TY - JOUR
T1 - Prognostic value of high-risk human papillomavirus DNA and p16INK4a immunohistochemistry in patients with anal cancer: An individual patient data meta-analysis
AU - Obermueller, Theresa
AU - Hautekiet, Joris
AU - Busto, Maria P.
AU - Reynders, Dries
AU - Belgioia, Liliana
AU - Cats, Annemieke
AU - Gilbert, Duncan C.
AU - Koerber, Stefan A.
AU - Mai, Sabine
AU - Meulendijks, Didier
AU - Rödel, Franz
AU - Yhim, Ho Young
AU - Hetjens, Svetlana
AU - Weiß, Christel
AU - Rasmussen, Christina L.
AU - Urbute, Aivara
AU - Verdoodt, Freija
AU - Kjaer, Susanne K.
AU - Reuschenbach, Miriam
AU - Goetghebeur, Els
AU - von Knebel Doeberitz, Magnus
AU - Arbyn, Marc
AU - Prigge, Elena Sophie
N1 - Funding Information:
M.A. was supported by the Horizon 2020 Framework Programme for Research and Innovation of the European Commission, through the RISCC Network (grant no. 847845), and the Belgian Foundation Against Cancer through the IHUVAC project. The funding sources had no role in study design, collection, analysis and interpretation of data.S.A.K. received grants from ViewRay Inc. and honoraria from IBA Dosimetry, outside the submitted work. S.K.K. has previously received speaker fee from Merck and a research grant through her institution from Merck outside the submitted work. D.M. is an employee and shareholder of AstraZeneca Ltd., UK. E-S.P. has received lecture fees by MSD Sharp & Dohme GmbH and Institut f?r Frauengesundheit (IFG) GmbH. E-S.P. is involved in a research project funded by MSD Sharp & Dohme GmbH outside the submitted work. M.R. is an inventor of patent applications related to therapeutic targeting of p16INK4a. M.R. is meanwhile an employee of MSD Sharp & Dohme GmbH, but completed all work associated with this manuscript while full-time employed at Heidelberg University Hospital. F.V. received a grant from the Danish Council for Independent Research outside the submitted work. M.v.K.D. is involved in a research project funded by MSD Sharp & Dohme GmbH outside the submitted work and has received consulting and lecture fees from MSD, Roche and Oncgnostics. All remaining authors have declared no conflicts of interest.
Funding Information:
M.A. was supported by the Horizon 2020 Framework Programme for Research and Innovation of the European Commission , through the RISCC Network (grant no. 847845 ), and the Belgian Foundation Against Cancer through the IHUVAC project. The funding sources had no role in study design, collection, analysis and interpretation of data.
Funding Information:
S.A.K. received grants from ViewRay Inc. and honoraria from IBA Dosimetry, outside the submitted work. S.K.K. has previously received speaker fee from Merck and a research grant through her institution from Merck outside the submitted work. D.M. is an employee and shareholder of AstraZeneca Ltd., UK. E-S.P. has received lecture fees by MSD Sharp & Dohme GmbH and Institut für Frauengesundheit (IFG) GmbH. E-S.P. is involved in a research project funded by MSD Sharp & Dohme GmbH outside the submitted work. M.R. is an inventor of patent applications related to therapeutic targeting of p16 INK4a . M.R. is meanwhile an employee of MSD Sharp & Dohme GmbH, but completed all work associated with this manuscript while full-time employed at Heidelberg University Hospital. F.V. received a grant from the Danish Council for Independent Research outside the submitted work. M.v.K.D. is involved in a research project funded by MSD Sharp & Dohme GmbH outside the submitted work and has received consulting and lecture fees from MSD, Roche and Oncgnostics. All remaining authors have declared no conflicts of interest.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11
Y1 - 2021/11
N2 - Background: High-risk human papillomavirus (hrHPV) types represent the aetiological agents in a major proportion of anal squamous cell carcinomas (ASCC). Several studies have suggested a prognostic relevance of HPV-related markers, particularly hrHPV DNA and p16INK4a (p16) protein expression, in patients with ASCC. However, broader evaluation of these prognostic marker candidates has been hampered by small cohort sizes and heterogeneous survival data among the individual studies. We conducted an individual patient data (IPD) meta-analysis to determine the prognostic value of hrHPV DNA and p16 in patients with ASCC while controlling for major clinical and tumour covariates. Patients and methods: A systematic literature search was conducted to identify all published studies analysing p16 alone or in combination with hrHPV DNA and reporting survival data in patients with ASCC. Clinical and tumour-related IPD were requested from authors of potentially eligible studies. Survival analyses were performed with a proportional hazard Cox model stratified by study and adjusted for relevant covariates. The study-specific hazard ratios (HRs) for the exposures were pooled using a random-effects model. Kaplan-Meier curves from different studies were pooled per exposure group and weighted by the study's total sample size. Results: Seven studies providing IPD from 693 patients with ASCC could be included in the meta-analysis. Seventy-six percent of patients were p16+/hrHPV DNA+, whereas 11% were negative for both markers. A discordant marker status was observed in 13% of cases. Patients with p16+/hrHPV DNA+ ASCC showed significantly superior overall survival (OS) compared with patients with p16-/hrHPV DNA- tumours (pooled adjusted HR = 0.26 [95% confidence interval {CI}, 0.14–0.50]) with pooled three-year OS rates of 86% (95% CI, 82–90%) versus 39% (95% CI, 24–54%). Patients with discordant p16 and hrHPV DNA status showed intermediate three-year OS rates (75% [95% CI, 56–86%] for p16+/hrHPV DNA- and 55% [95% CI, 35–71%] for p16-/hrHPV DNA+ ASCC). Conclusion: This first IPD meta-analysis controlling for confounding variables shows that patients with p16+/hrHPV DNA+ ASCC have a significantly better survival than patients with p16-/hrHPV DNA- tumours.
AB - Background: High-risk human papillomavirus (hrHPV) types represent the aetiological agents in a major proportion of anal squamous cell carcinomas (ASCC). Several studies have suggested a prognostic relevance of HPV-related markers, particularly hrHPV DNA and p16INK4a (p16) protein expression, in patients with ASCC. However, broader evaluation of these prognostic marker candidates has been hampered by small cohort sizes and heterogeneous survival data among the individual studies. We conducted an individual patient data (IPD) meta-analysis to determine the prognostic value of hrHPV DNA and p16 in patients with ASCC while controlling for major clinical and tumour covariates. Patients and methods: A systematic literature search was conducted to identify all published studies analysing p16 alone or in combination with hrHPV DNA and reporting survival data in patients with ASCC. Clinical and tumour-related IPD were requested from authors of potentially eligible studies. Survival analyses were performed with a proportional hazard Cox model stratified by study and adjusted for relevant covariates. The study-specific hazard ratios (HRs) for the exposures were pooled using a random-effects model. Kaplan-Meier curves from different studies were pooled per exposure group and weighted by the study's total sample size. Results: Seven studies providing IPD from 693 patients with ASCC could be included in the meta-analysis. Seventy-six percent of patients were p16+/hrHPV DNA+, whereas 11% were negative for both markers. A discordant marker status was observed in 13% of cases. Patients with p16+/hrHPV DNA+ ASCC showed significantly superior overall survival (OS) compared with patients with p16-/hrHPV DNA- tumours (pooled adjusted HR = 0.26 [95% confidence interval {CI}, 0.14–0.50]) with pooled three-year OS rates of 86% (95% CI, 82–90%) versus 39% (95% CI, 24–54%). Patients with discordant p16 and hrHPV DNA status showed intermediate three-year OS rates (75% [95% CI, 56–86%] for p16+/hrHPV DNA- and 55% [95% CI, 35–71%] for p16-/hrHPV DNA+ ASCC). Conclusion: This first IPD meta-analysis controlling for confounding variables shows that patients with p16+/hrHPV DNA+ ASCC have a significantly better survival than patients with p16-/hrHPV DNA- tumours.
KW - Anal squamous cell carcinoma
KW - ASCC
KW - HPV
KW - IPD
KW - Meta-analysis
KW - p16
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U2 - 10.1016/j.ejca.2021.07.041
DO - 10.1016/j.ejca.2021.07.041
M3 - Article
AN - SCOPUS:85114707251
SN - 0959-8049
VL - 157
SP - 165
EP - 178
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -