Gene Expression Profile Status Research Articles

Real-world impact of TAILORx on chemotherapy use and SOFT/TEXT on ovarian function suppression uptake in a population based-cohort of women 40 years and under with HR-positive, HER2-negative, axillary lymph node negative breast cancer.

534 Background: Gene expression profiling (GEP) testing is prognostic for distant recurrence risk in women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-), axillary lymph node negative (LN-) breast cancer (BC). The TAILORx trial generated prospective evidence demonstrating the 21-gene recurrence score (RS) is also predictive of chemotherapy (CT) benefit. The literature suggests that GEP testing reduces adjuvant CT prescription and is cost-effective. In the same era, the SOFT/TEXT trials demonstrated disease-free survival benefit for the addition of ovarian function suppression (OFS) to endocrine therapy in premenopausal women. Real-world uptake and impact of these advances in the management of HR+, HER2-, LN- BC in young women may be limited due to complex reasons. This retrospective study evaluated GEP and CT use post TAILORx and OFS use post SOFT/TEXT in women 40 years old or younger diagnosed with HR+, HER2-, LN BC from 2011 to 2020 in Alberta, Canada. Methods: Clinical variables were retrieved from the Alberta Health Services Cancer Care Breast Data Mart and through review of the electronic medical record. GEP testing and CT use were compared between 3 cohorts of women defined by diagnosis: pre RS funding/pre TAILORx (before April 2014), post RS funding/pre TAILORx (April 2014-May 2018), post TAILORx (June 2018 and beyond). OFS use was compared between 2 cohorts of women defined by diagnosis pre- and post SOFT/TEXT (May 2015). In subgroup analyses, we compared CT use by GEP status and RS category and OFS use by CT status. Results: Among the 291 women identified, GEP testing increased by 37% post GEP funding (pre 2% vs. post 39%; P = < .0001) and by additional 15% post TAILORx (pre 39% vs. post 54%; P < .0001) whereas overall CT use declined by 15% post GEP funding (pre 85% vs. post 70%; P = .01) and by additional 16% post TAILORx (pre 70% vs. post 54%; P = .01). Although not significant, OFS use increased by 8% post SOFT/TEXT (pre 13% vs. post 21%; P = .08). In subgroup analyses, post TAILORx was associated with a significant reduction in CT use of 19.5% in non-GEP tested women (pre 85% vs. post 65% P = .01) and non-significant increase in CT use of 6% in RS tested women (pre 40% vs. post 46%; P = .61) mainly driven by high mid range RS 21-25 and lower high range RS 26-30. There was no significant change in OFS use in non-CT treated women post SOFT/TEXT (Pre 5.3% vs. Post 8%, P = .68) whereas OFS use increased by 15% in women treated with CT post SOFT/TEXT (pre 15% vs. post 30%; P = .01). Conclusions: Public GEP funding and TAILORx led to widespread adoption of GEP and real-world decline in CT use in women 40 years of age or younger diagnosed with HR+, HER2-, LN- BC in Alberta. SOFT/TEXT led to real-world incline in OFS use in those treated with CT but adoption remained suboptimal.

Prognostic significance of T-cell-inflamed gene expression profile and PD-L1 expression in patients with esophageal cancer.

PurposeThe ability of the T‐cell–inflamed gene expression profile (GEP) to predict clinical outcome in esophageal cancer (EC) is unknown. This retrospective observational study assessed the prognostic value of GEP and programmed death ligand 1 (PD‐L1) expression in patients with EC treated in routine clinical practice.MethodsTumor samples of 294 patients from three centers in Denmark, South Korea, and the United States, collected between 2005 and 2017, were included. T‐cell–inflamed GEP score was defined as non‐low or low using a cutoff of −1.54. A combined positive score (CPS) ≥10 was defined as PD‐L1 expression positivity. Associations between overall survival (OS) and GEP status and PD‐L1 expression were explored by Cox proportional hazards models adjusting for age, sex, histology, stage, and performance status.ResultsMedian age was 65 years; 63% of patients had adenocarcinoma (AC) and 37% had squamous cell carcinoma (SCC). Thirty‐six percent of tumors were GEP non‐low, with higher prevalence in AC (46%) than SCC (18%). Twenty‐one percent were PD‐L1–positive: 32% in South Korean samples versus 16% in non‐Asian samples and 26% in SCC versus 18% in AC. GEP scores and PD‐L1 CPS were weakly correlated (Spearman’s R = 0.363). OS was not significantly associated with GEP status (non‐low vs low; adjusted hazard ratio, 0.91 [95% CI, 0.69–1.19]) or PD‐L1 expression status.ConclusionNeither GEP nor PD‐L1 expression was a prognostic marker in Asian and non‐Asian patients with EC.

A Systematic Review and Meta-Analysis of Gene Expression Profiling for Primary Cutaneous Melanoma Prognosis

To decrease morbidity and mortality from melanoma, it is imperative to identify patients who are at high risk for developing widespread disease. Gene expression profiling (GEP) technology may impact melanoma management as physicians are better equipped to measure prognosis. Many different GEP signatures have been investigated. We searched Pubmed, Cochrane CENTRAL, and Embase for studies on GEP in primary melanoma prognosis and assessed GEP signatures for prognostic and analytic validity and clinical impact. The relationship between GEP and survival was measured using hazard ratios (HR) and odds ratios (OR). We found twenty-nine articles comprising 9 gene signatures meeting inclusion criteria and conducted a meta-analysis on 6 studies on a 31-gene signature. High-risk GEP status was associated with poorer recurrence-free survival (HR=7.22; 95% CI, 4.75-10.98), distant metastasis-free survival (HR=6.62; 95% CI, 4.91-8.91), and overall survival (HR=7.06; 95% CI, 4.44-11.22); as well as sentinel lymph node biopsy positivity (OR=2.99; 95% CI, 2.15-4.15). With recent improvements in treating advanced melanoma, accurately assessing prognosis is important. This study has clinical implications for melanoma patients who may benefit from prognostic testing. These results may be useful to clinicians when ordering GEP testing and help them make better management decisions.

Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma.

Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status. This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/- status with all clinical and molecular variables. One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status. In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.

Risk-stratified systemic surveillance in uveal melanoma

Background/AimMolecular prognostication provides clinically applicable prognostic information for patients with uveal melanoma. Most ocular oncologists recommend intensive metastatic surveillance for patients with high-risk tumours. However, socioeconomic variables may limit a...

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

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). Retrospective cohort study. 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. 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 29months (mean 42months; range 1-195months). 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). In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.

Association between Tumor Regression Rate and Gene Expression Profile after Iodine 125 Plaque Radiotherapy for Uveal Melanoma

Gene expression profile (GEP) testing segregates uveal melanoma (UM) into 2 main prognostic classes. It is unknown if a greater tumor regression response after iodine 125 (I125) brachytherapy correlates with class 2 GEP status. The purpose of this study was to determine whether there is a significant relationship between the rate of UM height regression and GEP classification testing after I125 plaque brachytherapy. Multicenter, retrospective cohort study. Adult UM patients treated with I125 plaque brachytherapy who had concurrent tumor biopsy at the time of surgery with a GEP test result from January 1, 2010 through June 30,2014. Baseline clinical data and GEP class assignments were obtained. The ultrasonographic tumor height was recorded at baseline and at 3, 6, 9, and 12 months and at the most recent final follow-up visits. Subanalysis of paired cases based on pretreatment ultrasound height was performed. Statistical analysis was performed using Wilcoxon rank-sum tests, the Fisher exact test, and Kaplan-Meier analysis. Percentage change in tumor height from baseline. A total of 353 patients were included in the study. Median follow-up was 2.1 years (range, 0.5-5.3 years). Gene expression profile status was class 1 in 247 tumors (70%) and class 2 in 106 tumors (30%). Increased patient age, larger tumor dimensions, and greater tumor thickness were associated with class 2 GEP status (P= 0.006, P < 0.001, and P < 0.001, respectively). The percentage reduction in tumor height from baseline was significantly greater in class 1 than class 2 tumors at 3 months (17.5% vs. 11.8%; P= 0.007) and 6 months (26.8% vs. 17.1%; P= 0.007), respectively, but there was no significant difference in reduction between class 1 and 2 tumors at 9 months (P= 0.26) and 12 months (P= 0.57) after treatment. Class 1A and 1B tumors showed similar reduction compared with class 2 tumors (P < 0.05). Class 1 UM tumors tend to regress more rapidly than class 2 tumors in the first 6 months after plaque radiotherapy. Class 1A and 1B tumors regress at similar rates after plaque radiotherapy.

Current status of gene expression profiling to assist decision making in stage II colon cancer.

The decision regarding adjuvant therapy for patients with stage II colon cancer remains a challenge. In contrast to stage III colon cancer, for which compelling clinical data support the use of adjuvant chemotherapy, the clinical benefit of systemic therapy in unselected patients with stage II disease is modest at best. Risk stratification based on clinicopathologic features and DNA mismatch repair status is commonly used in adjuvant therapy decisions, but these factors do not have a desired level of precision in identifying patients at high risk. Recently, gene expression platforms have been developed to further define risk and to assist in therapeutic decision making for patients with stage II disease. This review describes those platforms that are furthest along in clinical development, in an effort to place their potential clinical application in context.

Current status of gene expression profiling in the diagnosis and management of acute leukaemia

Gene expression profiling (GEP) enables the simultaneous investigation of the expression of tens of thousands of genes and was successfully introduced in leukaemia research a decade ago. Aiming to better understand the diversity of genetic aberrations in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), pioneer studies investigated and confirmed the predictability of many cytogenetic and molecular subclasses in AML and ALL. In addition, GEP can define new prognostic subclasses within distinct leukaemia subgroups, as illustrated in AML with normal karyotype. Another approach is the development of treatment-specific sensitivity assays, which might contribute to targeted therapy studies. Finally, GEP might enable the detection of new molecular targets for therapy in patients with acute leukaemia. Meanwhile, large multicentre studies, e.g. the Microarray Innovations in LEukaemia (MILE) study, prepare for a standardised introduction of GEP in leukaemia diagnostic algorithms, aiming to translate this novel methodology into clinical routine for the benefit of patients with the complex disorders of AML and ALL.

Global Expression Profiling in Epileptogenesis: Does It Add to the Confusion?

Since the inception of global gene expression profiling platforms in the mid‐1990s, there has been a significant increase in publications of differentially expressed genes in the process of epileptogenesis. In particular for mesial temporal lobe epilepsy, the presence of a latency period between the first manifestation of seizures to chronic epilepsy provides the opportunity for therapeutic interventions at the molecular biology level. Using global expression profiling techniques, approximately 2000 genes have been published demonstrating differential expression in mesial temporal epilepsy. The majority of these changes, however, are specific to laboratory or experimental conditions with only 53 genes demonstrating changes in more than two publications. To this end, we review the current status of gene expression profiling in epileptogenesis and suggest standard guidelines to be followed for greater accuracy and reproducibility of results.