Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma

doi:10.1016/j.ajo.2018.07.045

American Journal of Ophthalmology

Volume 195, November 2018, Pages 154-160

https://doi.org/10.1016/j.ajo.2018.07.045 Get rights and content

Purpose

To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM).

Design

Retrospective cohort study.

Methods

The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint.

Results

GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10⁻⁸), largest basal tumor diameter (P = 2.5 × 10⁻⁶), PRAME status (P = 2.6 × 10⁻⁶), and TNM stage (P = 3.7 × 10⁻⁶). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10⁻¹⁴) was superior to an optimized TNM model (P = 1.3 × 10⁻⁵).

Conclusions

In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.

Section snippets

Clinical Data Collection

This retrospective cohort study was approved by the Institutional Review Board of the University of Miami School of Medicine. Patient information was accessed with proper informed consent and in accordance with the Health Insurance Portability and Accountability Act (HIPAA). The study included 240 patients with primary UMs arising from the choroid and/or ciliary body from the ocular oncology practice of J.W.H. The ocular pathology laboratory routinely provided cytologic verification of fine

Results

Among 240 consecutive patients diagnosed with UM arising from the choroid and/or ciliary body (Table 1), primary treatment consisted of I-125 plaque radiotherapy in 165 (68.8%) cases, enucleation in 74 (30.8%) cases, and observation in 1 case (0.4%). Tumor sample was obtained by fine needle aspiration biopsy in 166 (69.2%) and by postenucleation needle biopsy in 74 (30.8%). GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME was positive in 83 (34.6%) cases, including

Discussion

In this study, we confirmed that GEP, PRAME, and TNM stage were each prognostic of metastasis in UM. Individually, GEP and PRAME both demonstrated prognostic accuracy that was superior to the TNM staging system. Combining GEP and PRAME into a 3-category model further enhanced the prognostic accuracy of this molecular classification system.

There are several limitations to the use of the TNM system for prognostication in UM. First, the TNM assigns increased metastatic risk to all UMs with LBD >

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Immunohistochemical expression of PRAME is a marker of poor prognosis in uveal melanoma: A clinico-pathologic and immunohistochemical study on a series of 85 cases
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PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen, first isolated in tumor-reactive T-cell clones from a metastatic melanoma patient. It has been widely studied in skin pathology as an immunohistochemical marker capable of distinguishing between benign nevi and malignant melanomas. PRAME has been found to be also expressed in non-melanocytic tumors, including lung, breast, kidney and ovarian cancer. However, less is known about the diagnostic and/or prognostic role of this protein in uveal melanoma (UM); few studies have reported that PRAME expression seems to give to UM patients an additional metastatic risk beyond the other already-known prognostic parameters. In the present retrospective study, we aimed to correlate PRAME immunoreactivity to other clinico-pathologic features and follow-up data on a large series of 85 cases (45 non-metastasizing and 40 metastasizing tumors) of primary UM. A statistically significant correlation was found between PRAME expression and higher metastatic risk and lower metastasis-free survival. We propose to include PRAME in the immunohistochemical panel of UM as an easily usable marker capable of predicting higher metastatic risk and stratifying patients’ outcome.
Validation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma
2023, Ophthalmology
To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value.
Retrospective analysis.
Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center.
Patients’ demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome.
Metastasis-free survival (MFS).
Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61–6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86–4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%–62.8%).
Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Prognostic Value of BAP1 and Preferentially Expressed Antigen in Melanoma (PRAME) Immunohistochemistry in Uveal Melanomas
2023, Modern Pathology
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and despite excellent local control, more than 50% of patients develop and die from metastatic disease. Loss of BAP1 nuclear staining, a surrogate marker of BAP1 mutation, and preferentially expressed antigen in melanoma (PRAME) messenger RNA overexpression, as assessed using qPCR, have previously been shown to correlate with increased metastasis rate in UM. In this study, we demonstrated that UM could be successfully risk-stratified using a combination of BAP1 and PRAME immunohistochemical (IHC) stains. We retrospectively reviewed 318 UM cases with sufficient tissue and performed BAP1 and PRAME IHC to stratify them as BAP1+/PRAME− (group 1, n = 135), BAP1+/PRAME+ (group 2, n = 43), BAP1−/PRAME− (group 3, n = 94), and BAP1−/PRAME+ (group 4, n = 46). Increasing the study risk group on the basis of loss of BAP1 expression and positive PRAME staining was associated with a higher rate of metastasis and disease-specific death and lower metastasis-free survival (MFS) and disease-specific survival (DSS). Among tumors with loss of BAP1 staining, PRAME positivity was associated with shorter MFS (P = .018) and showed a trend toward shorter DSS (P = .061). Among tumors with retained BAP1 staining, PRAME positivity was associated with shorter MFS and DSS (P = .001 and P = .021, respectively). In summary, a combination of BAP1 and PRAME IHC can be used for risk stratification of UMs.
Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy
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PRAME also enhances cancer cell migration, invasion, and metastasis [35]. Furthermore, overexpression of PRAME is closely associated with poor prognosis in various types of cancer [26,42–47]. The CT45 family consists of nine members which are located at the chromosome Xq26-q28 narrow region.
Increasing evidence shows that numerous cancer-testis antigens (CTAs) are uniquely overexpressed in various types of cancer and most CTAs are oncogenic. Overexpression of oncogenic CTAs promotes carcinogenesis, cancer metastasis, and drug resistance. Oncogenic CTAs are generally associated with poor prognosis in cancer patients and are an important hallmark of cancer, making them a crucial target for cancer immunotherapy. CTAs-targeted antibodies, vaccines, and chimeric antigen receptor-modified T cells (CAR-T) have recently been used in cancer treatment and achieved promising outcomes in the preclinical and early clinical trials. However, the efficacy of current CTA-targeted therapeutics is either moderate or low in cancer therapy. CTA-targeted cancer immunotherapy is facing enormous challenges. Several critical scientific problems need to be resolved: (1) the antigen presentation function of MHC-I protein is usually deficient in cancer patients, so that very low amounts of intracellular CTA epitopes are presented to tumor cell membrane surface, leading to weak immune response and subsequent immunity to CTAs; (2) various immunosuppressive cells are rich in tumor tissues leading to diminished tumor immunity; (3) the tumor tissue microenvironment markedly reduces the efficacy of cancer immunotherapy. In the current review paper, the authors propose new strategies and approaches to overcome the barriers of CTAs-targeted immunotherapy and to develop novel potent immune therapeutics against cancer. Finally, we highlight that the oncogenic CTAs have high tumor specificity and immunogenicity, and are sensible targets for cancer immunotherapy. We predict that CTAs-targeted immunotherapy will bring about breakthroughs in cancer therapy in the near future.
Uveal melanoma pathobiology: Metastasis to the liver
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Citation Excerpt :
Retrospective studies have compared PRAME expression along with GEP and TNM staging [102,103]. They reported that GEP and PRAME showed a superior prognostic power than TNM staging, and that PRAME + status correlated with largest basal diameter, tumor volume, and worsening GEP class [102,103]. Another classification based on RNA expression, DNA methylation and chromosomal data from TCGA separated the UM primary tumors into categories A to D based on the presence of monosomy 3 and the degree of chromosome 8q gain [21,104].
Uveal melanoma (UM) is a type of intraocular tumor with a propensity to disseminate to the liver. Despite the identification of the early driver mutations during the development of the pathology, the process of UM metastasis is still not fully comprehended. A better understanding of the genetic, molecular, and environmental factors participating to its spread and metastatic outgrowth could provide additional approaches for UM treatment. In this review, we will discuss the advances made towards the understanding of the pathogenesis of metastatic UM, summarize the current and prospective treatments, and introduce some of the ongoing research in this field.
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Original articleGene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma

Purpose

Design

Methods

Results

Conclusions

Section snippets

Clinical Data Collection

Results

Discussion

Ophthalmology

Ophthalmology

Ophthalmology

Ophthalmology

Lancet Oncol

Ophthalmology

Ophthalmology

J Mol Diagn

Current management of uveal melanoma

Expert Rev Ophthalmol

AJCC Cancer Staging Manual

Outcome prediction and the future of the TNM staging system

J Natl Cancer Inst

Long-term survivors after pancreatectomy for cancer: the TNM classification is outdated

ANZ J Surg

Comparison of alternative tumor size classifications for posterior uveal melanomas

Invest Ophthalmol Vis Sci

Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas

Am J Ophthalmol

Original article
Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma