HPV Infection Drives Disparity in Head and Neck Cancer Survival
These CT scans show an HPV-positive tonsil cancer in a patient with no history of tobacco or alcohol use. The arrow in the left panel points to the swollen tonsil with the primary tumor. Arrows in the right panel point to cancerous lymph nodes on both sides of the neck. The patient went into complete remission following concomitant chemotherapy and radiation. Click to enlarge
A new study provides what researchers are calling a “missing link” that helps to explain why black patients with head and neck cancer live significantly shorter after treatment than white patients. Unlike several other cancers, where racial disparities in outcomes have been attributed in large part to socioeconomic factors, this new study points directly at a biological difference: infection rates of human papillomavirus type 16 (HPV 16).
The study, published July 29 in Cancer Prevention Research, is the latest to show that head and neck cancer patients, particularly those with cancer of the oropharynx, who are HPV 16-positive have superior outcomes with standard treatment (concurrent chemotherapy and radiation) compared with those who are HPV 16-negative. But this study is the first to show that black patients with head and neck cancer have dramatically lower rates of HPV infection than white patients and that HPV status directly correlates with the significant survival disparities between the two patient groups.
The finding that so few black patients are HPV positive “in a completely statistical sense explains why historically we have seen that black patients [with head and neck cancer] do poorly,” said Dr. Kevin J. Cullen, the study’s senior author and director of the University of Maryland (UMD) Marlene and Stewart Greenebaum Cancer Center.
The researchers performed a retrospective analysis of data from 95 black and 106 white patients with similar stages of head and neck cancer who received similar treatments at the Greenebaum Cancer Center, and a prospective analysis of 224 patients for whom HPV status could be determined in the recent randomized clinical trial TAX 324. In the prospective study, the majority of the patients (196) were white.
Both analyses showed that black patients with head and neck cancer fared far worse than white patients, but this difference was driven primarily by the outcomes for patients with oropharyngeal cancer. For example, explained Dr. Cullen during a press briefing, while there was a nearly twofold difference in overall survival between black and white patients in the cohort treated at UMD, it was entirely due to the threefold difference in survival between black and white patients with oropharyngeal cancer, 70 months versus 25 months. Patients with cancers at other sites in the head and neck, such as the larynx and hypopharynx, had identical survival regardless of race.
“Frankly, we were shocked to see that within our own institution, where half of the patients we treat are African Americans, that that difference existed,” Dr. Cullen said.
Explaining the Discrepancy in HPV Rates
In an accompanying editorial in Cancer Prevention Research, Dr. Otis Brawley, chief medical officer of the American Cancer Society, suggested that differences in sexual practices between young blacks and whites may explain, at least in part, the different rates of oral HPV infections. Dr. Brawley cited a study published earlier this year linking oral HPV infections with oral sex and survey data showing that white males and females were more likely to have engaged in oral sex than their black counterparts.
Dr. Brawley said during the press briefing that “the changing sexual practices over the last 20 years, especially as it relates to oral sex, are increasing rates of head and neck cancer, and may be increasing rates of other cancers, as well.”
Dr. Kreimer agreed that changing sexual practices clearly play an integral role in HPV infection rates and cancer incidence in the oropharynx and possibly other anatomical sites. But it’s important, she stressed, not to lose sight that tobacco and alcohol use remain the primary risk factors for other head and neck tumors.
The analysis of the TAX 324 trial revealed a similar survival disparity. But the research team then took the investigation a step further and showed that the disparity was explained entirely by HPV status. In the overall analysis, 34 percent of the 196 white patients were HPV positive, including approximately half of patients with oropharyngeal cancer. In contrast, just 1 of the 28 black patients was HPV positive. Patients who were HPV positive had a fivefold improvement in overall survival compared with HPV-negative patients.
HPV status was clearly the distinguishing factor. “When you subtracted out the HPV-positive white patients, the rest of the patients—the black and white patients—behaved identically,” Dr. Cullen stressed.
Dr. Aimee Kreimer, an investigator in NCI’s Division of Cancer Epidemiology and Genetics, said the study provides “very important data that might explain previously observed survival differences by race.” She cautioned, however, that replication of these initial findings would be important, since the study included only a modest number of black patients with HPV results. “Replication efforts should pay close attention to other known prognostic factors such as disease stage,” Dr. Kreimer noted.
The study does confirm that HPV-positive and HPV-negative oropharyngeal cancers have a distinct biology and natural history, and, as a result, require different treatments, said Dr. Scott Lippman, chair of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M. D. Anderson Cancer Center, during the press briefing.
Identifying these differences is particularly important, Dr. Lippman continued, because of oropharyngeal cancer’s rapidly increasing incidence (while rates of cancer at other sites in the head and neck are generally declining). Among head and neck cancer experts, he noted, there is “a real sense that the data are starting to show that we’re on the cusp of an epidemic of this disease.”
There is broad agreement among researchers that HPV infection is the major driver behind this trend, with as many as 70 percent of cases now being HPV-related, Dr. Lippman said. (See sidebar.) This is far different than it was just 20 years ago, when such cancers were less common and typically were more often related to heavy tobacco and alcohol use.
Exactly why HPV-positive cancers are so much more amenable to chemotherapy and radiation is unclear, Dr. Cullen said. His group at UMD, however, will publish a paper soon in which they show that HPV-positive cancers have a lower expression of genes linked to chemotherapy and radiation therapy resistance.
Clinical trials have been designed that stratify patients by their HPV status or will enroll patients based on their HPV status, Dr. Lippman said. For HPV-positive patients, they will assess whether patients can do just as well with lower chemotherapy and radiation doses. For HPV-negative patients, they will look at whether more aggressive treatments can improve outcomes.
The findings with regard to the role of HPV in head and neck cancer, Dr. Cullen said, should also cause those in the field to rethink some of the improvements in outcomes that have been seen over the past decade with chemotherapy and radiation. Those improvements may have had a lot to do with “a patient population that was shifting” toward HPV-positive patients, who are more likely to respond to those treatments.
HPV’s role in head and neck cancer, Dr. Cullen stressed, is rapidly changing the field. “Just in the month or so since we completed this study,” he said, “it’s changing the way I see patients in my clinic.”