Prognostic Significance of HPV DNA and p16 <sup>INK4a</sup> in Anal Cancer: A Systematic Review and Meta-Analysis

Abstract

Background: Human papillomavirus (HPV) DNA and p16INK4a are prognostic markers in several HPV-related cancers. We conducted a systematic review and meta-analysis of observational studies evaluating survival in anal cancer patients, according to HPV DNA, p16INK4a, and combined HPV DNA/p16INK4a status. Methods: In this systematic review and meta-analysis we searched PubMed, EMBASE, and Cochrane Library databases to identify studies published in English until July 25th 2018, directly providing or allowing estimation of survival of anal cancer patients according to presence of HPV DNA and/or overexpression of p16INK4a. We extracted information on overall survival (OS), disease-specific survival, and progression- or disease-free survival. We pooled published hazard ratios (HRs) and 95% confidence intervals (CIs) for OS using a random-effects model. I2 statistic described heterogeneity. Results: We included 16 studies, which comprised 1724 anal cancer patients tested for HPV DNA (65% positive), and 567 patients tested for p16INK4a (87% positive). The pooled HR for OS was 0·54 (95% CI 0·33 - 0·89) for HPV DNA-positive versus negative, 0·37 (95 % CI 0·24 - 0·57) for p16INK4apositive versus -negative, and 0·36 (95% CI 0·22 - 0·58) for HPV DNApositive/p16INK4a-positive versus HPV DNA-positive/p16INK4a-negative anal cancer patients. Interpretation: Patients with HPV DNA- or p16INK4a - positive anal cancer have significantly better OS compared to HPV DNA- or p16INK4a - negative. This points to the possible value of HPV DNA and/or p16INK4a testing when planning the individual management and follow-up strategy for patients diagnosed with anal cancer. Funding Statement: The authors stated: There was no funding source obtained specifically for this study. Declaration of Interests: SKK has received scientific advisory board and lecture fee from Merck, and research grant through the affiliating institute from Merck. Sciensano (employer of MA) collaborated with the University of Ghent to conduct the SEHIB (Surveillance of Effects of HPV Immunization in Belgium) study, funded by Sanofi-Pasteur MSD. ESP has received lecture fee from MSD SHARP & DOHME GmbH. AU, CLR, FB, TO, and FV declare no conflict of interest. Ethics Approval Statement: The authors used “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines to outline this study.