HPV Biomarkers Linked to Improved Survival With Esophageal Dysplasia, Adenocarcinoma

By Will Boggs MD

February 21, 2020

NEW YORK (Reuters Health) - Human papillomavirus (HPV) positivity and HPV biomarkers are associated with improved survival in adults with Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC), according to a new study.

"Endoscopists and gastroenterologists should be aware of the role of high-risk HPV in Barrett's dysplasia and esophageal adenocarcinoma, analogous to the case of head and neck tumors," Dr. Shanmugarajah Rajendra of Bankstown-Lidcombe Hospital, in Sydney, Australia, told Reuters Health by email.

Studies investigating the association between high-risk HPV infection and Barrett dysplasia and EAC have yielded conflicting results, with some studies showing no association.

Dr. Rajendra and colleagues investigated the association between survival in adult patients with Barrett HGD and EAC and HPV-related cell-cycle proteins (retinoblastoma protein, or pRb, and cyclin D1, or CD1) and surrogate markers of viral E6 and E7 oncogene expression (minichromosome maintenance protein, or MCM2, and Ki-67).

Among the 142 patients included in the study, 37 were HPV-positive and 105 were HPV-negative, the team reports in JAMA Network Open.

The expression of pRb, CD1 and Ki-67 did not differ significantly between HPV-positive and HPV-negative lesions, but high MCM2 expression was significantly lower in HPV-positive lesions (40.5%) than in HPV-negative lesions (66.7%).

None of the markers on their own had any association with disease-free survival, and only low expression of CD1 was associated with improved overall survival after adjusting for confounders.

Low pRb expression in patients with HPV-positive EAC was associated with significantly improved disease-free survival compared with HPV-negative, high-expression pRb, as were HPV-positive, low-expression CD1 and HPV-positive, high-expression MCM2.

Only HPV-positive, low-expression CD1 was associated with significant improvements in overall survival.

"This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC," the authors conclude. "Further confirmatory studies are required before clinical use of CD1 and HPV status as prognostic biomarkers."

"If these findings are confirmed by others, then understanding the underlying mechanism that underpins these differential survival outcomes between HPV-positive and HPV-negative Barrett HGD and EAC would be paramount," they add. "This understanding could translate into improved treatment selection for these patients based on HPV status."

Dr. Rajendra urged physicians to "Please check for high-risk HPV (alongside p53 which is recommended by the British Society of Gastroenterology), as it influences prognosis and in future, treatment as well."

"The HPV-positive subset of patients with Barrett's HGD and EAC may require less treatment but most importantly, therapeutic vaccination is a real possibility in the earlier stage of the metaplasia-dysplasia-adenocarcinoma sequence," he said.

Dr. Andrew Kunzmann of Queens University Belfast, in Northern Ireland, who recently reviewed the prevalence of viral agents in EAC and Barrett's esophagus, told Reuters Health by email, "The finding of improved prognosis in HPV-related tumors has been seen for other tumor types. However, the role of HPV in EAC is far less established and not all studies agree on whether HPV is frequently found in EAC tissue, with concerns raised that contamination of tissue samples is possible."

"This type of study is particularly difficult to conduct," he said. "It is particularly difficult to avoid tissue samples getting contaminated with HPV during sample preparation. Whilst the authors did try to minimise this risk, it is unclear if this would be sufficient to entirely prevent contamination. Other studies using even stricter anti-contamination procedures have found far lower rates of HPV in Barrett's and EAC tissue than found in this study."

"Whilst the findings are of interest from a scientific perspective, it is too early to say whether these results could influence the treatment of Barrett's HGD or EAC," Dr. Kunzmann said. "However, the study was fairly small and combined Barrett's HGD and EAC, which can have very different rates of survival. Further studies to independently replicate these results would be needed before we can determine whether testing for HPV will benefit patients and guide treatment decisions."

SOURCE: https://bit.ly/2VazWGS JAMA Network Open, online February 14, 2020.