Elsevier

European Journal of Cancer

Volume 47, Issue 3, February 2011, Pages 460-469
European Journal of Cancer

Cancer–testis antigen expression in primary cutaneous melanoma has independent prognostic value comparable to that of Breslow thickness, ulceration and mitotic rate*

https://doi.org/10.1016/j.ejca.2010.09.042Get rights and content

Abstract

To determine the effect of Cancer–Testis Antigen (CTAg) expression on the natural history of primary cutaneous melanoma we compared its impact on prognosis with that of known prognostic factors and its relationship with other clinicopathologic characteristics.

The immunohistochemical expression of three CTAgs (MAGE-A1, MAGE-A4 and NY-ESO-1) in 348 cases of stage I and stage II primary cutaneous melanoma was analysed and correlated with clinicopathologic characteristics, relapse free survival (RFS) and overall survival (OS). A Cox proportional hazards regression model was used to analyse factors which independently predicted RFS.

All three CTAgs were significantly co-expressed with each other (p < 0.001). The median RFS for patients with CTAg-negative tumours and CTAg-positive tumours was 72 months and 45 months, respectively, (P = 0.008). Univariate analysis demonstrated that the impact of CTAg expression on RFS was comparable in magnitude to that of Breslow thickness, ulceration and tumour mitotic rate. Multivariate Cox regression analysis indicated that CTAg expression was a powerful independent predictor of RFS (risk ratio (RR) = 1.715, 95% confidence interval (CI) = 0.430–0.902, P = 0.010). In contrast, CTAg expression was demonstrated to have no prognostic impact on overall survival.

This study demonstrates that CTAg expression in primary cutaneous melanoma is a strong independent predictor of RFS and it is comparable to other known important prognostic factors. CTAg expression has no relationship with overall survival, suggesting anti-melanoma immunity directed towards CTAg expression may contribute to the natural history of the disease. In view of these results, further investigation of the function of CTAgs and their potential use in therapeutic targeting is warranted.

Introduction

Cutaneous melanoma is a major and increasing public health issue worldwide and its incidence continues to rise in individuals of European origin.1 In the United States it is predicted to be the fifth and sixth most common cancer in men and women, respectively, in 2009.2 Wide local excision of the primary tumour is currently the standard treatment for cutaneous melanoma3 and is successful particularly for patients with thin tumours.4 In many melanoma treatment centres, sentinel lymph node biopsy is offered to patients with melanomas >1 mm thick or to those with melanomas <1 mm thick if other adverse prognostic factors are present. Surgery is also considered the mainstay for treating melanoma that has metastasised to regional lymph nodes.5 For patients with widespread metastatic disease, the outcome is poor,4 single agent or combination chemotherapy has little efficacy6 and at present treatment is directed at palliation of symptoms rather than curing the tumour.7

With such limited therapeutic options for advanced metastatic disease, interest in vaccine development is high. Antigens that are relatively specific for cancer, known as cancer–testis antigens (CTAgs), have been demonstrated to serve as targets through their presentation on HLA molecules for immune recognition by cytotoxic T lymphocytes (CTLs).8 CTAgs are expressed by many different tumours as well as by spermatogonia and trophoblast but not by other normal somatic cells.9 Previous work involving CTAgs has focused on assessment of the expression patterns of these antigens in cancers10, 11, 12 as well as the development, use and immune response monitoring of cancer vaccines in the clinical setting.13 However, very little is currently known about the correlation of CTAg expression with clinical data, such as known prognostic factors and survival in melanoma patients. Most previous studies are disadvantaged by the small number of tumours studied and/or the limited numbers of antigens tested.12, 14

This study assessed CTAg expression in a large series of primary cutaneous melanomas and correlated the expression of these antigens with other clinico-pathologic features, relapse free survival (RFS) and overall survival (OS).

Section snippets

Patients and clinical specimens

Archival formalin-fixed, paraffin-embedded tissue blocks of stage I or stage II primary cutaneous melanomas from patients treated at the Austin Health Melanoma Clinic (Melbourne, Australia) or the Melanoma Institute Australia (MIA) (Sydney, Australia) were retrieved. Sections were cut and stained with haematoxylin–eosin to confirm the diagnosis of primary melanoma and then immunohistochemistry was performed as described below. All protocols were approved by the Austin Health Human Research

Patients

In total, 348 primary stage I and II cutaneous melanomas were collected and typed for CTAg expression. These included 271 melanoma patients treated at the Austin Health Melanoma Clinic between 1994 and 2008, and 77 patients treated at the MIA between 1992 and 2004. Of these, 250 Austin tumours and 71 MIA tumours had complete clinical data and were subsequently included in the clinicopathologic/CTAg analysis (Table 1). Only stage II tumours were analysed for RFS (Fig. 2 and Table 2) and OS (Fig.

Discussion

The molecular analysis of melanoma is proving to be increasingly important for understanding subclassification and for determining optimal treatment. The CTAgs have proven to be of particular interest because they are targets for immune recognition and therefore immunotherapy.13 Little is known about their function and influence on the behaviour of melanoma, so we have performed the first detailed study that relates the expression of these key molecules to clinical outcomes.

Although there was

Conflict of interest statement

None declared.

Acknowledgements

The following Austin Health medical oncology fellows contributed patient tumours to this study: Mark Shackleton, Phillip Parente, Catherine Barrow and Oliver Klein. We also thank Sunanta Lee and Belinda Rutledge who created and maintain the melanoma database. I.D.D. is supported in part by a Victorian Cancer Agency Clinical Researcher Fellowship and is an Australian National Health and Medical Research Council (NHMRC) Honorary Practitioner Fellow. J.C. is an NHMRC Practitioner Fellow. R.A.S.

References (40)

  • A.J. Simpson et al.

    Cancer/testis antigens, gametogenesis and cancer

    Nat Rev

    (2005)
  • A.A. Jungbluth et al.

    Expression of MAGE-antigens in normal tissues and cancer

    Int J Cancer

    (2000)
  • C. Barrow et al.

    Tumor antigen expression in melanoma varies according to antigen and stage

    Clin Cancer Res

    (2006)
  • E.F. Velazquez et al.

    Expression of the cancer/testis antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM)-correlation with prognostic factors

    Cancer Immun

    (2007)
  • I.D. Davis et al.

    Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans

    Proc Natl Acad Sci USA

    (2004)
  • Y.T. Chen et al.

    Identification of the MAGE-1 gene product by monoclonal and polyclonal antibodies

    Proc Natl Acad Sci USA

    (1994)
  • H.A. Vaughan et al.

    Immunohistochemical and molecular analysis of human melanomas for expression of the human cancer–testis antigens NY-ESO-1 and LAGE-1

    Clin Cancer Res

    (2004)
  • D. Rimoldi et al.

    Anti-MAGE-3 antibody 57B and anti-MAGE-1 antibody 6C1 can be used to study different proteins of the MAGE-A family

    Int J Cancer

    (2000)
  • C. Landry et al.

    Monoclonal antibody 57B stains tumor tissues that express gene MAGE-A4

    Int J Cancer

    (2000)
  • A. Oberthuer et al.

    The tumor-associated antigen PRAME is universally expressed in high-stage neuroblastoma and associated with poor outcome

    Clin Cancer Res

    (2004)
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    *

    This work was conducted as part of the Hilton–Ludwig Cancer Metastasis Initiative, funded by the Conrad N. Hilton Foundation and the Ludwig Insitute for Cancer Research.

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