum untersucht. ...
... Zwar wird das p53 durch das high-risk-HPV-Onkogen E6 inhibiert, so dass es zeitweise seine Funktion nicht mehr ausüben kann, jedoch wird angenommen, dass immer noch eine höhere Restaktivität des p53 gegeben ist als bei HPV-negativen Tumoren, bei denen das Tumorsuppressorgen Mutationen unterliegt, die zu einem vollständigen Funktionsverlust führen. Außerdem können Chemotherapien die E6-und E7-Expression herunterregulieren und dadurch der p53-abängige Regulationsmechanismus des Zellzyklus und der Apoptoseeinleitung bei DNA-Mutationen wieder greifen(Douglas et al., 2010). Jedoch gibt es unter den Patienten mit HPV-positiven Kopf-Hals-Tumoren eine nicht unerhebliche Anzahl an Patienten, die entweder gar nicht oder nur unzureichend auf eine Radio-oder Radiochemotherapie ansprechen(Thibodeau et al., 2015). ...
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... cases (ASCO, 2020;Lowy and Munger, 2010;Sturgis and Cinciripini, 2007). However, even with the reduction of these cases, overall OPC incidence has continued to increase in the U.S., driven by HPV-positive cases (Lowy and Munger, 2010;Adelstein et al., 2019). ...
... cases (ASCO, 2020;Lowy and Munger, 2010;Sturgis and Cinciripini, 2007). However, even with the reduction of these cases, overall OPC incidence has continued to increase in the U.S., driven by HPV-positive cases (Lowy and Munger, 2010;Adelstein et al., 2019). The overall 5year survival rate for those with any type of OPC is 65%, increasing to 84% in those with early stage disease and no involvement of surrounding tissue or lymph nodes (ASCO, 2020). ...
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... Second, the effects of HPV on oropharyngeal cancer were not included. The causes and clinical manifestations of HPV-related oropharyngeal cancer are different from those of HPV-negative oropharyngeal cancer [39][40][41][42]. However, because the diagnosis in the Korea NHIS is based on the International Classification of Diseases, we could not distinguish between oropharynx cancer related to HPV. ...
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Background: We investigated the association between BMI and HNC subtype incidence in a cohort study of ten million people, adjusting for the effect of smoking and drinking. We also investigated the relationship between waist circumference (WC) and HNC subtype. Methods: All data used in this study originated from the Korean National Health Insurance Service database. We analysed subjects who had undergone health check-ups in 2009 and monitored subjects until 2018 (n = 10,585,852). Finally, 9,598,085 subjects were included after exclusions. We collected variables that could affect the risk of HNC. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: The overall incidence of HNC was higher in the low BMI category (BMI < 18.5 according to WHO recommendations for Asian people) (HR: 1.322; 95% CI: 1.195–1.464) compared with the normal BMI category. Among the HNC cases, the incidence rates of laryngeal (HR: 1.3; 95% CI: 1.085–1.558), oral cavity (HR: 1.277; 95% CI: 1.011–1.611), and oropharyngeal (HR: 1.584; 95% CI: 1.25–2.008) cancers were higher in the low BMI category compared with the normal BMI category. No significant association was detected between low BMI and sinus cancer, salivary gland cancer, or nasopharyngeal cancer. The low WC category (<80 cm in men and <75 cm in women) was related to a risk of hypopharyngeal (HR: 1.268; 95% CI: 1.061–1.514) and laryngeal (HR: 1.118; 95% CI: 1.007–1.241) cancers. The HR for occurrence of HNC was high in underweight participants according to smoking status (1.219 for never smoker vs. 1.448 for ever smoker, p for interaction = 0.0015) and drinking status (1.193 for never drinker vs. 1.448 for ever drinker, p for interaction = 0.0044). Conclusions: Low BMI was associated with the risk of some types of HNC. The results of this study could assist etiological investigations and prevention strategies.
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... However, several studies using either PCR or sequencing methods to define the HPV infection and its subtypes have reported that mortality rates were significantly lower in the hrHPV + when compared to hrHPVgroups (2,3). The fact that the presence of hrHPV can lead to a better prognosis in patients has also been observed in oropharyngeal cancer (4). To date the mechanisms involved are not clear and these need to be further explored. ...
Use of Single Cell Transcriptomic Techniques to Study the Role of High-Risk Human Papillomavirus Infection in Cervical Cancer
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High-risk human papillomavirus (hrHPV) infection has been associated with a higher probability of progression to cervical cancer. However, several extensive studies have reported that the presence of hrHPV can lead to a better prognosis, but the mechanism of how this occurs is unclear. In this study, microbiological analysis was used to identify HPV infection as a factor for the prognosis of patients with cervical squamous cell carcinoma (CSCC). Comparing the interactions of HPV⁺ and HPV⁻ malignant cells with immune cells as well as the trajectory of malignant cells either with or without HPV, we found that most of the HPV⁺ cells are well differentiated while HPV⁻ cells appear to be hypo-fractionated. Using transcriptomic and immunostaining data, we validated a set of unfavourable molecules in the HPV⁻ CSCC cells, including KRT16, ITGB1, CXCR1, VEGFA, CRCT1 and TNFRSF10B/DR5. This study provides a basis for the development of a rational post-operative follow-up programme and the development of an appropriate treatment plan for patients with cervical cancer.
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... Likewise, HPV-related HNSCCs are on the rise, and this oncogenic virus has bypassed tobacco as the main carcinogen in the oropharyngeal region (3,11,54). Despite HPVϩHNSCCs and HPVϪHNSCCs being very different both phenotypically and genotypically in terms of their pathological and molecular mechanisms of carcinogenesis and in their response to therapy, they are still treated the same in the clinic (55). It is therefore of particular interest to develop HPV-specific treatments for HPVϩHNSCCs. ...
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Human papillomaviruses cause around 5% of all human cancers, yet there are no specific antiviral therapeutic approaches available for combatting these cancers. These cancers are currently treated with standard chemoradiation therapy (CRT). Specific antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ERα) is overexpressed in HPV+HNSCC and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combatting HPV+cancers. Here, we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.
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... Treatment decisions for OPSCC patients are made based on disease stage and tumor location, without taking into account the tumor's HPV status [5]. Recent studies have suggested that HPV-pos and HPV-neg OPSCCs are biologically unique entities [4], with different tumor biologies and characteristics. ...
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Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role of centrosome amplification (CA) as a prognostic biomarker in HPV-neg OPSCCs. A quantitative evaluation of CA in clinical specimens of OPSCC revealed that (a) HPV-neg OPSCCs exhibit higher CA compared with HPV-pos OPSCCs, and (b) CA was associated with poor OS, even after adjusting for potentially confounding clinicopathologic variables. Contrastingly, CA was higher in HPV-pos cultured cell lines compared to HPV-neg ones. This divergence in CA phenotypes between clinical specimens and cultured cells can therefore be attributed to an inaccurate recapitulation of the in vivo tumor microenvironment in the cultured cell lines, namely a hypoxic environment. The exposure of HPV-neg OPSCC cultured cells to hypoxia or stabilizing HIF-1α genetically increased CA. Both the 26-gene hypoxia signature as well as the overexpression of HIF-1α positively correlated with increased CA in HPV-neg OPSCCs. In addition, we showed that HIF-1α upregulation is associated with the downregulation of miR-34a, increase in CA and expression of cyclin- D1. Our findings demonstrate that the evaluation of CA may aid in therapeutic decision-making, and CA can serve as a promising therapeutic target for HPV-neg OPSCC patients.
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Almost all cases of cervical cancer (CC) can be attributed to high-risk HPVs infections in keratinocytes. However, it is unknown whether HPV invades immune cells such as macrophages and T cells. We analyzed the single-cell transcriptome of the CC and its adjacent tissues and found that HPV16 genes, including E1, E6, and E7, expressed in the macrophages and CD8⁺ T cells in addition to the malignant cells. HPV16⁺ macrophages highly expressed the genes that promote cell adhesion and the favorable genes such as WAS, IQCB1, MYO1F, and PDZD11 in CC prognosis. The transcription factor KLF5 potentially accounted for the induction of these protective genes and thus facilitated the infiltration of the immune cells in tumor tissues. Our single-cell transcriptome analysis suggests the potential value of the HPV16⁺ macrophage in CC prognosis. However, extensive experimental studies investigating the characteristics and functions of the HPV⁺ immune cells are still required. This article is protected by copyright. All rights reserved.
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Stricter Postoperative Oropharyngeal Cancer Radiotherapy Normal Tissue Dose Constraints Are Feasible
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Purpose : While dose de-escalation is one proposed strategy to mitigate long term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control. Methods and Materials : We identified 92 patients at our institution between 2015-2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared to recommended dose constraints from a recent cooperative group head and neck cancer trial of radiotherapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis and xerostomia relevant to oropharyngeal cancer. Results : Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional). Conclusions : Modern radiotherapy planning techniques allow for improved normal tissue sparing compared to currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.
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  • Jul 2010
  • NEW ENGL J MED
Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)
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Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer
Article
Full-text available
  • Mar 2010
Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status. Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months). Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the <40% of patients whose primary tumors were Bcl2 positive. Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC.
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E6 and E7 Gene Silencing and Transformed Phenotype of Human Papillomavirus 16-Positive Oropharyngeal Cancer Cells
Article
Full-text available
  • Apr 2009
  • J NATL CANCER I
The E6 and E7 genes of human papillomavirus type 16 (HPV16) encode oncoproteins that bind and degrade p53 and retinoblastoma (pRb) tumor suppressors, respectively. We examined the effects of repressing E6 and E7 oncogene expression on the transformed phenotype of HPV16-positive oropharyngeal cancer cell lines. Human oropharyngeal squamous cell cancer 147T and 090 (harboring integrated HPV16 DNA) and 040T (HPV DNA-negative) cells were infected with retroviruses that expressed a short hairpin RNA (shRNA) targeting the HPV16 E6 and E7 genes or a scrambled-sequence control shRNA. Flow cytometry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and immunoblotting for annexin V were used to assess apoptosis in shRNA-infected cell lines. Biochemical analysis involved quantitative real-time polymerase chain reaction analysis of p53- and pRb-target gene expression and immunoblotting for p53 and pRb protein expression. In 147T and 090 cells, shRNA-mediated inhibition of HPV16 E6 and E7 expression reduced the E6 and E7 mRNA levels by more than 85% compared with control cells that expressed a scrambled-sequence shRNA. E6 and E7 repression resulted in restoration of p53 and pRB protein expression, increased expression of p53-target genes (p21 and FAS), decreased expression of genes whose expression is increased in the absence of functional pRb (DEK and B-MYB), and induced substantial apoptosis in 147T and 090 cells compared with the control shRNA-infected cells (from 13.4% in uninfected to 84.3% in infected 147T cells and from 3.3% in uninfected to 71.2% in infected 090 cells). Repression of E6 and E7 oncogenes results in restoration of p53 and pRb suppressor pathways and induced apoptosis in HPV16-positive oropharyngeal squamous cell cancer cell lines.
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Beyond Cervical Cancer: Burden of Other HPV-Related Cancers Among Men and Women
Article
  • Apr 2010
Human papillomavirus (HPV) infection is a necessary cause of cervical cancer, and is etiologically associated with a subset of cancers of the anus, oropharynx, penis, vagina, and vulva. Current data indicate that HPV infection is potentially associated with 90%-93% of anal cancers, 12%-63% of oropharyngeal cancers, 36%-40% of penile cancers, 40%-64% of vaginal cancers, and 40%-51% of vulvar cancers. HPV infection accounts for up to 492,800 cervical cancers and 97,215 cases of noncervical HPV-related cancers worldwide during 2002, including up to 50,780 cancers among men (13,485 anal cancers, 26,775 oropharyngeal cancers, and 10,520 penile cancers) and up to 46,435 cancers among women (14,787 anal cancers, 6,048 oropharyngeal cancers, and 25,600 vaginal/vulvar cancers). In the United States annually (1998-2003), up to 10,846 cervical cancers, 4,753 noncervical cancers among men, and 4,128 noncervical cancers among women are potentially attributable to HPV infection. Incidence rates for cervical cancer have declined significantly during the past 30 years in the United States, consistent with the success of Pap smear screening. However, incidence rates for anal, oropharyngeal, and vulvar cancers have increased substantially in recent years. The high proportion of cervical and noncervical cancers caused by HPV types 16 and 18, that is, 70%-76% for cervical cancers and 63%-95% for noncervical cancers, underscores the potential for prevention of a majority of cervical as well as noncervical HPV-related cancers through prophylactic HPV vaccination.
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Immune Response During Therapy With Cisplatin or Radiation for Human Papillomavirus–Related Head and Neck Cancer
Article
  • Nov 2009
Human papillomavirus (HPV) is the most identifiable cause of head and neck squamous cell cancer (HNSCC). Compared with HPV-negative HNSCC, HPV-positive HNSCC presents at an advanced stage but with significantly better survival. We created a syngeneic mouse model of HPV-positive and HPV-negative HNSCC by transforming mouse primary tonsil epithelial cells with either HPV oncogenes or a nonantigenic RNA interference strategy that affects similar oncogenic pathways. To examine the effect of radiation therapy on HPV-positive and HPV-negative tumors in immune-competent and immune-incompetent mice and to examine responses in human cancer cell lines. Prospective in vivo murine model. Survival and tumor growth. For human and murine transformed cell lines, HPV-positive cells were more resistant to radiation and cisplatin therapy compared with HPV-negative cells. In vivo, HPV-positive tumors were more sensitive to radiation, with complete clearance at 20 Gy, compared with their HPV-negative counterparts, which showed persistent growth. Cisplatin in vivo cleared HPV-positive tumors but not HPV-negative tumors. However, neither radiation or cisplatin therapy cured immune-incompetent mice. Adoptive transfer of wild-type immune cells into immune-incompetent mice restored HPV-positive tumor clearance with cisplatin therapy. The HPV-positive tumors are not more curable based on increased epithelial sensitivity to cisplatin or radiation therapy. Instead, radiation and cisplatin induce an immune response to this antigenic cancer. The implications of these results may lead to novel therapies that enhance tumor eradication for HPV-positive cancers.
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Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?
Article
The incidence of human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) increases in the western countries. These OPSCC show distinct molecular characteristics and are characterized by an overexpression of p16, considered a surrogate marker for HPV infection. When compared to patients with p16 negative OPSCC, patients with HPV induced p16 positive OPSCC show a significantly better prognosis, which is reported to be caused by increased radiosensitivity. The objective of the present study was to analyze the impact of p16 expression status on the prognosis of OPSCC treated by either radiotherapy (RT) or primary surgery. Results are based upon a tissue microarray (TMA) of 365 head neck squamous cell carcinomas (HNSCC) including 85 OPSCC with clinico-pathological and follow-up data. p16 positivity correlated significantly with oropharyngeal tumor localization (p < 0.001). Patients with p16 positive OPSCC exhibited a significantly better overall survival than those with p16 negative tumors (p = 0.007). In a multivariate analysis, survival benefit of patients with p16 positive OPSCC was independent of clinico-pathological parameters such as cT and cN classification and treatment modality. The improved prognosis of p16 positive OPSCC is found after RT as well as after surgery.
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Oncogenic Activities of Human Papillomaviruses
Article
  • Jul 2009
Infectious etiologies for certain human cancers have long been suggested by epidemiological studies and studies with experimental animals. Important support for this concept came from the discovery by Harald zur Hausen's group that human cervical carcinoma almost universally contains certain "high-risk" human papillomavirus (HPV) types. Over the years, much has been learned about the carcinogenic activities of high-risk HPVs. These studies have revealed that two viral proteins, E6 and E7, that are consistently expressed in HPV-associated carcinomas, are necessary for induction and maintenance of the transformed phenotype. Hence, HPV-associated tumors are unique amongst human solid tumors in that they are universally caused by exposure to the same, molecularly defined oncogenic agents, and the molecular signal transduction pathways subverted by these viral transforming agents are frequently disrupted in other, non-virus-associated human cancers.
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Human papillomavirus-related head and neck tumors: Clinical and research implication
Article
  • Jun 2009
  • CURR OPIN ONCOL
High-risk human papillomaviruses (HPVs) are implicated in the development of a subset of head and neck squamous cell cancers (HNSCCs), especially those arising from the lingual or palatine tonsils. HPV-associated HNSCCs represent a different disease entity from those associated with the traditional risk factors of tobacco and alcohol use. The demonstration that HPV is causally associated with a subset of HNSCC has tremendous clinical and research implications. In recent years, there has been an increase in the annual incidence of HPV-related HNSCC in the United States and Europe. It has now become clear that a subset of HNSCC is a sexually transmitted disease with distinct pathogenesis and clinical/pathological features. HPV-associated HNSCCs have a better prognosis compared with stage-matched non-HPV-related HNSCC in the majority of studies. Research efforts are now focusing on deintensification of treatment to reduce treatment-associated morbidity. HPV-targeted therapies are under investigation. The increasing incidence of HPV-related HNSCC has led to the development of novel research strategies in HNSCC. This review summarizes the epidemiology, clinical presentation, molecular pathogenesis, diagnosis, and therapy of HPV-associated HNSCC; it also summarizes how a better understanding of the molecular pathogenesis of HPV-associated HNSCC is expected to change treatment.
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