Oropharyngeal cancer biology and treatment: insights from messenger RNA sequence analysis and transoral robotic surgery.

Tobacco and alcohol abuse have long been recognized as traditional risk factors for the development of oropharyngeal squamous cell carcinoma (OPSCC).1,2 However, recent data have confirmed that human papillomavirus (HPV) infection has become the most common cause of oropharyngeal carcinoma in Europe and the United States.2 Patients with HPV-associated oropharyngeal carcinoma typically present at a younger age and often do not have the traditional risk factors of tobacco or alcohol abuse.2 The treatment options for the management of tonsillar and base-of-tongue cancer include open surgery or high-dose radiotherapy with concomitant systemic chemotherapy. Clinical and experimental studies clearly indicate that HPV-positive vs HPV-negative OPSCC combined with the other risk factors define different disease subgroups in terms of both biology and the manner in which these subclasses of tumors respond to treatment. Insight into the genetics and epigenetics of these tumors will clearly improve our understanding of their responses to therapy and the identification of new treatment strategies. In this issue of Mayo Clinic Proceedings, 2 original articles address the problem of oropharyngeal cancer. Moore et al3 evaluate the use of a minimally invasive surgery technique known as transoral robotic surgery (TORS)4 for the management of HPV-positive OPSCC. Laborde et al5 evaluate state-of-the-art messenger RNA (mRNA) sequencing technology to gain insight into the role of gene expression in distinguishing and driving subclasses of OPSCC. The data of Moore et al support the role of minimally invasive surgery for the management of HPV-associated oropharyngeal carcinoma. TORS provides a minimally invasive approach that is associated with significantly less morbidity and a reduced hospital stay than those associated with open surgery.4 Moore et al also demonstrate that patients with TORS can be treated effectively with a reduced dose of external beam radiotherapy and, in many cases, do not require systemic chemotherapy. This finding is important because the dose of therapy is directly associated with the risk of complications and permanent functional deficits. In addition to superior oncologic outcomes, Moore et al report that patients with oropharyngeal carcinoma can be treated effectively with minimal functional compromise. This finding is especially important given that this patient population is relatively young. The long-term impact of external beam radiotherapy has been well documented. The opportunity to reduce therapy, improve functional outcome, and improve oncologic outcomes (when compared with other treatments) demonstrates progress. Advances such as the one identified by Moore et al are greatly welcomed because, until recently, there has been minimal incremental progress in the treatment of oropharyngeal carcinoma. Finally, Moore et al have established that TORS provides a means to obtain tumor tissue that can be used to guide therapy. All squamous cell carcinomas are not equal. The ability to acquire tumor specimens for analysis allows us to prognosticate and direct therapy. More aggressive tumors may require multimodality therapy, whereas less aggressive tumors may be treated with surgery alone or, in some cases, a reduced dose of adjuvant radiotherapy. Moore et al report that important prognosticators, such as extracapsular spread, perineural invasion, and lymphovascular invasion, could be used to personalize therapy. On the other end of the spectrum, investigators are probing the molecular basis of OPSCC.6-8 Advances in mRNA analysis and whole-genome sequencing are rapidly creating an opportunity to provide personalized information on the genetic and gene expression makeup of individual tumors. It is anticipated that these advances will help reduce disease risk in patients who do not already have evidence of OPSCC and guide therapy in those who do. In their article in the current issue of the Proceedings, Laborde et al5 describe the use of mRNA massive parallel sequencing technology to perform expression profiling of 9 types of OPSCC tumors vs matched normal tissue covering the spectrum of HPV-positive and HPV-negative tumors derived from never, former, and current smokers. This analysis provides interesting insights into the global gene expression patterns of these patients and reveals an unexpected similarity between the profiles from former and never smokers. Indeed, these 2 subgroups clustered away from the tumors from current smokers, as determined by hierarchical clustering and principal component analysis. The investigators propose that patients who cease smoking for more than 10 years show a reversible pattern in gene expression, and any OPSCC tumors more closely resemble those of nonsmokers. These data suggest that epigenetic mechanisms most likely drive major changes in gene expression and the OPSCC phenotype associated with smoking history. As acknowledged by the authors, their study did not probe into genetic rearrangements or mutation analysis. As such, their analysis cannot offer insights into whether these clinical subgroups of current and former smokers have similar or dissimilar genetic alterations. In the future, determining the genetic makeup of these tumors may guide novel therapy designs tailored for former smokers, and it also may provide valuable information on the dominance of genetic vs epigenetic mechanisms in driving the biology of these subgroups of tumors. The additional analysis by Laborde et al showed a trend in the expression of p53 gene pathway components associated with HPV-negative current smokers when compared with those of past smokers or nonsmokers. Although the mRNA massive parallel sequencing data did not provide a statistically significant association (perhaps because of the small number of patient samples sequenced), a more focused analysis of p53 pathway genes in a larger cohort of patients determined that there indeed are significant changes in the gene expression levels of the DNA damage and repair machinery genes ATR and CHK2. These 2 genes were significantly upregulated in the current smoker group vs never and former smokers. This finding again suggests that the upregulation of these genes is reversible and possibly driven by tobacco exposure. Further studies might reveal whether specific mutations affect this pathway in these subgroups. Finally, the authors analyzed the expression of ATR and CHK2 in both HPV-positive and HPV-negative individuals in the smoker vs nonsmoker groups. These data revealed that the 2 genes (and primarily CHK2) are not differentially regulated in the HPV-positive subgroup, even if the patients are smokers. This finding is the opposite of that from the HPV-negative subgroup, in which there is a significant increase in the expression of both ATR and CHK2 in the smoker vs nonsmoker groups. These data add to the growing evidence that HPV-positive and HPV-negative tumors are mechanistically different. This difference may be due to the dependence of the HPV-positive tumor cells on the viral genome/proteome driving their biology; the HPV-negative tumors develop a different genetic and epigenetic landscape. Studies like the one by Laborde et al add to a growing body of knowledge from other groups engaged in genetically and epigenetically profiling OPSCC tumors.6-8 Previous data from conventional expression profiling of head and neck squamous cell cancer have provided potential guidance on treatment modalities or decision making and have also converged on the identification of pathways such as p53 as key to the development and possibly maintenance of these tumors.7,8 Furthermore, studies such as these not only will surely shed light on the mechanisms of OPSCC progression but also may identify novel targets that will allow tailoring therapies for specific patients. Studies such as those of Moore et al and Laborde et al demonstrate that combined advances in surgical and tumor profiling technologies are changing the way we treat OPSCC. With the increased ability and decreasing costs of mRNA massive parallel sequencing analysis of patient samples, we appear much closer to someday personalizing the treatment of OPSCC based on the genetic and epigenetic makeup of each tumor.