HPV’s Connection to Head and Neck Cancers Determines the Present and Future of This Treatment Landscape


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For Head and Neck Cancer Awareness Month, we looked at the connection between the human papillomavirus and this disease, and the role it has in determining treatment now and in the future.

Head and neck cancers account for 4% of all cancers in the United States. In 2023, approximately 66,920 people will receive this diagnosis.1 Receiving a head and neck cancer diagnosis can come from several different factors, but one of the largest preventable factors is the human papillomavirus (HPV) infection.

Geoffrey D. Young, MD, PhD

Geoffrey D. Young, MD, PhD

Approximately 13 million new infections of HPV occur every year in the United States. While 9 out of 10 HPV infections will go away within 2 years, some infections last long enough to cause cancers.2 Approximately 70% of oropharyngeal cancers are caused by HPV infection, and 4% of head and neck cancers are linked to alcohol alone, 33% is due to tobacco alone, and 35% was due to tobacco and alcohol combined.3,4

“When society hears about HPV, they often think of cervical cancer and associate it with women-related cancers. However, HPV can also cause a subset of head and neck cancers, particularly those located in the tonsil or back of the tongue,” explained Sara Pai, MD, PhD, in an interview with Targeted OncologyTM for Head and Neck Cancer Awareness Month. “These HPV-associated cancers most often occur in men with no smoking history. In fact, 1 out of every 4 head and neck cancers are caused by HPV infection.”

According to the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program, the estimated deaths from oral cavity and pharynx cancers was 11,230 people, but the 5-year survival rate of HPV-associated head and neck cancers is approximately 85-90%.5,6 Living with this type of disease can be deeply impactful for patients as it can disrupt their speech and eating patterns, which can be permanently altered by potential surgeries. Wider awareness of the connection between HPV and head and neck cancers provides an avenue for clinicians to treat patients and possibly prevent more cases of head and neck cancer.

HPV’s Molecular Connection to Head and Neck Cancers

Head and neck squamous cell carcinomas are a group of malignancies that impact the mucosal linings at different anatomic sites along the upper aerodigestive tract, nasopharynx, paranasal sinuses, oral cavity, oropharynx, or hypopharynx and larynx. Research has shown that patients with HPV-positive oropharyngeal carcinoma are highly responsive to treatment and have a better prognosis in comparison to patients with HPV-negative head and neck cancers whose disease is more genomically complex.7

When a patient is infected with HPV, it infects their stratified squamous epithelia, both cutaneous and mucosal, including the skin of their hands and feet, and the anogenital tract, mouth, throat, and respiratory tract. The single layer of epithelial cells at the tonsillar crypts are the most susceptible cells for transforming into cancer because they are hosts for bacterial infections and foreign materials that drive the expression of PD-L1.8

This overexpression in the tonsils favors persistent infection of HPV, which allows for tumorigenesis. If the patient is infected with high-risk types of HPV —HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59 and HPV68—they will also have a higher likelihood of carcinogenic transformation of their infected mucosal epithelium.

“If one sees a new patient with tonsil cancer, one should test for the presence of HPV within the tumor. This can be done via HPV16/18 in situ hybridization or p16 immunohistochemistry,” explained Pai, associate professor of surgical oncology and director of translational head and neck cancer research at Massachusetts General Hospital/Harvard Medical School. “This information can give prognostic information and assess their eligibility for clinical trials targeted to their specific cancer.”

These persistent infections are established by the virus escaping cell-cycle checkpoints through the mediated E6 and E7 degradation of p53 and Rb proteins that cause the infected cells to be terminally differentiated.8 Once HPV 6 or 11 infects the lungs, it is associated with a 32-fold increased cancer risk.9 However, while the viral proteins are synthesized, no viral particles are produced by the virus, meaning that the nonproductive infection of HPV allows for the induction of tumorigenesis.

Patients with low-risk HPVs, such as HPV6, and HPV11, will usually cause benign tumors, such as genital warts or recurrent respiratory papillomas.10 Yet, where many other cancers do not have clear cut preventative measures, the association of HPV and head and neck cancers gives clinicians the ability to educate patients on cancer prevention and the benefits of getting the HPV vaccine.

HPV Prevention and Treatments in Head and Neck Cancers

According to Pai, an analysis of 2 prospective and 4 retrospective studies evaluating HPV vaccination to prevent head and neck cancer showed a lower prevalence of oral HPV infection of up to 4 years following the vaccination.11 The investigators used the rate of persistent oral infection as a surrogate for efficacy and estimated that vaccine efficacy was between 88% and 93.3%. Because of low vaccine coverage, the estimated population-level impact against high-risk, cancer-causing HPV infections was just 17%.

Sara Pai, MD, PhD

Sara Pai, MD, PhD

The importance of getting an HPV vaccine is mainly advocated for adolescents between the age of 13 to 17 years, as the virus is a sexually transmitted disease and earlier vaccination of the virus will potentially allow for long term protection.12 While sexual transmission is the most documented form of HPV transmission, some studies have suggested non-sexual transmission of HPV can occur via fomites, fingers, mouth, and skin contact. However, the investigators noted that even though the duration of protection is not known for the vaccine, the vaccine can provide protection from re-infection, suggesting it can still be useful later in life.

While prevention remains an area of greater need for head and neck cancers, the field has advanced to better treat these patients, specifically those with HPV-positive head and neck cancer. For instance, over the last 15 years, 123 clinical trials concerning patients with HPV-positive head and neck cancers were done, with most of them being phase 2 trials.13 These trials have given patients the opportunity to receive new treatments, and 30 publications resulted from these 123 trials with only half of the published articles showing primary results.

“[Clinicians] are trying to figure out the optimal patient for those trials and trying to reduce [adverse events (AEs)], but still achieve high cure rates,” said Geoffrey D. Young, MD, PhD, in another interview with Targeted OncologyTM on the impact of HPV-positive head and neck cancers. Young, chief of head and neck cancer surgery at Miami Cancer Institute, part of Baptist Health, cited an example of a trial at his institution, in partnership with Memorial Sloan Kettering Cancer Center, to use biological determination of treatment effectiveness that will give clinicians a sense of whether it’s appropriate to reduce the dose of treatment.

Young also explained that the ability to do surveillance for some of these tumors with better imaging and bloodborne assays for tumor markers has impacted the ability to tailor treatment to patients. Moreover, according to Young, this has allowed for clinicians to better detect recurrence for disease and find the levels of treatment that don’t lower a patient’s quality of life. With this increase in surveillance, it has allowed for targeted treatments to find a role in the treatment landscape, but only as a secondary or tertiary treatment right now.

Immunotherapies and The Future of Head and Neck Cancer

It remains a major challenge to find ways to individualize these treatments and also maintain a patient’s quality of life. As the disease progresses, it impacts the patient’s speech and eating, which then requires the help of a wider interdisciplinary team for each patient.

As Young puts it, “it takes a village” to manage the patient’s disease and have everyone on board from all the different subspecialties to help make a treatment decision. This includes not only oncologists, but nutritionists, speech and language pathologists, and oncology nurses to provide the patients with total care.

According to Young, some of these challenges have been overcome by the use of robotic surgery to remove a patient’s tumor in the head and neck region. Robotic surgery in this space allows for a 360-degree range of motion, 3D panoramic vison, and a hand tremor filter.14 

Another option with a promising future in the space is the use of immunotherapy. While the role it will play in head and neck cancers is still being determined, the phase 3 KEYNOTE-048 study (NCT02358031) investigating pembrolizumab (Keytruda) has provided some answers as to what that future looks like.15

“The KEYNOTE-048 clinical trial was practice-changing because it provided patients with recurrent/metastsatic head and neck cancer with another treatment option, specifically immunotherapy, which could improve overall survival [OS] for the first time in 50 years,” explained Pai. “The drug also had a relatively good tolerability profile compared with the current standard of care—a regimen of several chemotherapeutic agents, which can result in severe adverse events [AEs].”

The study showed that among 882 participants, patients with recurrent or metastatic head and neck squamous cell carcinoma receiving pembrolizumab alone (n= 301) or pembrolizumab plus chemotherapy (n = 281) had an improved OS compared with patients on cetuximab plus chemotherapy (n = 300).

At a second interim analysis, patients with a PD-L1 combined positive score (CPS) of 20 or more given pembrolizumab alone had a median OS of 14.9 months compared with 10.7 months for those on cetuximab with chemotherapy (HR, 0.61; 95% CI, 0.45-0.83; P = .0007). Moreover, patients with a CPS of 20 or more given pembrolizumab combined with chemotherapy had a median OS of 14.7 months vs 11.0 months for those given cetuximab (HR, 0.60; 95% CI, 0.45-0.82, P = .0004).

These results were reflected in the overall population, with the combination of pembrolizumab and chemotherapy having the longest median OS at 13.0 months. Although pembrolizumab alone or in combination with chemotherapy did not improved progression-free survival, the combination received FDA approval.16

“Several other novel therapies are showing promise for HPV-associated head and neck cancers,” said Pai. Many of these therapies, including DNA, RNA, peptide, or protein therapeutic vaccines, are being given with immune checkpoint inhibitors, including pembrolizumab. Newer treatments in the space also include cell-based therapies for HPV-associated cancers like the differentiated HPV-targeted biologic currently being evaluated called CUE-101.

The novel therapeutic fusion protein was found to be consistent with its design in an ongoing phase 1 trial (NCT03978689) and demonstrated a selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+ T cells.17 According to Pai, ongoing trials now show that patients are achieivng durable responses with CUE-101 as a monotherapy and in combination with pembrolizumab, even those with a CPS of less than 20.

As treatments and trials like these continue to gather more data and provide new avenues for care, the ability to reach more people with an HPV vaccine remains a high priority for clinicians treating this disease.

“We have a vaccine against HPV related cancers that if we are really good at giving in this country, we can eradicate some of these cancers,” Young concluded. “I've always said, I will not be sad if we eradicate these cancers and I'm out of a job. I'd rather be out of a job and people not have these cancers than the other way around. So, we need to do a good job of making awareness for screenings and encouraging vaccination against HPV related cancers.”


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3. HPV and oropharyngeal cancer. Centers for Disease Control and Prevention. October 3, 2022. Accessed April 20, 2023. https://bit.ly/441pzpM

4. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18(2):541-50. doi:10.1158/1055-9965.EPI-08-0347

5. Cancer stat facts: oral cavity and pharynx cancer. National Cancer Institute SEER Program. 2023. Accessed April 20, 2023. https://bit.ly/3UUHKsP

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8. Lyfrod-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013 Mar 15;73(6):1733-401. doi: 10.1158/00008-5472.CAN-12-2384

9. Pai SI, Wasserman I, Ji YD, et al. Pulmonary manifestations of chronic HPV infection in patients with recurrent respiratory papillomatosis. Lancet Respir Med. 2022 Oct;10(10):997-1008. doi: 10.1016/S2213-2600(22)00008-X

10. Gaglia MM, Munger K. More than just oncogenes: mechanisms of tumorigenesis by human viruses. Curr Opin Virol. 2018;32:48-59. doi:10.1016/j.coviro.2018.09.003

11. Diana G, Corica C. Human Papilloma Virus vaccine and prevention of head and neck cancer, what is the current evidence? Oral Oncol. 2021;115:105168. doi:10.1016/j.oraloncology.2020.105168

12. Petca A, Borislavschi A, Zvanca ME, et al. Non-sexual HPV transmission and role of vaccination for a better future (Review). Exp Ther Med. 2020;20(6):186. doi:10.3892/etm.2020.9316

13. Bteich YT, Hosri JE, Wehbi JA, Daou LR. Current landscape of clinical trials for HPV-positive head and neck squamous cell carcinoma (HNSCC). Ecancermedicalscience. 2022;16:1447. doi:10.3332/ecancer.2022.1447

14. Kalantari F, Rajaeih S, Daneshvar A, et al. Robotic surgery of head and neck cancers, a narrative review. Eur J Transl Myol. 2020;30(2):8727. doi:10.4081/ejtm.2019.8727

15. Burtness B, Harrington KJ, Greil R, et al; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928. doi:10.1016/S0140-6736(19)32591-7

16. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. News release. June 11, 2019. Accessed April 24, 2023. https://bit.ly/2wP4Oz8

17. Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies. Clin Cancer Res. 2020 Apr 15;26(8):1953-1964. doi: 10.1158/1078-0432.CCR-19-3354

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