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CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

ABSTRACT: PURPOSE:To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM). METHODS:A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and October 28, 2014. Patient demographics and UM features were analyzed by both GEP and AJCC status. RESULTS:Gene expression profile class divided the cohort into three groups: Class 1a (n = 186), Class 1b (n = 77), and Class 2 (n = 113). When classified using AJCC staging criteria, we found the following: Stage I in 91 cases (25.3%), Stage IIA in 143 cases (39.7%), Stage IIB in 89 cases (24.7%), Stage IIIA in 36 cases (10%), and Stage IIIB in 1 case (0.3%). There were no Stage IV cases, as lymph node and metastatic data were not collected as a part of this study. Among Stage I tumors, both high tumor height and high largest basal diameter were associated with a higher frequency of Class 2 status (P < 0.05). As UMs progress to a larger AJCC tumor group (T1-T4), the odds ratio of having a worse prognosis based on GEP class was 1.75 (95% CI, 1.36-2.25; P < 0.001). Similarly, as UMs progress to a higher AJCC stage, the odds ratio of having a worse prognosis based on GEP class was 1.69 (95% CI, 1.36-2.10; P < 0.001). CONCLUSION:This report details the differences in clinical features between GEP subclasses and how they are distributed among the AJCC stages. When the tumors were grouped by AJCC staging criteria, both larger AJCC tumor (T) group and worsening AJCC stage were associated with worsening predicted prognosis, based on GEP subclass.

SUBMITTER: Berry DE

PROVIDER: S-EPMC6506408 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

Berry Duncan E DE Schefler Amy C AC Seider Michael I MI Materin Miguel M Stinnett Sandra S Mruthyunjaya Prithvi P

Retina (Philadelphia, Pa.) 20200201 2

<h4>Purpose</h4>To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM).<h4>Methods</h4>A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and Oc ...[more]

PMID: 31972790

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Project description:This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns.

Project description:ImportanceFrequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine.ObjectiveTo determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM.Design, setting, and participantsRetrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014.Main outcomes and measuresClinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded.ResultsThe study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6-69.1) (P < .001 for both). After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4-33.5) and melanoma-specific mortality (relative risk, 9.0; 95% CI, 2.8-29.2) (P < .001 for both).Conclusions and relevanceBAP1, SF3B1, and EIF1AX mutations occur during UM tumor progression in an almost mutually exclusive manner and are associated with different levels of metastatic risk. These mutations may have value as prognostic markers in UM.

Project description:ImportanceUveal melanoma (UM) can be divided into prognostically significant subgroups based on a prospectively validated and widely used 15-gene expression profile (GEP) test. Class 1 UMs have a low risk and class 2 UMs have a high risk for metastasis.ObjectiveTo determine whether any clinicopathologic factors provide independent prognostic information that may enhance the accuracy of the GEP classification.Design, setting, and participantsThis retrospective observational study performed at 2 ocular oncology referral centers included 339 patients in a primary cohort and 241 patients in a validation cohort. Both cohorts had a diagnosis of UM arising from the ciliary body and/or choroid. All patients underwent tumor biopsy for GEP prognostic testing. Clinicopathologic variables included patient age and sex, tumor thickness, largest basal tumor diameter (LBD), ciliary body involvement, and pathologic cell type. Patients from the primary cohort were enrolled from November 1, 1998, to March 16, 2012; from the validation cohort, from November 4, 1996, to November 7, 2013. Follow-up for the primary cohort was completed on August 18, 2013; for the validation cohort, December 10, 2013. Data were analyzed from November 12, 2013, to November 25, 2015.Main outcome and measuresProgression-free survival (PFS). The secondary outcome was overall survival.ResultsThe primary cohort included 339 patients (175 women [51.6%]; mean [SD] age, 61.8 [13.6] years). The most significant prognostic factor was GEP classification (exp[b], 10.33; 95% CI, 4.30-24.84; P?<?.001). The only other variable that provided independent prognostic information was LBD (exp[b], 1.13; 95% CI, 1.02-1.26; P?=?.02). Among class 2 UMs, LBD showed a modest but significant association with PFS (exp[b], 1.13; 95% CI, 1.04-1.24; P?=?.005). The 5-year actuarial metastasis-free survival estimates (SE) were 97% (3%) for class 1 UMs with LBD of less than 12 mm, 90% (4%) for class 1 UMs with LBD of at least 12 mm, 90% (9%) for class 2 UMs with LBD of less than 12 mm, and 30% (7%) for class 2 UMs with LBDs of at least 12 mm. The independent prognostic value of LBD and the 12-mm LBD cutoff were corroborated in the independent validation 241-patient cohort.Conclusions and relevanceClass 2 UMs had better prognosis when the LBD was less than 12 mm at the time of treatment. These findings could have important implications for patient counseling, primary tumor treatment, clinical trial enrollment, metastatic surveillance, and adjuvant therapy.

Project description:A 15-gene expression profile test has been clinically validated and is widely utilized in newly diagnosed uveal melanoma (UM) patients to assess metastatic potential of the tumor. As most patients are treated with eye-sparing radiotherapy, there is limited tumor tissue available for testing, and technical reliability and success of prognostic testing are critical. This study assessed the analytical performance of the 15-gene expression test for UM and the correlation of molecular class with pathologic characteristics.Inter-assay, intra-assay, inter-instrument/operator, and inter-site experiments were conducted, and concordance of the 15-gene expression profile test results and associated discriminant scores for matched tumor samples were evaluated. Technical success was determined from de-identified clinical reports from January 2010 - May 2016. Pathologic characteristics of enucleated tumors were correlated with molecular class results.Inter-assay concordance on 16 samples run on 3 consecutive days was 100%, and matched discriminant scores were strongly correlated (R2 = 0.9944). Inter-assay concordance of 46 samples assayed within a one year period was 100%, with an R2 value of 0.9747 for the discriminant scores. Intra-assay concordance of 12 samples run concurrently in duplicates was 100%; discriminant score correlation yielded an R2 of 0.9934. Concordance between two sites assessing the same tumors was 100% with an R2 of 0.9818 between discriminant scores. Inter-operator/instrument concordance was 96% for Class 1/2 calls and 90% for Class 1A/1B calls, and the discriminant scores had a correlation R2 of 0.9636. Technical success was 96.3% on 5516 samples tested since 2010. Increased largest basal diameter and thickness were significantly associated with Class 1B and Class 2 vs. Class 1A signatures.These results show that the 15-gene expression profile test for UM has robust, reproducible performance characteristics. The technical success rate during clinical testing remains as high as first reported during validation. As molecular testing becomes more prevalent for supporting precision medicine efforts, high technical success and reliability are key characteristics when testing such limited and precious samples. The performance of the 15-gene expression profile test in this study should provide confidence to physicians who use the test's molecular classification to inform patient management decisions.

Dataset Information

CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

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CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA.

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