SCOTTSDALE, ARIZ. – The human papillomavirus (HPV)–positive oropharyngeal cancers of heavy smokers and light smokers have distinctly different molecular profiles, which may have implications for treatment, according to a study presented at the Multidisciplinary Head and Neck Cancer Symposium.
The population-based cohort study of 66 patients found that mutations in certain genes associated with tobacco exposure and poorer survival – for example, NOTCH1, TP53, CDKN2A, and KRAS – were found almost exclusively in heavy smokers, investigators reported in a session and related press briefing. Also, the number of HPV reads detected in tumors was lower for heavy smokers as compared with light smokers.
Taken together, the findings suggest that although HPV-positive cancers in heavy smokers may be initiated through virus-related mutations, they go on to acquire tobacco-related mutations and become less dependent on the E6/E7 carcinogenesis mechanisms typically associated with the virus, said first author Dr. Jose P. Zevallos of the University of North Carolina, Chapel Hill.
“We think that this study and future studies based on this work will have important implications for personalizing treatment and decision making in HPV-positive oropharynx cancer, particularly in the era of less aggressive treatments for HPV-positive tumors because of their excellent prognosis,” he said. “As opposed to arbitrarily deciding that 10 pack-years [of smoking] is a number that we use to define more aggressive disease, we are trying to provide a molecular basis for more aggressive disease in order to decide who will benefit from less-aggressive versus more-aggressive treatment.”
Press briefing moderator Dr. Christine Gourin of Johns Hopkins University, Baltimore, said “This study is so important because we know that the molecular fingerprint of HPV-related oropharyngeal cancer is really different from anything that we have seen before – different patient population, different outcomes than when I was in training.”
“We don’t really understand fully why this fingerprint is so different and why tobacco affects the fingerprint,” she added. “The finding of differences in the molecular phenotypes of light smokers versus heavy smokers is something that we all appreciate clinically and we need to understand better to tailor treatment.”
Introducing the study, Dr. Zevallos noted that the HPV-positive cancers of smokers are known to have prognosis intermediate between those of the more favorable HPV-positive cancers of never smokers and the less favorable HPV-negative cancers. What remains unclear is the molecular basis for these differences.
Patients came from the population-based CHANCE (Carolina Head and Neck Cancer Epidemiology) study conducted during 2001-2006. The investigators performed targeted next-generation DNA sequencing in tumors with an assay for more than 700 genes associated with human cancers.
“We focused our attention on genes that overlap with those in COSMIC [the Catalogue of Somatic Mutations in Cancer] as well as on TCGA [The Cancer Genome Atlas] genes that were demonstrated to be significant in head and neck cancer,” Dr. Zevallos explained.
All 66 patients studied had HPV-positive tumors according to p16 expression or HPV polymerase chain reaction findings. Overall, 61% were heavy smokers, defined as having a greater than 10 pack-year history of smoking.
In terms of clinical outcome, the 5-year overall survival rate was 82% among the heavy smokers and 60% among the light or never smokers.
Mutations associated with tobacco use were found almost exclusively in the heavy smokers, Dr. Zevallos reported. For example, they had higher prevalences of mutations in NOTCH1 (18% vs. 0%), FAT1 (14% vs. 6%), and FGFR3 (10% vs. 0%), among others. On the other hand, the light and never smokers had a higher prevalence of mutations in PIK3CA (50% vs. 34%). Additionally, KRAS mutations were found only in the heavy smokers (4% vs. 0%), whereas HRAS mutations were found in the light and never smokers only (6% vs. 0%).
A pathway analysis incorporating the new information for HPV-positive heavy smokers confirmed that despite persistence of the HPV-related signature, these tumors also had signaling in several of the pathways typically associated with HPV-negative cancers, according to Dr. Zevallos.
HPV DNA was detected in all of the tumors, and in 95% of cases, the viral type was type 16. However, PCR for HPV was falsely negative in 9%. “This is a very important number as we rely on this as a surrogate for HPV status,” he commented. “p16 was the main inclusion criterion for this particular study, but this should be noted.”
Heavy smokers and patients who had died had a lower number of HPV reads per tumor. “This tells us that there are potentially subclones developing in these patients that are driven by tobacco-associated mutations, and this may explain worse outcomes in this patient population and warrants further exploration,” Dr. Zevallos elaborated.