Low expression of the human papillomavirus (HPV)-related marker cyclin D1 (CD1) appears to be an independent prognostic marker in Barrett high-grade dysplasia and esophageal adenocarcinoma, according to study results published in JAMA Network Open. HPV positivity in combination with the markers retinoblastomaprotein (pRb), CD1, minichromosome maintenance protein (MCM2), and Ki-67 were also associated with a survival benefit in esophageal tumors.

The presence of high-risk HPV infection has previously been associated with Barrett high-grade dysplasia and esophageal adenocarcinoma, but the prognostic significance of other HPV-related markers has yet to be explored. Therefore, investigators used a retrospective case-control study to examine 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 high-grade dysplasia and EAC.

A total of 142 patients with Barrett high-grade dysplasia or esophageal adenocarcinomawere recruited from secondary and tertiary care referral centers between December 1, 2002 and November 28, 2017. HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers was performed on pre-treatment biopsies.

Of the 142 patients, 37 were HPV-positive and 105 were negative. There was no association with disease-free survival noted for pRb, CD1, Ki-67, and MCM2. In terms of overall survival, only CD1 had a favorable prognosis (HR 0.53; 95%CI 0.30-0.95; adjusted P = .03). When all biomarkers were stratified by HPV status they showed significant associations with survival.


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Patients with HPV-positive, low-expression pRb esophageal tumors were associated with significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (hazard ratio [HR], 0.33; 95% CI, 0.12-0.93; adjusted P =.04). HPV-positive, low-expression CD1 was similarly associated with significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P =.01), along with HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P =.02). Improved outcomes in terms of overall survival in patients with HPV was only significantly associated with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P =.04).

However, the study is limited by its small sample size and the retrospective nature and case control design introduced biases involving selection, information, observation, and confounding. Selection bias is further exacerbated by recruitment from secondary and tertiary medical centers. This was mitigated, however, by the unknown HPV status at enrollment and treatment decisions. Measurement bias was minimized by blinding scientists and pathologists to patients’ clinical, virologic, and biomarker status along with treatment outcomes. Furthermore, some problems with tissue sampling occurred. Multiple biopsies from the Barrett high-grade dysplasia and esophageal adenocarcinoma segments were unavailable for assessment of circumferential and longitudinal discordance for viral and protein marker detection and microdissection of tissue specimens may have increased the yield of lesional cells for analysis. Finally, investigators noted that immunohistochemistry analysis is subjective and lacks uniform scoring systems and DNA invalidity can result from the age of some samples.

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The study findings suggested that, “low expression of CD1 appears to be an independent prognostic marker in Barrett [high-grade dysplasia] and [esophageal adenocarcinoma].” Also, HPV status in combination with the makers tested has a significant association with survival, disease relapse and progression, and disease-specific death. The investigators recommended that further confirmatory studies are needed before the clinical use of CD1 and HPV status as prognostic biomarkers. If confirmed, “then understanding the underlying mechanism that underpins these differential survival outcomes between HPV-positive and HPV-negative Barrett [high-grade dysplasia] and [esophageal adenocarcinoma] would be paramount,” stated investigators, as this could translate to improved treatment selection for these patients based on HPV status.

Reference

Rajendra S, Sharma P, Gautam SD, et al. Association of biomarkers for human papillomavirus with survival among adults with Barrett high-grade dysplasia and esophageal adenocarcinoma. JAMA Netw Open. 2020;3:e1921189.