SCOTTSDALE, Ariz.—While most patients with oropharyngeal squamous cell carcinoma (OPSCC) caused by human papillomavirus (HPV) have an excellent prognosis for disease-free survival, those with OPSCC associated with tobacco use generally face more dire prognoses.
But what about HPV-positive OPSCC patients who have been smokers? These cases represent a distinct clinical entity compared with HPV-positive never smokers and HPV-negative cases, but the interplay between smoking and HPV have not been well-defined.
Now, researchers at the University of North Carolina, Chapel Hill, report head and neck cancer patients exposed to both HPV and tobacco smoke show a particular pattern of mutations along several key cancer genes, and say this molecular signature may help predict lower disease-free and overall survival rates among HPV-positive head and neck cancer patients who smoke.
This new prognostic tool could further stratify risk in HPV-positive OPSCC and provide a rationale for de-intensification of standard treatments which are often highly toxic with long-term side effects, the researchers said, in a presentation.
The symposium was sponsored by the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), and the American Head & Neck Society (AHNS).
The study's first author, Jose P. Zevallos, MD, Assistant Professor and Director of Oncologic Research in the Division of Head and Neck Surgical Oncology at the University of North Carolina, Chapel Hill, and a member of the Lineberger Comprehensive Cancer Center, also reported finding a novel immune signature in patients who smoked fewer than 10 packs a year that is different from the known tobacco-associated mutations in patients who smoked more than 10 packs per year.
“These distinct molecular profiles of heavy and light smokers who develop HPV-positive oropharyngeal squamous cell carcinoma may one day inform our decisions about treatment intensity by establishing additional criteria for these patients,” Zevallos said.
The study included 66 cases of HPV-positive OPSCC that were split into heavy and light smoking behavior groups based on pack years, based on the number of years a person has smoked multiplied by the average number of packs of cigarettes smoked per day.
The cases were from a North Carolina population-based epidemiologic study by the cancer center. Forty of the 66 patients were heavy smokers, reporting more than 10 pack years, that is, more than one pack per day for 10 years or two packs per day for five years; 26 patients reported fewer than 10 pack years.
As expected, HPV type 16 was seen in 95 percent of patients, with rare cases of HPV 35 and HPV 58.
Overall mutation rates were higher for HPV-positive OPSCC heavy smokers; HLA-A mutations occurred more often in those patients; and mutations associated with tobacco exposure and poor survival occurred almost exclusively within the heavy smoker group, including mutations in the TP53, CDKN2A, FAT1, CASP8, NOTCH1, FGFR3, and KRAS genes.
The researchers found that in the OPSCC patients identified as HPV-positive by p16 and PCR analysis, the number of reads was inversely related to smoking and survival status.
One intriguing study finding pointed a new way of thinking about carcinogenesis in HPV-related OPSCC.
“Study patients who smoked and patients who were deceased from their cancer both had lower numbers of HPV viral reads,” Zevallos said. “Potentially, this means that these tumors began as HPV-driven but over the course of time developed subclones that were driven by tobacco-associated gene mutations as a result of exposure to smoking.”
The mean number of HPV reads per sample was 838.52, so there was excellent depth of coverage of the HPV viral genome, Zevallos said.
“We propose that HPV-positive smokers acquire these mutations later on in carcinogenesis,” he said. “It may suggest that a lower number of HPV reads is associated with smoking and poor survival and may suggest an accumulation of tobacco-associated mutations and less dependence on the traditional HPV carcinogenesis mechanisms, namely E6 and E7 oncogene-driven tumors.”
Not Your Usual Fingerprint
At an online/audio preview of the meeting for the press, moderator Christine G. Gourin, MD, Associate Professor of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, said the study is important because the molecular fingerprint for HPV-related OPSCC is really different from anything seen before.
“This is a different patient population and different outcomes than the in population when I was in training,” Gourin said. “We don't understand fully why this fingerprint is so different, and why tobacco affects the fingerprint. But the finding of difference in the molecular phenotype between light smokers sand heavy smokers is something we all appreciate clinically and we need to understand better in order to tailor treatment.”
Novel Mutations in Tobacco Users
“What is most striking is that these genes are mutated almost exclusively in smokers,” Zevallos said.
He said this molecular profile suggests that while HPV-positive and HPV-negative OPSCC carcinogenesis initiate similarly, tumors in patients who smoke acquire novel mutations not traditionally associated with HPV-associated cancers.
“The differences identified in this study by smoking status between immune-related and tobacco-related gene mutations may explain why HPV-positive cancer in smokers may be more aggressive,” he said.
Zevallos said these data begin to set criteria-based changes in tumor DNA to personalize treatment.
“Rather than arbitrarily using 10 pack years as a number to define more aggressive disease, we are trying to provide a molecular basis for more aggressive disease in order to decide who would benefit from more versus less aggressive treatment.”
Robert H. Carlson is a contributing writer.