ICTR 2000
bcl-2 expression in head and neck cancer: an enigmatic prognostic marker

Presented at ICTR 2000, Lugano, Switzerland, March 5–8, 2000.
https://doi.org/10.1016/S0360-3016(00)01498-XGet rights and content

Abstract

Purpose: The role of bcl-2 overexpression in cancer presents a paradox. In some tumor types, it is associated with favorable outcome, whereas in others the reverse is true. The purpose of this study was to explore the influence of bcl-2 in a large series of head and neck cancer patients treated in the CHART randomized trial.

Methods and Materials: Histologic material was obtained from 400 patients; bcl-2 expression was assessed by immunohistochemistry as either positive or negative cytoplasmic staining.

Results: Positivity of bcl-2 was recorded in 12.8% (9.5–16.5%, 95% confidence limits) of tumors. There were significant differences in positive tumors within different sites with nasopharynx showing the highest incidence (46.2%). A multivariate logistic regression analysis showed that bcl-2 was strongly associated with histologic dedifferentiation, as well as increasing N stage and female gender. In univariate analyses, bcl-2 positive patients had a lower locoregional relapse rate (RR 0.57, p = 0.02) and improved survival (RR 0.49, p = 0.004) compared to bcl-2 negative patients; this became more significant in multivariate analysis.

Conclusion: These data demonstrate that bcl-2 overexpression is a marker of what is considered to be more advanced and aggressive disease yet it is associated with a more favorable outcome irrespective of the treatment schedule.

Introduction

The regulation of apoptosis is of prime importance during morphogenesis and in maintaining normal tissue homeostasis, and, as a consequence, genes involved in this process are key targets for carcinogenesis (1). Alterations in the function of apoptosis-related genes should have a profound influence on not only tumor progression but also the efficacy of cytotoxic therapy including radiation. Perhaps the most studied gene in this process is bcl-2 (2). The bcl-2 proto-oncogene was discovered as a result of its involvement in the 14;18 translocation common in human follicular lymphomas (3). In these lymphomas, bcl-2, which normally resides at 18q21, becomes juxtapositioned to powerful enhancer elements in the immunoglobulin heavy chain (IgH) locus at 14q32. The result is overproduction of bcl-2 mRNA and protein. Alterations in bcl-2 have since been reported in many neoplasms including cancers of breast (4), colorectum (5), lung (6), prostate (7), thyroid (8), gastric (9), bladder (10), ovary (11), cervix (12), melanomas (13), and head and neck cancer 14, 15, 16, 17, 18.

However the clinical significance of bcl-2 protein overexpression is far from clear. Intuitively, the anti-apoptotic function of bcl-2 might be expected to be associated with a worse prognosis due to the inhibition of cell death in response to treatment and in the potential to accumulate further mutation leading to disease progression. Yet, the paradigm exists that, in some tumor types (breast, colon, lung), bcl-2 overexpression is consistently associated with a more favorable outcome, in others the reverse is true (cervix, melanoma, bladder, prostate), whereas a third group shows either ambiguity of reports or no significance (head and neck, endometrial, gastric, thyroid, and ovary). In breast cancer, the expression of bcl-2 has been correlated with the presence of steroid receptors and evidence of a differentiated phenotype, i.e., low proliferation index and lack of p53 staining (19). In contrast, in metatstatic prostate cancer bcl-2 positivity is associated with androgen receptor negative tumors and thus a poor prognosis (20). It is also known that, paradoxically, bcl-2 can inhibit tumor growth (21). These observations would suggest there is no a priori correlation between either spontaneous or therapy-induced apoptosis, expression of bcl-2 and probable clinical outcome. Instead, the role of bcl-2 would appear to be specific to the initiation and progression of different cancers. In colorectal cancer, bcl-2 overexpression is characteristic of the early phase of carcinogenesis where higher expression is found in adenomas compared to carcinomas (22). The same may be true for head and neck cancer in which expression of bcl-2 was greater in leukoplakia and dysplastic lesions compared to carcinomas 23, 24, 25, 26. However, within clinical studies relating expression of bcl-2 to outcome in oral cancer there are divergent reports as to the prognostic significance of this proto-oncogene. A favorable outcome associated with bcl-2 overexpression has been previously reported by our group (15) and also by other workers 27, 28, whereas, in contrast, Gallo et al. (16) and Costa et al. (29) found bcl-2 negative tumors to have better prognosis although this was only significant in patients who achieved pathologic remission to induction chemotherapy. In addition, there are consistent findings in larynx carcinomas suggesting no prognostic significance of bcl-2 expression despite the observation that apoptosis may be important 30, 31, 32.

In this study, we have examined a large cohort of head and neck cancer patients (400>) treated in the CHART randomized trial (33) and correlated bcl-2 expression to clinicopathologic features and outcome of treatment.

Section snippets

Clinical study

The patients involved in this study were drawn from the randomized multicenter trial of CHART vs. conventional radiotherapy in head and neck cancer (34). A total of 918 patients were included in the randomized trial over a 5-year period beginning March 1990. Patients with squamous cell cancer in the main sites within the head and neck region, with the general exception of early T1 N0 tumors, were entered into the study by 11 centers. There was a 3:2 randomization to either CHART, where a dose

Results

Of the 400 patients studied, 51 (12.8%, 95% confidence limits, 9.5–16.0%) were classified as positive for bcl-2 cytoplasmic staining.

The clinicopathologic correlations with bcl-2 expression are presented in Table 1. Significant differences (p = 0.001) were observed in the incidence of bcl-2 positive tumors as a function of the site within the head and neck. The highest incidence of bcl-2 positive tumors was found in nasopharyngeal tumors with a frequency of 46.2%. There was a trend for bcl-2

Discussion

Apoptosis, both intrinsic and induced, is considered to be an important component of the tumor response to radiation treatment (35) although its significance has yet to be established for the major solid cancers. As a genetic program, alterations in key genes involved in the pathways leading to apoptosis could have profound influence on radio-responsiveness. Studies have highlighted that the bcl-2 proto-oncogene is a key regulator of the apoptotic program induced by anticancer agents including

Acknowledgements

This work was funded by the Cancer Research Campaign and Gray Laboratory Cancer Research Trust. We gratefully acknowledge the CHART Steering Committee and the clinicians and pathologists who provided the material for this study.

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