Comparison of PI3K Pathway in HPV‐Associated Oropharyngeal Cancer With and Without Tobacco Exposure

Abstract

ObjectivesThe aim of the study was to evaluate whether HPV associated OPSCC with tobacco exposure follows a different carcinogenic pathway compared to HPV associated OPSCC without tobacco exposure and to investigate its prognostic significance. The question was addressed with focus on components of the PI3K pathway.Methods184 patients with newly diagnosed OPSCC treated with curative intent were consecutively enrolled. The expression level of p16, p53, PI3K, mTOR, and PTEN was assessed by immunohistochemistry and analyzed in relation to the risk factors HPV status and tobacco exposure.Results94 of 184 (51%) patients were p16 positive, p53 overexpression was detected in 48 of 184 (26%) cases. PI3K overexpression with 70 of 184 (38%) cases was significantly higher in p16 positive tumors. mTOR overexpression was present in 90 of 184 (49%) cases and significantly higher in p16 negative tumors. PTEN loss was found in 42 of 184 (23%) cases without association to p16 expression. p16 positive OPSCC showed lower rates of p53 expression and mTOR expression as well as higher rates of PI3K expression irrespective of tobacco exposure. Survival analysis showed a distinct intermediate survival rate of p16 positive smokers. The markers PI3K, mTOR, and PTEN did not have a significant impact on survival.ConclusionHPV associated OPSCC with tobacco exposure follows the same expression level of the PI3K pathway as HPV associated OPSCC without tobacco exposure. The impaired survival rate of the intermediate risk group cannot be explained by different expression patterns of PI3K, mTOR, and PTEN.Level of Evidence2b

Association of Nonsteroidal Anti-inflammatory Drug Use With Survival in Patients With Squamous Cell Carcinoma of the Head and Neck Treated With Chemoradiation Therapy

“…1,2 HPV-associated tumors more frequently have phosphoinositide 3-kinase (PI3K) gene variations independent of tobacco exposure. 3,4 By exploiting this oncogenic addiction phenotype, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been identified as potential chemotherapeutic agents owing to the effect they have on cyclooxygenase inhibition, which is required for prostaglandin synthesis. 5 Concurrent use of NSAIDs has been shown to be associated with a survival advantage for colorectal cancer and a wide range of cancer histologies.…”

Prognostic significance of MTOR expression in HPV positive and negative head and neck cancers treated by chemoradiation

“…The continued development of targeted agents against this signaling pathway highlights the need to study the prognostic significance of MTOR pathway activation. For patients with HNSCC, there have been several studies examining this question that have resulted in inconsistent findings although the majority of investigations indicate that overexpression of MTOR is associated with poorer prognosis. As HPV+ and HPV− tumors have a different mutational spectrum, we have specifically asked the question whether MTOR expression differed between the subtypes and whether it was associated with prognosis.…”

EGFR/PI3K/Akt/mTOR pathway in head and neck squamous cell carcinoma patients with different HPV status

“…Similar to us, Kiessling et al [47] in 184 patients with oropharyngeal SCC did not report significant influence of mTOR expression on survival, however, contrary to us, they found significantly higher incidence of mTOR overexpression among p16 negative tumors. In turn, some authors, in the groups of patients with oropharyngeal cancers [48,49], have reported opposite results, i.e. inferior survival for patients with tumors overexpressing mTOR.…”

“…This protein is a surrogate marker of HPV presence and its use is related to risk of false positive results obtainment. On the other hand, taking into account the possibility of treatment with mTOR inhibitors, such as everolimus [48] or rapamycin [50] in HNSCC patients, the question about mutual relation between HPV infection and mTOR expression requires further studies.…”