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Invited Commentary
Gastroenterology and Hepatology
August 3, 2018

Human Papillomavirus Status and Esophageal Adenocarcinoma: Worth a Closer Look?

Author Affiliations
  • 1Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, Ontario, Canada
JAMA Netw Open. 2018;1(4):e181415. doi:10.1001/jamanetworkopen.2018.1415

Esophageal cancer remains one of the most lethal malignant neoplasms, with an estimated 456 000 new cases worldwide and 400 000 deaths in 2012.1 With the reduction in smoking rates, the incidence of squamous cell carcinoma of the esophagus has been decreasing in many developed nations. However, this is not the case for esophageal adenocarcinoma (EAC).1 Environmental and lifestyle factors have been implicated, including a potential carcinogenic role of viral agents such as human papillomavirus (HPV).

Rajendra et al2 report on the prognosis of HPV status in a retrospective case-control study of 142 patients with Siewert class I or II high-grade dysplasia or EAC. The authors used a robust panel of HPV tests beyond standard HPV DNA and included markers of biologic viral activity, including overexpression of E6 and E7 messenger RNA, which is a more specific assay for oncoprotein detection and more relevant for malignant progression of the virus. Immunohistochemical staining for the tumor suppressor proteins p16INK4A and p53 and TP53 gene sequencing were also conducted. Improved disease-free survival in those patients with HPV-positive Barrett high-grade dysplasia and EAC was demonstrated. This was most notable in both patients with HPV-positive cancers (hazard ratio, 0.33; 95% CI, 0.16-0.67; P = .002) and patients with transcriptionally active HPV–positive cancers (hazard ratio, 0.44; 95% CI, 0.22-0.88; P = .02). Mean disease-free survival was 40.3 months in the HPV-positive patient population compared with only 24.1 months in the HPV-negative group. Patients with HPV-positive cancers had reduced recurrence rates and distant metastases. From a pathological perspective, HPV-positive tumors had lower T stage and differentiation and more complete (R0) resections as well as fewer TP53 mutations, all factors that may independently contribute to a more favorable survival outcome. Whether this is a causal association remains unknown; ie, does HPV infection result in a more indolent malignant tumor, and does the presence of HPV in patient tissue samples identify a more favorable pathology? The authors rationalize that the prognostic findings of this cohort study justify investigation of HPV positivity as a predictive marker to treat selective patients with EAC with less intensive therapy. Given the dismal prognosis of this type of tumor and presence of conflicting studies, this is a rather significant inference.

The role of HPV in the pathogenesis of cervical and other anogenital cancers has been recognized with a number of high-risk HPV genotypes implicated in carcinogenesis.3 The viral oncogenes E6 and E7 have been consistently demonstrated in tumor samples and shown to downregulate tumor suppressor protein p53 and retinoblastoma proteins with impairment in cell cycle regulation.4 The virus also has a putative role in initiation of tumorigenesis via activation of the Wnt/β-catenin signaling pathway.5 Given the association of HPV with squamous cell malignant tumors of the head and neck6 and anogenital tract, studies investigating the role of HPV in squamous cell cancer of the esophagus followed.

Several factors suggest a possible role for HPV in the pathogenesis of esophageal cancer, including studies demonstrating HPV across the spectrum of neoplastic transformation beginning with benign squamous tumors, precancerous lesions, and esophageal cancer; malignant transformation in in vitro studies of esophageal epithelial cells by oncogenic HPV types as well as in animal studies; and the detection of HPV antibodies in the serum of patients with esophageal cancer.7 Estimates of HPV prevalence in esophageal cancer have varied significantly among studies, with differences in patient demographic characteristics, ethnic and genetic factors, and methods of HPV testing and detection possibly explaining this variation.8 The data for EAC have been conflicting, with rates of HPV positivity varying from 13% to 35%8,9 and 1 study reporting no HPV positivity in a cohort of 233 tumor samples.10

Although the presence of HPV has been documented in many cancer sites, the rationale for why these cancers may have better outcomes is not well elucidated. It is hypothesized that HPV-positive tumors may elicit an enhanced antitumor immune response or potentially have increased responsiveness to radiation and chemotherapy. The literature suggesting an improved prognosis in HPV-positive oropharyngeal cancers has been more robust and consistent than studies in esophageal cancer and has led to a number of de-escalation of treatment studies (ClinicalTrials.gov identifiers NCT02945631, NCT01663259, NCT02908477, NCT03215719, and NCT03416153).

The study by Rajendra et al2 is important in highlighting the potential role of HPV status in the prognosis of EAC. However, the use of HPV as a predictive marker for treatment remains unproven, and many questions abound. Important considerations for studies of de-escalation of treatment in HPV-positive EAC include how best to select patients for less intensive treatment: should trials be restricted to nonsmoking patients with better prognosis pathology characteristics, including lower T stage and lack of lymph node involvement? What is the best method to assess HPV status in a cost-effective and easily available assay for broad international use? Should there be a de-escalation of chemotherapy, radiation, or both? Is there potentially a role for de-escalation of surgery? Are these trials that patients would consider participation in given the lethality of these cancers?

Finally, the presence of a vaccine for HPV may affect the incidence of cervical, oropharyngeal, and other cancers. If HPV is an important risk factor for EAC, we may see a reduction in the rates of this highly lethal cancer over time. These benefits may take some time to bear out and are highly dependent on rates of vaccination. Nonetheless, primary prevention of HPV infection may result in a significant reduction in the global burden of this disease. In the meantime, larger-scale studies of the role of HPV in the pathogenesis of EAC are warranted, particularly before moving toward trials of less intensive therapy. While the results of this small cohort study are impressive, they are preliminary, and the study requires confirmation in a larger prospective trial.

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Article Information

Published: August 3, 2018. doi:10.1001/jamanetworkopen.2018.1415

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Dhesy-Thind S. JAMA Network Open.

Corresponding Author: Sukhbinder Dhesy-Thind, MD, FRCPC, Division of Medical Oncology, Department of Oncology, McMaster University, Hamilton, Canada, Juravinski Hospital and Cancer Centre, 699 Concession St, Hamilton, ON L8V 5C2, Canada (dhesy@hhsc.ca).

Conflict of Interest Disclosure: Dr Dhesy-Thind reported personal fees from Teva Canada Innovation and Novartis Pharmaceuticals Canada Inc outside the submitted work.

References
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Ferlay  J, Soerjomataram  I, Ervik  M,  et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013. http://globocan.iarc.fr. Accessed June 9, 2018.
2.
Rajendra  S, Xuan  W, Merrett  N,  et al.  Survival rates for patients with Barrett high-grade dysplasia and esophageal adenocarcinoma with or without human papillomavirus infection.  JAMA Netw Open. 2018;1(4):e181054. doi:10.1001/jamanetworkopen.2018.1054Google ScholarCrossref
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Syrjänen  K, Syrjänen  S.  Papillomavirus Infections in Human Pathology. New York, NY: Wiley & Sons; 2000.
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Li  X, Gao  C, Yang  Y,  et al.  Systematic review with meta-analysis: the association between human papillomavirus infection and oesophageal cancer.  Aliment Pharmacol Ther. 2014;39(3):270-281. doi:10.1111/apt.12574PubMedGoogle ScholarCrossref
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Kunzmann  AT, Graham  S, McShane  CM,  et al.  The prevalence of viral agents in esophageal adenocarcinoma and Barrett’s esophagus: a systematic review.  Eur J Gastroenterol Hepatol. 2017;29(7):817-825. doi:10.1097/MEG.0000000000000868PubMedGoogle ScholarCrossref
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