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HPV, p16 May Offer Different Prognostic Clues in Oropharyngeal Cancer, ESMO Data Reveals

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NEW YORK – The use of p16 profiling to indirectly detect human papillomavirus (HPV)-related cancers of the oropharynx may fail to pick up a subset of HPV-positive cases, according to early results from the EPIC-OPC study.

Rather, data from the study presented at the European Society for Medical Oncology's Virtual Congress on Saturday suggested that p16 and HPV — measured by immunohistochemistry (IHC) and the HPV DNA in situ hybridization (ISH) assay, respectively — can identify clusters of oropharyngeal cancers that appear to be at intermediate risk of recurrence or death compared to tumors that are p16-positive and HPV-positive and those lacking both markers.

Miren Taberna, a cancer researcher at the Catalan Institute of Oncology, outlined the strategies that she and her colleagues used to retrospectively analyze clinical features and outcomes in relation to p16 and HPV status in more than 7,700 individuals with oropharyngeal cancer enrolled in 13 cohorts from sites in nine European or North American countries.

Oropharyngeal cancer patients with HPV-related tumors fare better than their HPV-free counterparts, Taberna explained, noting that the risk of death is roughly 59 percent lower for HPV-positive oropharyngeal cancer cases, based on prior data. Even so, there are a range of methods for distinguishing between HPV-positive and -negative cases, and some are more amenable to the clinical setting than others.

RT-PCR testing aimed at the messenger RNAs that code for the HPV E6 and E7 oncoproteins has high sensitivity and high specificity, for example, identifying transcriptionally active HPV. But that strategy "is really difficult to implement in the clinical setting," Taberna said, leading to the development of alternative detection methods.

IHC profiling is a sensitive approach for picking up p16 — a surrogated marker for HPV — albeit with reduced specificity, she explained, since that host protein sometimes has enhanced expression even in the absence of HPV infection. On the other hand, the DNA ISH test is less sensitive, since it depends to some extent on the viral load, though it is also far more specific for finding risky HPV strains.

Broadly speaking, much of the clinical HPV testing done in oropharyngeal cancer patients initially relies on the p16 profiling approach, in line with the College of American Pathologists' 2018 guidance that calls for p16-based HPV classification, followed by additional HPV testing if recommended by a pathologist. Similarly, p16 is typically used to determine HPV status in the TNM classification scheme for these head and neck cancers, which takes primary tumor size, lymph node involvement, and metastases into account.

Accurate classifications may be particularly important in the context of treatment de-escalation clinical trials, Taberna explained, since the prognostically favorable HPV-positive oropharyngeal cancer cases may be more likely to get siphoned into such studies.

Even so, she said, "there are few data regarding p16-positive, HPV-negative oropharyngeal cancer patients published, with a small sample size, and no geographic comparisons have been done. It has been proposed that double positivity for p16 and HPV DNA detection may have diagnostic and prognostic value."

In an effort to understand the clinical trajectory of cases in which p16 and HPV markers do not line up, the researchers considered 7,702 oropharyngeal cancer cases collected internationally between the late 1980s to 2018, taking available tumor IHC-based p16 status and HPV DNA ISH or PCR data into account, as well as individuals' alcohol or tobacco use, demographics, and clinical information.

Based on analyses done at a centralized site, the team classified 416 cases as p16-positive and HPV-negative, while 279 individuals with oropharyngeal cancer had p16-negative tumors testing positive for HPV by DNA ISH. The remaining patients included 3,598 with p16-negative and HPV-negative tumors and 3,409 cases classified as positive for both markers.

"Using p16 staining alone, 11 percent of oropharyngeal cancer patients would be incorrectly classified as HPV-related," Taberna reported, suggesting incorrect prognostic conclusions could be drawn from p16 testing alone, which would potentially place these patients in a de-escalation group inappropriately.

Still, the proportion of HPV-free cases with p16 staining were not equally distributed across the international sites included in the study. A relatively small proportion of cases from Toronto were p16-positive, HPV-negative, while the proportion of biomarker discordant cases jumped in Barcelona, where a large subset of cases had p16 positivity, but HPV-positive cases were much less common.

Nearly 90 percent of the p16-negative, HPV-negative cancers occurred in smokers, compared to a smoking rate of 62 percent in the patients with p16-positive, HPV-positive tumors. Notably, the cases showing discordant p16 and HPV marker status had smoking history in between these two groups.

The team also saw a range of treatment interventions, including an uptick in surgeries and palliative care in the p16- and HPV-negative cases, followed by cases with HPV but not p16.

Likewise, when the investigators looked at overall survival in the biomarker-defined groups of stage III or IVa/b, locally advanced oropharyngeal cancer cases, they found that significantly more patients with p16- and HPV-positive tumors were alive after five years, whereas outcomes were more dire for the p16- and HPV-negative cases.

Cases with p16-positive, HPV-negative or p16-negative, HPV-positive tumors fell in the middle on the five-year survival analysis — a pattern that carried over to the team's analysis of progression-free survival after five years.

Together, the study suggested that distinct prognostic insights can be gained by assessing both p16 and HPV in oropharyngeal tumors in the clinic, particularly for picking up intermediate-risk cases that might otherwise be missed.

Commenting on the EPIC-OPC study at the meeting, the University of Lausanne's Christian Simon, who was not involved in the research, noted that dual p16 and HPV testing at oropharyngeal cancer diagnoses could potentially detect the roughly 10 percent of patients that fall into those intermediate-risk groups.

Although smoking rates were somewhat higher in the cases lacking either the p16 or the HPV biomarker, Simon pointed out that the new data delineated "a true intermediate group, which was smoking less than the classical p16-negative, HPV-negative patients, and more than the p16-positive, HPV-positive ones."

However, he cautioned that treatment differences may influence the overall survival and disease-free survival patterns detected in the biomarker discordant groups, at least to some extent, though the findings also raise questions about the biological differences that may exist between tumors with high p16 expression alone and those that are HPV-positive with low expression of p16, along with the environmental contributors to those cancers including smoking history.

"What the investigators seem to have achieved in this study is to redefine the intermediate group, but this time on the molecular level, with all the important impact on trial design in the future, in particular de-escalation trials," Simon said.

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