| 11. |
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| 12. |
- Loughman, T., et al.
(författare)
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Analytical validation of OncoMasTR, a multigene test for predicting risk of distant recurrence in hormone receptor-positive early stage breast cancer
- 2018
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 29:Suppl. 8, s. 65-65
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: OncoMasTR is a new multigene prognostic test that was discovered via a novel transcriptional network analysis method that identified upstream Master Transcription Regulators (MTRs), which regulate previously identified prognostic biomarkers. The optimised OncoMasTR signature incorporating clinicopathological information has been shown to be significantly prognostic for predicting distant recurrence in two independent cohorts (TransATAC & a subset of TAILORx from participating Irish centres). The analytical performance characteristics of the OncoMasTR test, comprising solely three prognostic MTRs, were determined. Methods: Relative gene expression levels were measured by RT-qPCR. Assay precision and input ranges were determined using a panel of samples representative of low and high recurrence risk tested across a number of runs incorporating different sources of variation. Serial dilutions of a pooled patient RNA sample was used to establish the linear range and efficiency of the individual gene assays. Results: The overall standard deviation of the OncoMasTR risk score was 0.15, which represents less than 2% of the 10-unit risk score range. The majority of the variability in OncoMasTR results was related to within-run variation (78.2%) with other between-run variation sources contributing relatively little (PCR instrument (0.6%), assay operator (5.2%), reagent lots (7.3%) or loading position (8.7%)). Consistent risk scores were measured for individual samples from 40ng down to < 1ng RNA per PCR reaction. Individual gene assays were linear over >500-fold RNA input range corresponding to CT values of 23 – 36, demonstrating the ability of the test to reliably detect low level expression of the OncoMasTR panel. Importantly, PCR efficiencies were similar for the individual MTR and reference gene assays which ranged from 79 – 95%. Conclusions: The OncoMasTR prognostic test displays robust analytical and clinical performance and is being launched as a CE-marked test. The concise nature of the three gene signature and a simplified workflow that can be readily adopted using standard laboratory equipment will enable convenient qualification by local laboratories for decentralised use.
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| 13. |
- Lundgren, S., et al.
(författare)
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Discovery of KIRREL as a biomarker for prognostic stratification of patients with thin melanoma
- 2018
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 29:Suppl. 8, s. 463-463
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: There is a great unmet clinical need to identify patients with thin primary cutaneous melanomas (T1, Breslow thickness ≤ 1 mm) who have a high risk for tumor recurrence and death from melanoma. Kin of IRRE-like protein 1 (KIRREL/NEPH1) is expressed in podocytes and involved in glomerular filtration, but its expression in human cancer has not yet been reported. Screening in the Human Protein Atlas portal revealed a particularly high expression of KIRREL in melanoma, both at the mRNA and protein levels. In this study, we followed up on these findings and examined the prognostic value of KIRREL in a population-based cohort of melanoma. Methods: Immunohistochemical analysis of KIRREL was performed on tissue microarrays with a subset of primary tumors and paired lymph node metastases from an original cohort of 268 incident cases of melanoma in the Malmö Diet and Cancer study. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the relationship between KIRREL expression and time to recurrence (TTR) and melanoma-specific survival (MSS). The prognostic value of KIRREL mRNA expression was examined in 102 melanoma cases in The Cancer Genome Atlas (TCGA). Results: Membranous/cytoplasmic expression of KIRREL was detected in 158/185 (85.4%) primary tumours and 18/19 (94.7%) metastases, in various fractions and intensities. High expression of KIRREL was significantly associated with several unfavourable clinicopathological factors. KIRREL expression was not prognostic in tumours >1 mm thickness, but in T1 tumours (n = 106, median thickness 0.58, range 0.08-1.00), high expression of KIRREL was significantly associated with a reduced TTR, independent of and outperforming absolute thickness in mm and ulceration (HR = 4.54, 95% CI 1.01-20.45), and borderline significantly associated with MSS. High mRNA levels of KIRREL were associated with a significantly reduced overall survival in the TCGA (p = 0.028). Conclusions: KIRREL is not only a novel potential diagnostic marker for melanoma, but may also be a useful prognostic biomarker for improved stratification of patients with thin melanoma. These findings may be of high clinical relevance and therefore merit further validation.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Siesing, C., et al.
(författare)
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Prognostic significance of lymphocyte-activation gene-3 expression in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma
- 2018
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 29:Suppl. 8, s. 220-220
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neoadjuvant and/or adjuvant treatment has led to an improved survival in patients with resectable gastroesophageal adenocarcinoma (GEAC). Nevertheless, survival rates remain poor and, hence, there is a great need to identify novel treatment strategies and relevant complementary diagnostics. Immunotherapies targeting the PD‐1/PD‐L1 checkpoints have shown promising results, but simultaneous inhibition of other fundamental checkpoints, such as lymphocyte-activation gene-3 (LAG‐3), may further improve clinical outcome. The expression and prognostic significance of LAG-3 in GEAC has however not yet been described. Herein, we examined the expression of LAG-3 in tumour-infiltrating immune cells (TIC) in chemoradiotherapy-naïve GEAC and paired lymph node metastases, with particular reference to its relationship with PD-1 and PD-L1 expression, mismatch repair (MMR) status, and survival. Methods: Immunohistochemical LAG-3 expression was analysed in tissue microarrays with 165 primary tumours and 72 paired lymph node metastases from a retrospective consecutive cohort of patients with chemoradiotherapy-naïve resected GEAC. LAG-3 expression was denoted in categories of negative (0), low (1-10) and high (>10). PD-1, PD-L1 expression and MMR status had been previously analysed. Results: The distribution of LAG-3 expression in primary tumours was 55.8% negative, 28.5% low, and 15.8% high. The corresponding figures in lymph node metastases were 48.6% negative, 37.5% low, and 13.9% high. LAG-3 expression did not differ by tumour location. Positive LAG-3 expression in primary tumours was an independent factor for prolonged overall survival in the entire cohort (HR = 0.64, 95% CI 0.43-0.96), and in gastric cancer (HR = 0.35, 95% CI 0.17-0.74). LAG-3 expression in primary tumours was significantly associated with PD-L1 expression in both tumour cells and TIC, and with PD-1 expression in TIC, but not with MMR status. Conclusions: LAG-3 is expressed in a considerable proportion of GEAC, with a similar distribution in primary tumours and lymph node metastases. Positive LAG-3 expression is an independent favourable prognostic factor, particularly in gastric cancer.
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