The role of HPV in head and neck cancer and review of the HPV vaccine
TL;DR: The known clinical indications for human papillomavirus vaccination are reviewed, and other potential clinical targets for the vaccine that have not yet been demonstrated in clinical trials but for which there is biologic plausibility are highlighted.
About: This article is published in Preventive Medicine.The article was published on 2011-10-01 and is currently open access. It has received 244 citations till now. The article focuses on the topics: Genital warts & Recurrent Respiratory Papillomatosis.
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University of California, San Diego1, Yale University2, University of Texas MD Anderson Cancer Center3, Institute of Cancer Research4, Stanford University5, Memorial Sloan Kettering Cancer Center6, University of Pittsburgh7, University of Milan8, University of Birmingham9, Baylor College of Medicine10, Brigham and Women's Hospital11
TL;DR: An expert committee formed by the Society for Immunotherapy of Cancer formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing serve as a foundation to assist clinicians’ understanding of the role of immunotherAPies.
Abstract: Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals – the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab – for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians’ understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.
346 citations
Cites background from "The role of HPV in head and neck ca..."
...infection [73]; these cancers are predominantly found in the oropharynx, and are clinically and biologically dis-...
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TL;DR: Despite the common etiologic role of HPV in the development of cervical cancer and HPV‐associated OPC, great disparity exists between incidence, screening modalities, treatment, and prevention in these 2 very distinct cohorts.
Abstract: Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017;123:2219-2229. © 2017 American Cancer Society.
250 citations
Cites background from "The role of HPV in head and neck ca..."
...Also, transmissibility of oral HPV may be greater for men performing oral sex on women, possibly because of higher vaginal/cervical HPV copy numbers.(36) It is noteworthy that a similar male-to-female predominance exists in non-HPV-related head and neck cancers, although this may reflect the 5:1 worldwide smoking prevalence among men versus women....
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...It is noteworthy that partners of patients with HPV-related oropharyngeal tumors do not seem to have more frequent oral HPV infections, downplaying the role of oral-to-oral transmission.(36) Persistent HPV infection can progress to cancer over a period of decades, if untreated....
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TL;DR: Tumor HPV status (as determined by certain HPV16 in situ hybridization assays or certain p16 immunohistochemistry assays) is the strongest determinant of survival for patients with local-regionally advanced oropharyngeal cancer: patients with HPV-positive cancer have at least a 50% improvement in overall survival at 5 years, which is equivalent to an approximate 30% difference in absolute survival.
246 citations
TL;DR: Given the superior survival, younger age, and good performance status of HPV-positive oropharyngeal cancer patients, de-intensified therapies are currently being considered for this group of patients.
Abstract: Human papillomavirus (HPV) infection is now established as a major etiologic factor for oropharyngeal cancers. Case–control studies conducted around the world show strong and consistent associations of markers of HPV exposure with risk of oropharyngeal cancers (range of odds ratios [OR] for oral oncogenic HPV infections = 3.6–230.0, ORs for HPV16 L1 antibodies = 2.3–182.0, and ORs for HPV16 E6/E7 antibodies = 9.2–231.0. HPV-positive oropharyngeal cancers are epidemiologically distinct from HPV-negative ones, and are characterized by younger age at onset, male predominance, and strong association with sexual behaviors. Importantly, HPV-positive oropharyngeal cancer patients have substantially improved outcomes (28–80 % reductions in the risk of death) than HPV-negative patients. Given the superior survival, younger age, and good performance status of HPV-positive oropharyngeal cancer patients, de-intensified therapies are currently being considered for this group of patients. Recent analyses of cancer registry data show dramatic increases in incidence of oropharyngeal cancers during the past 15–20 years in several parts of the world, highlighting the need for prevention strategies. If proven efficacious, currently available prophylactic HPV vaccines hold great promise for primary prevention of HPV-associated oropharyngeal cancers.
228 citations
Cites background from "The role of HPV in head and neck ca..."
...Indeed, data from Australia, Sweden, and the US show that markers of high-risk sexual behaviors, such as earlier ages of sexual debut, practice of premarital sex, average number of lifetime partners, and practice of oral sex, have all increased among recent birth cohorts [61]....
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TL;DR: The accuracy of the test algorithm for HPV detection in FFPE tumor specimen is confirmed and a significant increase in the prevalence of HPV in OPSCC over the last two decades at the authors' center is found.
Abstract: Human papillomavirus (HPV) infection has been etiologically linked to oropharyngeal squamous cell carcinoma (OPSCC). The prevalence of HPV-positive OPSCC varies between studies, ranging from 20 to 90%. This may be related to the lack of a standardized HPV detection assay as well as to the time period in which HPV prevalence is investigated, as rising incidence rates are reported over the last decades. Here, we validated our previously defined test algorithm for HPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen consisting of p16INK4A immunostaining followed by high-risk HPV DNA detection by GP5+/6+ PCR on the positive cases (Smeets et al., Int J Cancer 2007;121:2465-72). In addition, we analyzed HPV prevalence rates in OPSCCs in the years 1990-2010. The test algorithm was validated on a consecutive series of 86 OPSCCs collected during 2008-2011, of which both fresh frozen and FFPE samples were available. We performed HPV-E6 RT-PCR on the frozen samples as gold standard and applied the algorithm to the corresponding FFPE samples. The test algorithm showed an accuracy of 98%. Using the validated algorithm, we determined the presence of an oncogenic HPV infection in 240 OPSCCs of patients diagnosed in the years 1990-2010 at our center. A significant increase in the proportion of HPV-positive samples was observed, from 5.1% in 1990 to 29.0% in 2010 (p = 0.001). In conclusion, we confirmed the accuracy of the test algorithm for HPV detection in FFPE tumor specimen and we found a significant increase in the prevalence of HPV in OPSCC over the last two decades at our center.
196 citations
Cites background or result from "The role of HPV in head and neck ca..."
...As HPV infection usually takes more than 10 years to progress from infection to malignancy, a temporal change in sexual behavior could explain the increased incidence and observed in HPV-positive OPSCC one to two decades later.(34) In concordance with other studies published, oropharyngeal HPV prevalence was higher in males compared to females, and higher in the tonsils compared to the other oropharyngeal subsites....
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...Interestingly, smoking patterns and alcohol use remained stable in our patient cohort in the years 1990–2010, while in most developed countries smoking and alcohol use are declining.(19,34,35) Notwithstanding the continuous exposure to these classical risk factors, the number of HPV positive OPSCCs in this patient population increased....
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References
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University of Texas MD Anderson Cancer Center1, University of Utah2, Université de Montréal3, Johns Hopkins University4, Vanderbilt University5, University of California, San Francisco6, Wayne State University7, Thomas Jefferson University8, University of Louisville9, University of Cincinnati10, Ohio State University11
TL;DR: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer and the risk of death significantly increased with each additional pack-year of tobacco smoking.
Abstract: Background 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. Methods 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. Results 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 packyear 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. Conclusions Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)
5,263 citations
TL;DR: In this article, the prevalence of human papillomavirus (HPV) infection in oropharyngeal cancer was determined for all 271 oropharygeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program.
Abstract: Purpose Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. Patients and Methods HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. Results HPV prevalence in oropharyngeal cancers significantly increased over ...
2,950 citations
TL;DR: It is suggested that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
Abstract: Background: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Methods: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5‐9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPVpositive tumors was determined by proportional hazards regression analysis. Results: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%‐30%). Highrisk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2‐ 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1‐12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPVpositive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05‐0.61) and smokers (OR = 0.16; 95% CI = 0.02‐1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1‐167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01‐0.36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07‐0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4‐ 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4‐4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8‐2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20‐0.88). Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis. [J Natl Cancer Inst 2000; 92:709‐20]
2,887 citations
"The role of HPV in head and neck ca..." refers background in this paper
...transcriptionally active, clonal, and not found in the surrounding benign tissue (Gillison et al., 2000)....
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...…al., 2006; Niedobitek et al., 1990; Ogura et al., 1991), 1990’s (Brachman et al., 1992; Cruz et al., 1996; Fouret et al., 1997; Fukushima et al., 1994; Gillison et al., 2000; Hammarstedt et al., 2006; Koch et al., 1999; Mineta et al., 1998; Nishioka et al., 1999; Reimers et al., 2007; Ringstrom et…...
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...N IH -PA Author M anuscript N IH -PA Author M anuscript transcriptionally active, clonal, and not found in the surrounding benign tissue (Gillison et al., 2000)....
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TL;DR: Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection, and the degree of association increased with the number of vaginal-sex and oral-sex partners, among subjects with or without the established risk factors of tobacco and alcohol use.
Abstract: BACKGROUND Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent. METHODS We performed a hospital-based, case-control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case-control comparisons. RESULTS A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16. CONCLUSIONS Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use.
2,529 citations
"The role of HPV in head and neck ca..." refers background in this paper
...…Lindel et al., 2001; Pintos et al., 2008; Settle et al., 2009; Tachezy et al., 2005; van Houten et al., 2001), and 2004– 2009 (Chaturvedi et al., 2011; D’Souza et al., 2007a; El-Mofty and Patil, 2006; Nasman et al., 2009; Romanitan et al., 2008; Tachezy et al., 2009) (Chaturvedi et al., 2011;…...
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...1) (D’Souza et al., 2007a; Kreimer et al., 2005; Nasman et al., 2009)....
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...…and 2004– 2009 (Chaturvedi et al., 2011; D’Souza et al., 2007a; El-Mofty and Patil, 2006; Nasman et al., 2009; Romanitan et al., 2008; Tachezy et al., 2009) (Chaturvedi et al., 2011; D’Souza et al., 2007a; El-Mofty and Patil, 2006; Nasman et al., 2009; Romanitan et al., 2008; Tachezy et al., 2009)....
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...Initial oral HPV natural history studies suggest that oral HPV persistence is similar to that known for anogenital HPV infection (D’Souza et al., 2007b; Fakhry et al., 2010), and that most prevalent infections clear within a year on their own (Kreimer et al., 2010b)....
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