New Markers Predict Progression in Oral Cancer

Roxanne Nelson

August 21, 2012

August 21, 2012 — Researchers have made a possible breakthrough that could help curtail the rising incidence of oral cancer. A group of molecular markers has been identified that can differentiate which oral premalignant lesions have a high risk for progression to cancer.

"The results of our study should help to build awareness that not everyone with a low-grade oral premalignant lesion will progress to cancer," said Miriam Rosin, PhD, director of the Oral Cancer Prevention Program at the BC Cancer Agency in Vancouver, British Columbia, Canada. "They should also begin to give clinicians a better idea of which patients need closer follow-up."

The prospective cohort study, published online August 21 in Cancer Prevention Research, is the largest longitudinal study of low-grade oral premalignant lesions from a population-based patient group. It confirms previously reported data and provides the first validated molecular model to differentiate low-grade oral dysplasia at low risk for progression from lesions at greater risk, the researchers note.

Dr. Rosin and colleagues found that intermediate-risk groups had an 11.6-fold increased risk for progression and that high-risk groups had a 52.1-fold increased risk (P < .001), compared with the low-risk group.

Only 3.1% of the low-risk group had lesions that progressed to cancer within 5 years. Conversely, 16.3% of the intermediate-risk group progressed within 5 years, as did 63.1% of the high-risk group.

"The importance of this study is that it provides a definitive validation of the markers so they can be used clinically," Dr. Rosin told Medscape Medical News.

Loss of Heterozygosity

Previous research conducted by the same group showed that "loss of heterozygosity" (LOH) at chromosomes 3p and 9p occurs at a high rate of frequency in oral dysplasia and squamous cell carcinoma of the head and neck (Clin Cancer Res. 2000;6:357-362). That retrospective analysis showed that there was a greater than 20-fold increase in risk for progression for lesions with LOH at chromosomes 3p and/or 9p, compared with lesions with no LOH at these regions.

"The LOH assessment tool is at this point a research tool," said Dr. Rosin. "One of our goals is to look for ways to bring it to dental clinics.

In an accompanying editorial, Webster K. Cavenee, PhD, from the Ludwig Institute for Cancer Research, University of California, San Diego, points out that almost 3 decades have passed since chromosomal mechanisms were described that "unmasked the inactivating, recessive mutations in human cancer that had been theoretically predicted a decade before."

This group of mechanisms was called LOH because the data showed that "specific regions of a patient's normal genome that were biallelic could become monoallelic in their tumors," he writes.

LOH provides direct genetic proof that this type of tumor-suppressor gene mutation could cause predisposition to a malignancy, he writes.

This represents a major advance for a decades-old idea.

"These extraordinarily well-done and well-analyzed studies underscore the use of LOH in community-based risk assessment and, perhaps, in patient therapeutic and prevention stratification schemes," Dr. Cavenee explains. "As such, this represents a major advance for a decades-old idea that has been waiting for such a test."

Dr. Cavenee adds that LOH markers are being used to stratify patients with oral cancer for treatment with epidermal growth-factor receptor (EGFR) inhibitors in phase 2 trials and to define eligibility for EGFR inhibitor treatment in the phase 3 Erlotinib Prevention of Oral Cancer (EPOC) trial.

Lingering Questions

In another editorial, Mark W. Lingen, DDS, PhD, from the University of Chicago in Illinois, and Eva Szabo, MD, from the National Cancer institute in Bethesda, Maryland, note that this study clearly establishes low-risk and high-risk categories, which can help guide the care of patients.

It has direct implications for standard care in the community setting.

"It has direct implications for standard care in the community setting, identifying low-risk individuals who are not in need of aggressive monitoring or treatment," Drs. Lingen and Szabo write. "It also has the potential to enrich prevention and screening trials with the highest-risk populations...most likely to benefit from intervention."

However, the study raises questions, Drs. Lingen and Szabo note. One is what to do about patients with low- and intermediate-risk lesions that progress and show changes in the LOH profile that resemble lesions in the high-risk category.

Another is what to do with patients with oral premalignant lesions who present with multiple lesions or develop new lesions over time. "It will be of interest to determine the relationship between the LOH profile and the risk of multiple or new lesions as well as the profile's relationship with progression in these 'secondary' lesions," they write.

The predictive potential of the LOH profile will need to be investigated in the setting of squamous cell carcinoma of the head and neck because a significant percentage of patients with oral dysplasia have a history of this cancer, Drs. Lingen and Szabo note.

In addition, "not all loci of LOH have the same prognostic impact, suggesting that specific losses may be integral to carcinogenic progression," they write.

HPV Role Unclear

The main reasons for the increasing incidence of oropharyngeal squamous cell carcinoma are chronic exposure to tobacco and alcohol and infection with certain high-risk subtypes of the human papillomavirus (HPV). Although smoking and alcohol use have been the primary established risk factors for head and neck cancers, some data suggest that HPV infection is the strongest risk factor for oropharyngeal cancer.

Unfortunately, very little is known about the role of HPV in premalignant lesions, Dr. Rosin explained. Whether smoking and alcohol use and HPV are independent pathways to disease progression or whether they interact to produce risk is not clear.

The data for the tonsil area, in the back of the mouth and throat, are very compelling for the existence of 2 independent pathways that can also interact, Dr. Rosin noted. However, the sites at the front of the mouth (the oral cavity) are less well understood, she said. "We are now working to determine the HPV status of the different categories of lesions in this study to determine the prevalence of such infection and whether it has biologic and clinical consequences," she explained.

Data Validated, Some Differences

In their prospective study, Dr. Rosin and colleagues analyzed 296 patients with primary mild/moderate oral dysplasia who were enrolled in the Oral Cancer Prediction Longitudinal Study from January 1, 1997 to December 31, 2007. Study participants were classified as having a high-risk or low-risk profile to validate the model developed using the retrospective cohort.

Median follow-up time was 44.6 months. During the study period, 41 (13.9%) cases progressed — 17 to severe dysplasia, 2 to carcinoma in situ, and 22 to squamous cell carcinoma.

Disease progression was associated with smoking status and lesion site, but not with variables such as sex, age, race, and histologic diagnosis at study entry. On univariate analysis, the researchers noted that lesions from never-smokers had a 2.1-fold increased risk, compared with former and current smokers (95% confidence interval [CI], 1.1 to 3.9; P = .02).

Even though oral cancer and leukoplakia occur mostly in smokers, some studies have shown that when leukoplakia occurs in nonsmokers, they are at higher risk for cancer progression, the researchers report.

Lesions from high-risk sites, such as the tongue and floor of the mouth, had a 3.2-fold increased risk, compared with other oral sites (95% CI, 1. 5 to 6.7; P = .002).

The researchers found that only 1 of every 100 lesions with the low-risk pattern progressed, whereas 39 of 40 lesions with the high-risk pattern progressed. High-risk lesions were also associated with a 22.6-fold increased risk for progression (P = .002).

The researchers explain that these findings are similar to what was observed with the previous retrospective cohort.

There were some differences between the current prospective and previous retrospective cohorts. In the prospective cohort, LOH at chromosome 3p was not a significant predictor for progression by itself (hazard ratio [HR], 1.3; P = .48), but LOH at 9p showed a strong association with progression in the prospective cohort (HR, 17.0; P < .001) and the retrospective cohort (HR, 3.8; P = .002).

In addition, chromosomes 4q and 17p were identified as markers for improving risk prediction when used in conjunction with 9p.

The study was funded by grants from the National Institutes of Health and the National Institute of Dental and Craniofacial Research. The authors and editorialists have disclosed no relevant financial relationships.

Cancer Prev Res. Published online August 21, 2012. Abstract, Cavenee Editorial, Lingen and Szabo Editorial


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