Correlation of histology with biomarker status after photodynamic therapy in Barrett esophagus.

Barrett esophagus (BE) predisposes patients to esophageal adenocarcinoma, a cancer with one of the fastest rising incidence rates over the past decade and a highly lethal malignancy once it is symptomatic.1,2 It is believed that esophageal adenocarcinoma arises as the final step of a postulated sequential change in the metaplastic epithelium, progressing from low-grade dysplasia (LGD), to high-grade dysplasia (HGD), and finally carcinoma. HGD on histologic samples has been used as the most reliable clinical biomarker of potential carcinogenesis, with studies reporting variable rates of progression to esophageal carcinoma (range, 16%–59%).3–5 Interruption of the metaplasia-dysplasia-carcinoma sequence by ablating or resecting this at-risk mucosa has been proposed as a strategy to reduce the incidence of esophageal adenocarcinoma and has served as the rationale for the recommendation of esophagectomy for patients with HGD. Over the past few years, endoscopic therapy has emerged as an alternative to esophagectomy because of the significant mortality and morbidity associated with esophagectomy.6,7 Multiple modalities, including photodynamic therapy (PDT),8 argon plasma coagulation,9 and multipolar electrocoagulation10 in isolation and in combination with endoscopic mucosal resection (EMR),11,12 have been reported in the treatment of HGD. Variable success rates have been reported (range, 75%–90%). A randomized multicenter trial compared PDT with surveillance and treatment with omeprazole in patients with HGD. After a 24-month follow-up, complete ablation of HGD was noted in 77% of patients versus 39% in the omeprazole group. Thirteen percent of patients who received PDT plus omeprazole progressed to cancer compared with 28% of patients in the omeprazole group.13 This led to U.S. Food and Drug Administration approval for the use of PDT for the treatment of HGD in BE. We recently reported that long-term outcomes (overall mortality and cancer-free survival) were comparable between patients who underwent esophagectomy and patients who received PDT.14 Several genetic alterations have been described in BE. These include loss of cell cycle checkpoint genes, such as p16 and p53. Loss of these genes by allelic loss (deletions or loss of heterozygosity [LOH]), point mutations, or promoter hypermethylation (for p16) have been observed in a substantial number of patients with BE.15,16 Several other genetic alterations that involve gains/amplifications of proto-oncogenes (and growth factors/growth factor receptors) as well as changes in DNA content (as assessed by flow cytometry and image cytometry) also have been described.17,18 Currently, histology is used as the endpoint to define success with ablative therapy in HGD. However, recurrences and/or progression to cancer despite ‘successful’ ablation/resection are common. To our knowledge, predictors of recurrent dysplasia have not been defined. Few studies have assessed genetic alterations after ablation of BE19–21: those studies primarily assessed patients with predominantly nondysplastic BE (a category for which ablation currently is not recommended) rather than HGD (in which endoscopic ablation is gaining acceptance as an alternative to esophagectomy) by using techniques that lack long-term data on successful ablation. Studies also have raised concern about the appearance of cancer-associated biomarkers after ablation (in patients with nondysplastic BE)20: however, data are lacking on the clinical implication of this phenomenon in terms of the recurrence or progression of dysplasia. The role of biomarkers in defining response to PDT remains unclear. The correlation between histologic response and ‘biomarker response’ also is unknown. We hypothesized that patients who remain positive for genetic alterations despite achieving a histologic response to PDT would be at risk for recurrence of dysplasia. In this study, we used fluorescence in situ hybridization (FISH) to characterize genetic alterations that were present in patients with HGD and mucosal cancer before treatment with PDT and compared them with the alterations observed after PDT. In addition, we assessed the recurrence of dysplasia after initial histologic response and correlated those findings with post-PDT genetic alterations assessed by FISH.