Association of Biomarkers for Human Papillomavirus With Survival Among Adults With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma
Authors: Shanmugarajah Rajendra, Preeti Sharma, Shweta Dutta Gautam, Manoj Saxena, Amit Kapur, Prateek Sharma, Neil Merrett, Tao Yang, Leonardo D. Santos, Darren Pavey, Omar Sharaiha, Owen McKay, Hugh Dixson, Wei Xuan
Journal: JAMA Network Open (2020)

IMPORTANCEThe presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC).Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown.OBJECTIVE To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC.DESIGN, SETTING, AND PARTICIPANTS This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC.Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers.Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility.The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017.MAIN OUTCOMES AND MEASURES Disease-free survival and overall survival. RESULTSOf 151 patients assessed for eligibility, 9 were excluded.Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative.No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2.In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95;adjusted P = .03).All the biomarkers stratified by HPV status showed significant associations with survival.Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93;adjusted P = .04).Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76;adjusted P = .01),as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78;adjusted P = .02).In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94;adjusted P = .04).CONCLUSIONS AND RELEVANCE This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC.Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal (continued) Key Points Question What is the prognostic significance of human papillomavirusrelated biomarkers (ie, retinoblastoma protein, cyclin D1, minichromosome maintenance protein, and Ki-67) in Barrett high-grade dysplasia and esophageal adenocarcinoma?Findings In this case-control study of 142 patients with Barrett high-grade dysplasia and esophageal adenocarcinoma, only low cyclin D1 levels were associated with a favorable prognosis for overall survival.None of the biomarkers tested independently had any association with disease-free survival: pRb, CD1, MCM2, and Ki-67 stratified by human papillomavirus status was associated with a survival benefit in esophageal tumors.Meaning These findings suggest the possibility of personalization of therapy for Barrett high-grade dysplasia and esophageal adenocarcinoma based on human papillomavirus status.