Biomarkers Linked to Therapy Response, Survival in Oropharyngeal Cancers

A new study finds that epidermal growth factor receptor (EGFR), human papillomavirus (HPV) status, sex, and smoking are markers for response to therapy and overall survival in patients with oropharyngeal cancer.

“We participated in a study starting in the late 1980s to determine if radiation and chemotherapy could be used as an alternative to surgery for larynx cancer,” says Thomas Carey, PhD, professor of pharmacology and cell biology in the Departments of Otolaryngology and Pharmacology at the University of Michigan in Ann Arbor. “Looking at survival rates, there was a drop off in both arms. It occurred to me that since both arms worked, there were probably some [patients] getting chemotherapy who would have benefited from radiation and surgery, and vice versa.”

Carey and his colleagues included 66 patients with stage III and IV squamous cell carcinoma of oropharynx (SCCOP) in their most recent study. In 50 patients, pretreatment biopsies were available for study of biomarkers. These were examined for expression of EGFR, the p16 protein as a surrogate for HPV infection, the p53 gene, and Bcl-extra long (BCL-xL) expression. In addition, response to therapy, survival data, and smoking histories were obtained.

“We wanted to look at biomarkers to see if they could help us tell which patients were going to respond to chemotherapy and which were not,” says Carey. “For example, the p53 gene is known to be important in causing programmed cell death when DNA damage occurs. Thus, tumors with intact p53 were expected to respond the best to induction chemotherapy.”

However, the researchers observed that more patients with intact p53 required laryngectomy for non-response to chemotherapy. They also found that overexpression of the anti-apoptotic protein BCL-xL, in combination with a functioning p53 gene, actually protected tumors from cisplatin and 5FU. With these two markers, p53 status and BCL-xL expression in pretreatment biopsies, they could identify three categories of response to therapy.

The lowest risk tumors had intact p53 but low BCL-xL. These responded well to therapy, presumably because p53 could induce tumor cells to undergo programmed cell death upon treatment. No patient with this marker profile had a laryngectomy for persistent tumor. High-risk patients had functional p53 in their tumor cells and high BCL-xL expression. Of these, 54% required laryngectomy for persistent tumor. An intermediate risk group with mutant p53 and either low or high BCL-xL had a 76% larynx preservation rate.

Oropharynx cancer patients also fell into low, intermediate, and high-risk groups based on p53 and BCL-xL expression. Only one patient with the low risk phenotype died of a late recurrence. All but one patient with the high-risk phenotype died of their tumors.

In contrast, EGFR expression was inversely associated with response to induction chemotherapy (IC), chemo/radiotherapy (CRT), overall survival (OS), disease-specific survival (DSS), and was directly associated with current smoking, female gender, and lower HPV titer. HPV titer was significantly associated with p16 expression, which in turn was significantly associated with response to IC, CRT, and both survival measures. When combined, lower HPV titer and higher EGFR expression was tied to lower survival. Low p53 and high Bcl-xL expression was linked to poorer OS and DSS.

“There is an epidemic of oropharyngeal cancers caused by the same high-risk human papilloma viruses (HPV) that result in cervical, penile, and anal cancers,” said Dr. Carey. “The presence of high HPV copy numbers in oropharynx tumors in our and other studies is associated with good response to therapy and prolonged survival.”

Prediction of outcomes is an important piece of information when treating any kind of cancer, according to Joseph Califano, MD, professor in the Department of Otolaryngology at Johns Hopkins University School of Medicine in Baltimore.

“We have known for 10 years that the presence of HPV and high EGFR expression are independently associated with improved survival response to combined chemo/radiation therapy,” Califano says. “This confirms [that HPV and high EGFR expression] have an effect when added together as well. Also, everyone in this series got the same treatment, so you are less worried about possible confounding effects.”

There are two major pieces of information to take from this study, says Wendell Yarbrough, MD, associate professor of otolaryngology and cancer biology at Vanderbilt University in Nashville, TN. One is that current smokers have worse outcomes, making smoking cessation a very important part of treatment.

“It is well established that HPV status is becoming a very important prognostic indicator in patients with oropharyngeal cancer,” he continues. “The more information we can give our patients, the better they understand and appreciate their disease process. Even in the poor prognosis group, it is important that they understand that as well.”

Dr. Yarbrough also stresses that there is currently not enough data available to suggest changes in therapy based on HPV measures. Trials addressing that question are currently ongoing.

All three experts agree that with the release of tyrosine kinase inhibitors such as gefitinib (Iressa®, AstraZeneca, Wilmington, DE) and erlotinib (Tarceva^®, OSI Pharmaceuticals Inc, Melville, NY), and the monoclonal antibody cetuximab (Erbitux® Bristol-Myers Squibb Company, Princeton, N.J.) inhibition of EGFR is possible as a therapeutic intervention. They also agree that even with the results of this study, there is not yet clear guidance available.

“While this study does not directly address this issue, it does give us a tantalizing suggestion given that those with high EGFR do worse,” says Dr. Yarbrough. “Will these be tumors that respond to inhibition of this pathway? That is an interesting question raised, but not answered, in this article.”