Biomedical subjects

Christos Sotiriou

Publications and source records attributed to Christos Sotiriou.

3 recordsLinked to original sources

PubMed2026

Prognostic role of thymidine kinase 1 activity in hormone receptor positive metastatic breast cancer. A systematic review and meta-analysis.

INTRODUCTION: Circulating thymidine kinase 1 activity (TKa) is a potential prognostic biomarker in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC); however, results are heterogeneous. In this study we aimed to summarize the current evidence on the prognostic role of circulating TKa in women with HR+ MBC. METHODS: We conducted a systematic review of PubMed, Embase, and Cochrane CENTRAL databases and abstracts from main international oncology meetings. Phase II-IV clinical trials and prospective observational studies in patients with MBC assessing circulating TK1 levels or TKa and reporting hazard ratios (HRs) for progression-free survival (PFS) and/or overall survival (OS) were included. HRs were pooled using random-effects models (restricted maximum likelihood with Hartung-Knapp adjustment), with heterogeneity quantified by I2 and prediction intervals. The primary study outcome was the association of baseline and on-treatment TKa with PFS and OS. Secondary analyses aimed at exploring the source of heterogeneity. RESULTS: Eighteen studies, reporting data from nearly 3000 women, were included in the systematic review and 15 studies were meta-analyzed. Patients with HR+ MBC and high baseline TKa showed a significantly higher risk of progression (PFS: HR 1.90; 95% CI 1.57-2.30; p < 0.001) and death (OS: HR 2.48; 95% CI 1.94-3.17; p < 0.001) than those with low TKa. TKa at 2 and 4 weeks on-treatment was also prognostic (2 weeks, PFS: HR 2.76; 95% CI 2.34-3.26; p < 0.001; 4 weeks, HR 2.26; 95% CI 1.93-2.66; p < 0.001). Similar pooled effects were obtained when accounting for different cut-offs, TKa assessment, and sample-type. CONCLUSION: Pre-treatment high TKa is an adverse prognostic factor in women with HR+ MBC. High on-treatment TKa is also associated with worse outcome, potentially serving as an early signal of treatment resistance. We provide a comprehensive summary of the currently available evidence on the prognostic value of circulating TKa.

Breast cancer↗

PubMed2026

Artificial intelligence-based tumour infiltrating lymphocyte quantification in patients with triple-negative breast cancer: an independent validation study.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are a robust prognostic marker in patients with triple-negative breast cancer. Artificial intelligence (AI)-derived computational tools assessing TILs could improve efficiency, but require independent validation against clinical outcomes. We aimed to compare the prognostic performance of AI-derived TIL scores with pathologist-scored TILs in a large, prospectively collected dataset pooled from randomised controlled trials. METHODS: CATALINA was an independent, external validation study using prospectively collected long-term clinical outcome data pooled from seven randomised clinical trials conducted at multiple sites. We independently evaluated two previously validated AI pipelines that generate five computationally assessed tumour-infiltrating lymphocyte (cTIL) scores by masked, independent deployment of locked models. cTIL scores were correlated with the mean of the pathologist-scored stromal TILs (sTILs) in 220 digitised haematoxylin and eosin whole slide images in a cohort of patients with early-stage triple-negative or HER-2 positive breast cancer, previously scored by trained pathologists in a TIL-reproducibility study. Prognostic performance was assessed in a separate cohort of patients with early triple-negative breast cancer pooled from seven prospective, randomised adjuvant trials. Multivariable Cox regression models adjusted for clinicopathological factors and study heterogeneity assessed associations of cTIL score and sTIL score with invasive disease-free survival, distant disease-free survival, and overall survival. 5-year discrimination was estimated using time-dependent area under the receiver operating characteristic curve (AUC). FINDINGS: Individual data were collated from 1759 patients, of whom 1356 had complete clinicopathological data, pathologist sTIL scores, and cTIL scores available. Modest correlation (r 0·375-0·473) was observed between cTIL scores and the mean pathologist sTIL score. Both sTIL and cTIL were independently associated with 5-year invasive disease-free survival, distant disease-free survival, and overall survival after adjustment for clinicopathological factors (hazard ratio for invasive disease-free survival was 0·73 [95% CI 0·66-0·82]; q<0·0001, distant disease-free survival was 0·70 [0·61-0·79]; q<0·0001, and overall survival was 0·72 [0·63-0·82]; q<0·0001 for sTIL scores and 0·80 [0·73-0·89]; q<0·0001, 0·77 [0·69-0·86]; q<0·0001, and 0·79 [0·70-0·88]; q=0·0002, respectively, for percentage_lymphocyte scores). In models adjusted for clinicopathological variables and sTIL score, cTIL score did not maintain a statistically significant prognostic association. Both sTIL and cTIL scores improved the 5-year AUC over clinicopathological variables alone, while cTIL score did not significantly further improve AUC when combined with clinicopathological variables and sTIL score. INTERPRETATION: Two cTIL models deployed entirely without retraining or modification provided statistically significant prognostic information and improved risk discrimination compared with clinicopathological variables alone in this large, platform-based, independent validation study. Although cTIL score did not incrementally improve prognostication compared with models combining clinicopathological variables with sTIL score, these findings support the application of cTILs as a reproducible prognostic biomarker, particularly in settings where routine or widespread pathologist assessment is unavailable. FUNDING: Breast Cancer Research Foundation (USA).

Humans↗

PubMed2022

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.

UNLABELLED: Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. SIGNIFICANCE: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells ("pre-DTPs") that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873.

Breast Neoplasms↗