| 1. |
- Chen, Xinsong, et al.
(författare)
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Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.
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| 2. |
- Matikas, Alexios, et al.
(författare)
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PD-1 protein and gene expression as prognostic factors in early breast cancer
- 2020
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Ingår i: ESMO Open. - : BMJ Publishing Group Ltd. - 2059-7029. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a paucity of data on the prognostic value of programmed cell death protein 1 (PD-1) protein and gene expression in early breast cancer (BC) and the present study's aim was to comprehensively investigate it.Methods: The study consisted of three parts: a correlative analysis of PD-1 protein and gene expression from an original patient cohort of 564 patients with early BC; a systematic review and trial-level meta-analysis on the association between PD-1 protein expression and disease-free survival/overall survival (OS) in early BC; and a pooled gene expression analysis from publicly available transcriptomic datasets regarding PDCD1 expression.Results: In the study cohort, PD-1 protein, but not gene expression, was associated with improved OS (HRadj=0.73, 95% CI 0.55 to 0.97, p=0.027 and HRadj=0.88, 95% CI 0.68 to 1.13, p=0.312, respectively). In the trial-level meta-analysis, PD-1 protein expression was not found to be statistically significantly associated with outcomes in the overall population. Finally, in the pooled gene expression analysis, higher PDCD1 expression was associated with better OS in multivariable analysis in the entire population (HRadj=0.89, 95% CI 0.80 to 0.99, p=0.025) and in basal-like tumours.Conclusions: PD-1 protein and gene expression seem to be promising prognostic factors in early BC. Standardisation of detection and assessment methods is of utmost importance.
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| 3. |
- Schagerholm, Caroline, et al.
(författare)
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PIK3CA mutations in endocrine-resistant breast cancer
- 2024
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 14:1, s. 12542-
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Tidskriftsartikel (refereegranskat)abstract
- Around 75% of breast cancer (BC) patients have tumors expressing the predictive biomarker estrogen receptor α (ER) and are offered endocrine therapy. One-third eventually develop endocrine resistance, a majority with retained ER expression. Mutations in the phosphatidylinositol bisphosphate 3-kinase (PI3K) catalytic subunit encoded by PIK3CA is a proposed resistance mechanism and a pharmacological target in the clinical setting. Here we explore the frequency of PIK3CA mutations in endocrine-resistant BC before and during treatment and correlate to clinical features. Patients with ER-positive (ER +), human epidermal growth factor receptor 2 (HER2)-negative primary BC with an ER + relapse within 5 years of ongoing endocrine therapy were retrospectively assessed. Tissue was collected from primary tumors (n = 58), relapse tumors (n = 54), and tumor-free lymph nodes (germline controls, n = 62). Extracted DNA was analyzed through panel sequencing. Somatic mutations were observed in 50% (31/62) of the patients, of which 29% occurred outside hotspot regions. The presence of PIK3CA mutations was significantly associated with nodal involvement and mutations were more frequent in relapse than primary tumors. Our study shows the different PIK3CA mutations in endocrine-resistant BC and their fluctuations during therapy. These results may aid investigations of response prediction, facilitating research deciphering the mechanisms of endocrine resistance.
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| 4. |
- Zerdes, Ioannis, et al.
(författare)
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PD-1 protein and gene expression in early breast cancer : Prognostic implications
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:15 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We have previously shown the prognostic value of PD-L1 protein and gene expression in early breast cancer (BC), however, the prognostic role of PD-1 expression remains unclear.Methods: The prognostic value of PD-1 in early BC was investigated using three different approaches: i) evaluation of PD-1 at the protein (IHC, immunohistochemistry in tissue microarrays) and mRNA levels in a retrospective patient cohort of 586 patients treated for early BC in Stockholm, Sweden between 1997-2005, ii) systematic review and trial-level meta-analysis of studies published in Medline, Embase, Cochrane Library and Web of Science Core Collection libraries on the prognostic value of PD-1 IHC expression, and iii) pooled analysis of transcriptomic data from 39 publicly available datasets for the prognostic capacity of PD-1 gene expression. Univariate and multivariable Cox regression models were used.Results: In the retrospective study cohort, PD-1 protein was significantly associated with biologically high-risk characteristics. PD-1 protein, but not gene expression, was correlated with improved overall survival (OS) (adjusted HR = 0.73, 95% CI 0.55 – 0.96, p = 0.023 and adjusted HR = 0.88, 95% CI 0.68 – 1.13, p = 0.307, respectively). In the trial-level meta-analysis, 4736 entries were initially identified and 15 studies, including our original cohort, fulfilled the predefined eligibility criteria. PD-1 IHC expression was not prognostic in unselected patients. However, a significant correlation to improved disease-free survival was seen within the triple-negative subtype (pooled multivariate HR = 0.57, 95% CI 0.29 – 0.90, p = 0.02). In the pooled gene expression analysis, PD-1 gene expression was associated with improved OS in the entire population (adjusted HR = 0.89, 95% CI 0.80 – 0.99, p = 0.025) and in basal-like (adjusted HR = 0.77, 95% CI 0.63 – 0.95, p = 0.014) tumors.Conclusions: PD-1 expression at the RNA and protein levels represent promising prognostic factors, especially in the triple-negative and basal-like subtypes. Standardization and further validation are needed prior to clinical implementation.
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