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Combination diagnostic test best for distinguishing HPV cancers
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A combination of two HPV diagnostic tests provided the most accurate determination of which oropharyngeal squamous cell carcinomas are positive from HPV 16, according to a recently published study.
Prior research has shown that a patient’s HPV status is an important prognostic biomarker for oropharyngeal squamous cell carcinoma. Because of this, it is used in clinical trials as an inclusion criteria or stratification parameter.
In this study, researchers hoped to clarify which diagnostic test would provide the most accurate diagnosis. To do that, they evaluated eight possible combinations of known diagnostic tests on 108 cases of HPV 16-derived oropharyngeal squamous cell carcinoma. The tests included p16 immunohistochemistry (p16 IHC), in situ hybridization for high-risk HPV (HR HPV ISH), quantitative Polymerase chain reaction (qPCR) for both viral E6 RNA (RNA qPCR) and DNA qPCR.
Results indicated that the combination of p16 IHC/DNA qPCR had a 97% sensitivity and a 94% specificity compared with what is considered to be the gold standard, the RNA qPCR test.
The combination tests of p16 immunohistochemistry/in situ hybridization for high-risk HPV had a 90% specificity; however, its prognostic value was deteriorated by an 88% sensitivity (P=.02).
In their discussion of the results, the researchers wrote that they hoped “that the design of forthcoming clinical trials, aimed at both de-escalating therapy in HPV-mediated oropharyngeal squamous cell carcinomas and perhaps intensifying therapy for HPV-negative cases, will be formed by these results.”
For more information:
- Schache A. Clin Cancer Res. 2011;17:6262-6271.
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The question of how best to determine favorable prognosis for virally associated oropharynx cancer is one with significant implications for clinical trial design. At present, there is no evidence to support treatment-deintensification for patients with human papillomavirus-associated oropharynx cancer; however, the recognition that patients with high p16 expression or positive HPV ISH have high cure rates with conventional therapy has raised the question of whether our current treatments — 7 weeks of radiation, high-dose cisplatin, three drug induction chemotherapy — are necessary for cure in these treatment-responsive cancers.
Two cooperative group trials are currently examining the question. E1308 uses clinical complete response after three cycles of induction chemotherapy as a dynamic biomarker of treatment responsiveness, and assigns complete responders to 54 Gy rather than 69 Gy of radiation. R1016 randomizes patients between a chemoradiation schedule using high-dose cisplatin 3 two during altered fractionation radiation or cetuximab concurrent with the same radiation course. Both trials utilize p16 overexpression as a surrogate for HPV association, on the rationale that the HPV viral oncoprotein E7 degrades Rb, removing its regulation of p16, with the result that p16 levels will rise. Data from the paper of Schache et al indicate that compared to a gold standard of HPV RNA determined by qt-PCR, a combination of p16 staining by immunohistochemistry with PCR for HPV DNA has sensitivity of 97% and specificity of 94%, superior to p16 staining alone.
The more important question is which test or combination of tests is most predictive of favorable prognosis. They demonstrate that testing for both p16 and HPV is also more predictive of outcome than p16 staining alone. However, there are some important caveats. The cases analyzed here were collected over a period extending from 1988 to 2009: Changes in staging, standards of care and competing causes of mortality over this time period would have contributed considerable heterogeneity in what is to start with a small series of 108 cases. T stage is also not adjusted for. Thus, these data make a strong case for collecting both p16 and HPV PCR data in our ongoing trials, but do not yet demonstrate that dual testing is necessary to determining favorable prognosis.
– Barbara Burtness, MD
Chief, head and neck oncology; and co-leader of the Developmental Therapeutics Program; Fox Chase Cancer Center; Philadelphia.
Disclosure: Dr. Burtness reports no relevant financial disclosures.