Could HPV Be Prognostic in Esophageal Cancer Too?

First Study to Show Relationship Akin to HNSCC

Megan Brooks

August 03, 2018

Patients with Barrett's high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) who are human papillomavirus (HPV) positive have a more favorable prognosis than their HPV-negative peers, a new study finds.

"If these findings of a favorable prognosis of HPV-positive HGD/EAC are confirmed in larger cohorts with more advanced disease, it presents an opportunity for treatment deescalation in the hope of reducing toxicity without deleteriously affecting survival," Shan Rajendra, MD, director, Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, Australia, told Medscape Medical News.

"These data can also be exploited for diagnosis, disease stratification, surveillance, and treatment, including vaccination," said Rajendra.

The study was published online August 3 in JAMA Network Open.

It has been well documented that for patients with HPV-positive head and neck squamous cell carcinoma (HNSCC), rates of survival are higher and there is a reduced risk for recurrence in comparison with patients with HPV-negative HNSCC. The current study is the first to demonstrate a similar relationship in HGD/EAC, Rajendra and colleagues say.

The team conducted a retrospective case-control study of 142 patients with HGD/EAC. Thirty-seven patients were HPV positive, and 105 were HPV negative. Mean follow-up time was 33.4 months for the whole group and 43.8 months for survivors.

HPV positivity was associated with significantly improved disease-free survival (DFS). This was most notable both in patients with HPV-positive cancers (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.16 - 0.67; P = .002) and in patients with transcriptionally active HPV-positive cancers (HR, 0.44; 95% CI, 0.22 - 0.88; P = .02).

HPV positivity was also associated with reduced rates of recurrence and progression, as well as distant metastasis and death from EAC.

Table. Comparison of Outcomes by HPV Status

Outcome HPV+ HPV- P Value
DFS (mean mo) 40.3 24.1 .003
Recurrence/progression 24.3% 58.1% <.001
Distant metastasis 8.1% 27.6% .02
EAC death 13.5% 36.2% .01


The mean duration of overall survival (OS) was significantly improved in the HPV-positive group, but the association of HPV status with OS failed to reach significance by the log-rank test. Although 26 of 37 HPV-positive individuals (70.3%) were alive at the end of follow-up, compared with 58 of 105 HPV-negative individuals (55.2%), the difference was not statistically significant, possibly because of the modest sample size and associated comorbid conditions, the investigators note.

HPV-positive tumors had lower T stage and differentiation, and more patients with HPV-positive tumors underwent complete (R0) resection. There were also fewer TP53 mutations in HPV-positive tumors, which may contribute to a more favorable outcome, the authors point out.

Important Study, but Questions Remain

This study 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," Sukhbinder Dhesy-Thind, MD, Department of Oncology, McMaster University, Hamilton, Ontario, Canada, points out in a linked commentary.

It remains unclear, for example, whether HPV infection results in a more indolent malignant tumor or whether the presence of HPV in tissue samples signifies a more favorable pathology, she notes.

"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," writes Dhesy-Thind.

The findings are important with regard to deescalation of treatment in HPV-positive EAC, she notes.

Important questions to be explored in future clinical trials include how best to select patients for less intensive treatment, how best to check for HPV status, and which modality (ie, chemotherapy, radiotherapy, or surgery) would be best to choose for deescalation.

Another question concerns whether patients would even consider participating in clinical trials, given the lethality of these cancers.

Dhesy-Thind says larger studies of the role of HPV in the pathogenesis of EAC are needed, particularly before conducting 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," she concludes.

This study was supported by the South Western Sydney Clinical School, the University of New South Wales, and the Oesophageal Cancer Research Fund. Dr Rajendra has received grants from the University of New South Wales and from the Oesophageal Cancer Research Fund during the conduct of the study. The other authors have disclosed no relevant financial relationships. Dr Dhesy-Thind has received personal fees from Teva Canada Innovation and Novartis Pharmaceuticals Canada.

JAMA Network Open. Published online August 3, 2018. Full text, Commentary

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