Meta analysis: HPV and p16 pattern determines survival in patients with HNSCC and identifies potential new biologic subtype

Abstract

Consistent discrepancies in the p16/HPV-positivity have been observed in head and neck squamous cell carcinoma (HNSCC). It is therefore questionable, if all HPV+ and/or p16+ tested cancers are HPV-driven. Patients down-staged according to the HPV-dependant TNM are at risk for undertreatment and data in clinical trials may be skewed due to false patient inclusion. We performed a meta-analysis to classify clinical outcomes of the distinct subgroups with combined p16 and HPV detection. 25 out of 1677 publications fulfilled the inclusion criteria. The proportion of the subgroups was 35.6% for HPV+/p16+, 50.4% for HPV−/p16−, 6.7% for HPV−/p16+ and 7.3% for HPV+/P16−. The HPV+/p16+ subgroup had a significantly improved 5-year overall-survival (OS) and disease-free-survival in comparison to others both for HNSCC and oropharyngeal cancers. The 5-year OS of the HPV−/p16+ HNSCC was intermediate while HPV+/p16− and HPV−/p16− had the shortest survival outcomes. The clearly distinct survival of HPV−/p16+ cancers may characterize a new relevant HPV-independent subtype yet to be biologically characterized. The possibility also exists that in some HPV+/p16+ cancers HPV is an innocent bystander and p16 is independently positive. Therefore, in perspective, HPV-testing should distinguish between bystander HPV and truly HPV-driven cancers to avoid potential undertreatment in HPV+ but non-HPV-driven HNSCC.

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…Among the key prognostic markers for survival, epidermal growth factor receptor (EGFR), cyclin D1(CCND1), ERCC1, p16, human papillomavirus (HPV), and B‐cell lymphoma‐extra large (Bcl‐xL)/Bcl‐2, as well as the amplification of genes including EMS1 , FGFR1 , and CCND1 have demonstrated some evidence in clinical trials. Others are slower to advance in clinical development because of unconvincing data and few published studies; for example, acetylcholinesterase(AchE), SNPs of specific genes, glutathione S‐transferase (GST), CD44, amplification of specific genes, hypoxic markers, KLK‐6, and MDA‐7/IL‐24; although, this does not preclude them from future investigations and clinical utility.…”

“…p53 is frequently inactivated in HNSCC, and dysregulation of the RB gene is increased by the expression of p16 . When testing for p16 and HPV, the two tests are not always concordance with each other (around 81.0%‐94.6%) . It has been suggested that performing combination testing of p16 and HPV status together may improve prognostic accuracy …”

“…97 When testing for p16 and HPV, the two tests are not always concordance with each other (around 81.0%-94.6%). 39,82,[104][105][106][107] It has been suggested that performing combination testing of p16 and HPV status together may improve prognostic accuracy. 108,109 p16 also has predictive value with regard to HNSCC outcomes with various specific treatments.…”

Competing mortality in oropharyngeal carcinoma according to human papillomavirus status

“…There is strong evidence that patients with HPV‐positive OPC have a better cancer‐specific survival regardless of the treatment modality received . However, few studies have analyzed the competing causes of death in patients with OPC depending on the HPV status …”

“…6,7 There is strong evidence that patients with HPV-positive OPC have a better cancer-specific survival regardless of the treatment modality received. [8][9][10][11] However, few studies have analyzed the competing causes of death in patients with OPC depending on the HPV status. 12 The objective of the present study is to analyze the overall survival of the patients with OPC and to assess differences in the competing causes of death depending on HPV status.…”