Correspondence to: Joel L. Weissfeld, M.D., M.P.H., University of Pittsburgh Cancer Institute, Keystone 510, 3520 Fifth Ave., Pittsburgh, PA 15213 (e-mail: jwepid{at}imap.pitt.edu).
As a result of rapid and dramatic increases in incidence during the past 2025 years, adenocarcinoma has eclipsed squamous cell carcinoma as the most frequent histopathologic esophageal cancer diagnosis in the United States and in other western countries (1). Adenocarcinoma and squamous cell carcinoma of the esophagus are epidemiologically distinct entities. Any coherent understanding of esophageal adenocarcinoma risk must explain the substantial associations with the male sex and the white race. Although obesity and some aspects of cigarette smoking history may contribute to risk, a growing body of evidence suggests that gastroesophageal reflux leads to a metaplastic change in the distal esophagus known as Barrett's esophagus, which is characterized by the replacement of the normal squamous epithelium with a columnar-lined epithelium of a specialized intestinal type (1,2). In response to gastroesophageal reflux and perhaps other environmental factors, Barrett's esophagus, in some relatively small fraction of cases, appears to undergo dysplastic and ultimately malignant transformation.
Much like squamous cell carcinoma, esophageal adenocarcinoma is generally associated with late diagnostic stage and associated poor prognosis. Although malignant transformation may occur no more frequently than once for every 100 person-years of follow-up, Barrett's esophagus appears to represent a true high-risk state. This condition is, therefore, an appropriate context for developing interventions capable of reversing the metaplastic change, preventing the malignant transformation, or detecting the malignant transformation at an earlier and more treatable stage. Any of these disease management and control approaches would greatly benefit from the availability of validated biomarkers that clearly distinguish instances of Barrett's esophagus according to transformation risk.
In this issue of the Journal, Bani-Hani et al. (3) examine the association between cyclin D1 overexpression in Barrett's esophagus and the later development of esophageal adenocarcinoma. The authors followed 307 Barrett's esophagus patients for an average of 3.5 years. Twelve patients developed esophageal adenocarcinoma after a mean follow-up interval of 4.3 years, for an overall incidence of 1.1 cases per 100 person-years of follow-up. Among Barrett's esophagus patients, analyses showed a strong association (odds ratio = 6.85; 95% confidence interval = 1.5729.91; P = .0106) between esophageal adenocarcinoma risk and the presence of metaplastic tissues overexpressing cyclin D1 at the very beginning of the follow-up interval. Moreover, a high proportion of the 12 esophageal adenocarcinoma patients (11 [92%]) overexpressed cyclin D1 at some point before the diagnosis of esophageal adenocarcinoma.
A useful and valid intermediate or surrogate end point marker should possess both a strong association with disease risk and a high prevalence among case patients (4). If borne out by subsequent studies, the results reported by Bani-Hani et al. identify cyclin D1 overexpression in Barrett's esophagus as a very promising intermediate end point for esophageal adenocarcinoma.
Other biomarkers, most prominently p53 overexpression and aneuploidy, have been identified in Barrett's esophagus in association with esophageal adenocarcinoma (1). However, most other studies have used casecontrol designs to compare Barrett's esophagus case patients coexisting with adenocarcinoma and Barrett's esophagus control subjects lacking adenocarcinoma. From such a design, one cannot distinguish cause from effect, that is, whether the excess expression of a biomarker truly precedes cancer or whether the cancer somehow influences biomarker expression in adjacent tissues. Moreover, the casecontrol design may be susceptible to selection and information bias, whether resulting from use of noncomparable control subjects or from dissimilar opportunities to detect biomarkers in control subjects relative to case patients. Cohort studies that make use of prospectively collected tissues establish the temporal association between cause and effect and potentially minimize these biases. Moreover, clinicians are eager to use these biomarkers to monitor and manage at-risk Barrett's esophagus patients. The cohort design anticipates this one potential application.
Therefore, the study by Bani-Hani et al. is unique. Using prospectively collected tissues, the authors compare case patients and control subjects nested within an at-risk cohort. Features of research design and analysis control for other important adenocarcinoma risk factors, including duration of follow-up, age, sex, and the length of Barrett's esophagus metaplastic epithelium at baseline. Together, these design features ensure the comparability of case patients and control subjects. By collecting tissues before cancer incidence and blinding laboratory investigators to casecontrol status, the authors mitigate further against biased assessments of cyclin D1 expression status. Other investigators (5,6) in the field have recognized the need for and have established large, multi-institutional cohorts containing patients with Barrett's esophagus. As these cohorts evolve and mature, studies linking baseline biomarker measurements with subsequent dysplastic or malignant change in Barrett's esophagus should become more frequent.
Even if other investigations verify a strong association between cyclin D1 and esophageal adenocarcinoma risk among cases of Barrett's esophagus, major challenges remain. In the article by Bani-Hani et al., cyclin D1 overexpression was relatively nonspecific. Fourteen 29% of 49 control subjects (Barrett's esophagus patients not yet experiencing malignant transformation) also overexpressed cyclin D1 in baseline esophageal biopsy samples. As indicated by Bani-Hani et al., one could, for example, propose a management strategy that restricts endoscopic surveillance for malignant transformation to Barrett's esophagus patients overexpressing cyclin D1 at baseline. In the cohort followed by Bani-Hani et al., this approach would have restricted surveillance to 30% of the cohort and still resulted in the detection of two of every three instances of malignant transformation. This particular management strategy may not yet be acceptable. However, this general approach may ultimately prove to be successful if future investigations produce better measures of the expression of cyclin D1 or other independent risk markers, perhaps other genes involved in cell cycle control.
Under current conditions, however, possession of a better marker set for distinguishing cancer risk in Barrett's esophagus patients would not necessarily be expected to affect esophageal adenocarcinoma mortality in the population overall. In a European population-based study, only 2% of all esophageal adenocarcinoma cases had known pre-existing Barrett's esophagus (7). Therefore, a comprehensive strategy may require increased detection of Barrett's esophagus in the general population, in combination with better diagnostic strategies for assessing transformation risk and treatment strategies for preventing malignant transformation.
REFERENCES
1 Kim R, Weissfeld JL, Reynolds JC, Kuller LH. Etiology of Barrett's metaplasia and esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 1997;6:36977.[Abstract]
2
Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:82531.
3
Bani-Hani K, Martin IG, Hardie LJ, Mapstone N, Briggs JA, Forman D, et al. Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adenocarcinoma. J Natl Cancer Inst 2000;92:131621.
4 Schatzkin A, Freedman LS, Schiffman MH, Dawsey SM. Validation of intermediate end points in cancer research. J Natl Cancer Inst 1990;82:174652.[Abstract]
5 Caygill CP, Reed PI, Hill MJ, Watson A. An initial comparison of nine centres registering patients with the UK National Barrett's Oesophagus Registry (UKBOR). Eur J Cancer Prev 1999;8:53942.[Medline]
6 O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry. Am J Gastroenterol 1999;94:203742.[Medline]
7 Bytzer P, Christensen PB, Damkier P, Vinding K, Seersholm N. Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study. Am J Gastroenterol 1999;94:8691.[Medline]
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |