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- Giltnane, Jennifer M., et al.
(författare)
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Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor - Positive premenopausal breast cancer
- 2007
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 25:21, s. 3007-3014
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Although there is evidence for interaction between epidermal growth factor receptor ( EGFR) and estrogen receptor ( ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology. Patients and Methods A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression. Results In ER-positive patients, tamoxifen-treated patients with low EGFR expression ( n = 113) showed a significant effect by 2 years of adjuvant tamoxifen ( P = .01), in contrast to no treatment effect in the EGFR-high group ( n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high ( P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group ( hazard ratio [ HR] = 0.43 ( 95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group ( HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model. Conclusion This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.
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| 2. |
- Mariathasan, Sanjeev, et al.
(författare)
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TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
- 2018
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 554:7693, s. 544-548
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8 + T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8 + T cells from the tumour parenchyma that were instead found in the fibroblast-and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-Administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-Tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-Tumour immunity by restricting T-cell infiltration.
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