Moving Toward Precision Medicine for HPV+ Oropharyngeal Cancers

This Clinician’s View is written by AdventHealth head and neck surgical oncologist Jean-Nicolas Gallant, MD, PhD.

Over the past two decades, human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has emerged as a distinct clinical entity, differing from traditional head and neck cancers in its risk factors, patient population, and response to treatment.

HPV now drives roughly 70% of OPCs in the United States, often affecting otherwise healthy individuals without traditional risk factors such as tobacco use. Fortunately, this type of cancer responds well to treatment with five-year survival rates above 85%. However, this statistic obscures a deeper issue: standard-of-care treatment remains aggressive, negatively impacting the long-term quality of life of usually healthy younger individuals.

The standard combination chemotherapy and radiation (chemoradiation, CRT), while effective, can cause long-term morbidities, including xerostomia, dysgeusia; and, in more severe cases, significant neck fibrosis. Additionally, severe oropharyngeal hemorrhage can occur decades after completion of chemoradiation, usually due to fibrotic carotid artery rupture.

So, we are curing patients with HPV-associated OPCs; but are we treating them as well as we could? Can we move beyond one-size-fits-all treatment to a more personalized, precise approach that improves long-term quality of life? Can we better stratify disease aggressiveness at diagnosis, refine prognostication, and identify those patients for whom treatment can be safely de-escalated without compromising oncologic outcomes?

I believe the path to answering these questions lies in improved molecular diagnostics, moving beyond uniform treatment strategies toward a more nuanced understanding of tumor biology and patient risk. That shift represents the next frontier in head and neck oncology.

The Standard Approach to Diagnosing Oropharyngeal Tumors

HPV-related cancers can develop years or even decades after exposure to the virus. HPV16 is the strain responsible for most HPV-associated OPC, which typically arise in the palatine and lingual tonsils. Primary oropharyngeal tumors tend to be small but frequently metastasize to cervical lymph nodes, which often form large neck masses and cause the initial presentation.

Diagnosis relies on pathology. Following biopsy, immunohistochemical (IHC) staining is performed, including for p16, a surrogate marker for HPV-associated disease. If p16 staining is above a certain threshold, the tumor is classified as HPV-associated. Based on clinical examination and imaging findings, patients are typically placed into one of two treatment pathways: 1) primary CRT or 2) surgery followed by risk-adapted adjuvant therapy.

A major limitation of this approach is its imprecision. Current clinical and imaging diagnostic tools do not reliably capture the true biological extent of disease. Critical molecular and microscopic features can be missed. One example is extranodal extension, which is strongly associated with worse outcomes.

Improving Precision and Personalizing Care

My interest in cancer research began early and was influenced by my father’s work leading oncology clinical trials in the pharmaceutical industry. That exposure led me to pursue a joint MD-PhD program and ultimately a career that bridges surgery and translational research.

While I love what I do, the field of head and neck surgery has relied on old science and approaches. This leaves substantial room for innovation. One major advancement came in the 2010s when one of my mentors at the University of Pennsylvania pioneered transoral robotic surgery (TORS) for head and neck cancers. TORS transformed surgical access to oropharyngeal tumors, making surgery more precise, less invasive, and often easier to recover from.

Even so, significant gaps remain. A central question now is whether next-generation molecular diagnostics can help us to further enhance precision, predicting patient outcomes better than our current clinical tools.

Incorporating Next Generation Diagnostics

In cancers such as those of the lung, breast, and colon, genomic and molecular profiling technologies have fundamentally changed diagnosis and treatment. We don’t currently have this level of molecular precision incorporated into the field of head and neck oncology, and I see that as an opportunity ripe for exploration and advancement.

One promising tool is NavDx, an FDA-approved blood test that detects circulating tumor HPV DNA (ctHPVDNA). Although not yet incorporated into standard clinical guidelines, I believe it is helpful. NavDx can be used in both the diagnostic phase and for post-treatment surveillance. However, its broader clinical implications remain under investigation. It’s easy to incorporate once we start treatment, but at that point, the treatment may have already done some harm.

One recent feasibility study explored the combined use of ctHPVDNA and HPV serology as diagnostic tests for HPV-associated OPC. The researchers found these techniques to be sensitive and to provide highly specific biomarkers for HPV-associated OPC at the time of presentation. Studies like this are encouraging, but we have much more work to do.

Quantifying HPV to Guide Treatment De-escalation

Given the strong survival outcomes in HPV-related OPC, the goal is not necessarily to develop new treatments but to refine our approach to existing ones. This means improving risk stratification so that we can identify which patients require aggressive therapy and which may benefit from treatment de-escalation.

Recently, I have been evaluating HPV RNA as a pretreatment prognosticator, examining the clinical significance of discordant p16 and HPV RNA tests to see if it can help us identify recurrence-prone tumors. In the context of p16-positive OPC, discordant HPV testing describes tumors that are p16-positive by IHC but negative for high-risk HPV by RNA or DNA assays. These cases represent approximately 5–10% of patients, tend to behave more like p16-negative/HPV-negative tumors, and are associated with a significantly poorer prognosis compared with concordant p16-positive/HPV-positive tumors.

My current research focuses on whether artificial intelligence and digital histopathology could be applied to initial biopsy samples to quantify HPV RNA expression at the cellular level. The goal is to develop a pretreatment risk score that could guide therapy selection before treatment even begins.

De-escalation Through Surgery: Taking a Multidisciplinary Team Approach

Another way to de-escalate the amount of chemotherapy and radiation patients with HPV-associated OPC receive is to take a more aggressive surgery-first approach with appropriate patients. Our head and neck surgery team at AdventHealth routinely uses TORS to push the boundaries of what can be achieved.

TORS has demonstrated lower rates of positive surgical margins compared to non-robotic techniques and, consequently, has been linked to reduced use of adjuvant chemoradiotherapy. As a de-intensification strategy, the ECOG 3311 trial evaluated primary TORS and reduced postoperative radiation therapy in intermediate-risk HPV-associated OPC. It concluded outstanding oncologic and favorable functional outcomes.

However, tradeoffs remain, and that is why it currently comes down to a personal discussion between the patient and their care team. An aggressive surgery-first approach can introduce short-term morbidity, including dysphagia, and patient selection remains imperfect due to limitations in our current diagnostic tools. This underscores the need for more precise pretreatment risk assessment to inform our treatment decisions.

Building on the Science

HPV-associated OPC has only been recognized as a distinct entity for about 20 years, and we are just beginning to understand the long-term consequences of our treatments and how they might be improved.

Our team of medical oncologists, radiation oncologists, and surgeons at AdventHealth are collaborating to provide patients with HPV-associated OPC the best possible outcomes, and I believe research aimed at advancing molecular diagnostics could help us redefine what it means not just to cure this type of cancer, but to cure it well.