SETER/PR: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer

npj Breast Cancer, Journal Year: 2019, Volume and Issue: 5(1)

Published: May 30, 2019

Abstract There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer endocrine therapy, targeted RNA sequencing (RNAseq) offers diagnostic potential measure both transcriptional activity functional mutation. We developed the SET ER/PR index gene expression microarray probe sets that were correlated with receptors ( ESR1 PGR ) robust preanalytical analytical influences. tested in biopsies metastastic HR+/HER2− against treatment outcomes 140 patients. Then we customized assay 18 informative, 10 reference transcripts, sequence ligand-binding domain (LBD) using droplet-based RNAseq, residual from 53 Higher samples predicted longer PFS OS when patients received therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 0.955, p = 0.035; OS: 0.315, 0.157 0.631, 0.001). Mutated LBD was detected 8/53 (15%) metastases, involving 1−98% transcripts (all had high index). A signature based on good performance facilitated our customization an accurate RNAseq phenotype genotype ER-related transcription. Elevated associated prolonged cancer, especially absence mutated transcript.

Language: Английский

---

Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(7), P. 989 - 998.e5

Published: June 17, 2021

Language: Английский

---

Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping

Cancer Cell, Journal Year: 2025, Volume and Issue: 43(2), P. 232 - 247.e4

Published: Feb. 1, 2025

Highlights•Classical intrinsic subtypes change during neoadjuvant therapy from LumB to LumA•A reverse-transition back is observed in metastatic disease•Improved dimension reduction by comparison of pre- and post-therapeutic samples•Identification adaptive prognostic subsets high-risk luminal breast cancerSummaryWe evaluate therapy-induced molecular heterogeneity longitudinal samples high-risk, hormone-receptor positive/HER2-negative cancer patients with residual tumor after chemotherapy the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic are pre-therapeutic (Tx) (n = 629, p < 0.0001) post-Tx tumors 782, 0.0001). After chemotherapy, a shift pre-Tx (Lum) B LumA, reverse transition metastases. In combined analysis 540 paired samples, we identify five clusters (AC-1–5) based on transcriptomic changes before chemotherapy. These AC-subtypes beyond classical subtyping, categorizing into groups excellent prognosis (AC-1 AC-2), poor (AC-3 AC-4), very (AC-5, enriched for basal-like subtype). Our provides basis an extended classification improved identification patient populations.Graphical abstract

Language: Английский

---

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(8), P. 2921 - 2921

Published: April 22, 2020

The vast majority of breast cancer death is a result metastasis. Thus, accurate identification patients who are likely to have metastasis expected improve survival. G2M checkpoint plays critical role in cell cycle. We hypothesized that tumors with high activity pathway genes more aggressive and metastasize. To test this, we used the single-sample gene set variation analysis method calculate score for Hallmark using expression data total 4626 samples from 12 human cohorts. As expected, correlated enriched tumor other proliferation-related sets. was significantly associated clinical features patient survival estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative cancer. Interestingly, also worse In primary as well scores, infiltration both pro- anti-cancerous immune cells increased. Tumor treatment response systemic chemotherapy ER-positive/HER2-negative cancer, predictive cyclin-dependent kinase inhibition therapy.

Language: Английский

---

The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer

Cells, Journal Year: 2020, Volume and Issue: 9(7), P. 1643 - 1643

Published: July 8, 2020

E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness therapy. We scored 3905 tumors of nine breast cancer cohorts for this based on gene expression Hallmark targets set. As expected, with a high score had an increased proliferation-related genes. A was significantly associated shorter patient survival, greater MKI67 expression, histological grade, stage, genomic aberrations. Furthermore, metastatic higher scores than primary from which they arose. Although infiltration by both pro- anti-cancerous immune cells, checkpoint Estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative achieved pathological complete response (pCR) rate neoadjuvant chemotherapy. The cyclin-dependent kinase (CDK)-related genes strongly correlated sensitivity CDK inhibition lines. In conclusion, marker predicts ER-positive/HER2-negative patients chemotherapy possibly inhibitors.

Language: Английский

---

MYC Targets Scores Are Associated with Cancer Aggressiveness and Poor Survival in ER-Positive Primary and Metastatic Breast Cancer

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(21), P. 8127 - 8127

Published: Oct. 30, 2020

MYC is one of the most studied oncogenes that known to promote cell proliferation. We utilized targets v1 and v2 scores gene set variation analysis hypothesized these correlate with tumor aggressiveness survival outcomes. examined a total 3109 breast cancer patients from TCGA, METABRIC, GSE124647 cohorts. In each cohort, were divided into high- low-score groups using upper third value as cut off. As expected, higher related increased proliferation worse clinical pathologic features. High associated survival, specifically in primary ER-positive cancer, consistently both TCGA METABRIC high v1, but not score, was mutation load, infiltration pro- anti-cancerous immune cells. found metastatic cancer. Our findings show are poor prognosis tumors, well

Language: Английский

---

Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 22, 2023

The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management era antibody‒drug conjugates. To address this issue, we established a cohort 434 patients with cancer (433 female one male) integrated genomic, transcriptomic, proteomic, metabolomic profiling data. In cohort, tumors more distinguished from HER2-0 hormone receptor-negative subgroup. Within tumors, significant interpatient also exists subgroup: basal-like resemble disease, non-basal-like mimic HER2-positive disease. These enriched HER2-enriched subtype luminal androgen receptor feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression lipid metabolism activation. Among receptor-positive show less loss/deletion 17q peaks than tumors. work, reveal cancers emphasize need for stratification regarding status subtype.

Language: Английский

---

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

Abstract Background Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER + ) cancer elucidate their importance in oestrogen‐dependent tumour growth. Methods Two PDXs ‘ER‐high’ cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) SC31 (40–90% models. The observation was validated via analyses an ‘ER‐low’ PDX, GS1 (5% ER). results from our further supported by public ER dataset protein‐based dual immunohistochemistry (IHC) examining important luminal markers (i.e., ER, progesterone receptor Ki67). translational implication findings assessed clinical outcome publicly available cohorts. Results Our space‐gene‐function study revealed four distinct compartments These showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced inflammation‐related). ‘proliferative’ population, rather than the ‘oestrogen‐responsive’ compartment, crucial for growth, leading acquisition B‐like features. cells expressing typical oestrogen‐responsive genes like PGR not directly linked proliferation. Dual IHC demonstrated contribution Ki67 proliferative toward response CDK4/6 inhibitor. gene signatures derived inflammation‐related significantly correlated worse outcomes, while patients signature better prognoses, suggesting that this compartment would be associated progression. Conclusions identified as determinant subtypes. This population causative feature B cancer, contributing its aggressive behaviours.

Language: Английский

---

Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies

Cancer Research, Journal Year: 2024, Volume and Issue: 84(21), P. 3669 - 3683

Published: Aug. 26, 2024

HER2-positive breast cancer is an aggressive subtype that accounts for 15% to 20% of all cancers. Recent studies have suggested a group heterogeneous diseases with different sensitivities standard treatment regimens. Revealing the molecular heterogeneity could potentially enable more precise strategies. In this study, we performed multiomics profiling on cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) comprised 28.3% samples displayed high ERBB2 activation significant benefit from anti-HER2 therapy. immunomodulatory (HER2-IM) (20%) featured immune-activated microenvironment, suitable de-escalated immunotherapy. luminal-like (HER2-LUM) (30.6%) possessed similar features hormone receptor-positive HER2-negative cancer, suggesting endocrine therapy CDK4/6 inhibitors as potential therapeutic strategy. Lastly, basal/mesenchymal-like (HER2-BM) (21.1%) had poor response current dual HER2-targeted tyrosine kinase inhibitors. characteristics clinical subtypes were further explored across multiple cohorts, feasibility proposed strategies was validated in patient-derived organoid tumor fragment models. This study elucidates paves way tailored treatment. Significance: Illumination inherent within cancers through delineation distinct lays groundwork developing personalized based specific patient characteristics.

Language: Английский

---

Adjuvant Dose-Dense Chemotherapy in Hormone Receptor–Positive Breast Cancer

Journal of Clinical Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

PURPOSE In light of evolving evidence that some patients with node-positive estrogen receptor–positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes the C9741 trial overall, and by sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring transcriptional activity, identify most likely dose-dense chemotherapy. METHODS all, 1,973 were randomly assigned versus conventional Hazard ratios (HRs) for prognosis predictive interaction chemotherapy schedule estimated Cox models long-term disease-free survival (DFS) overall (OS). SET2,3 was tested on 682 banked RNA samples ER+ cancers. RESULTS Dose-dense improved DFS in population 23% (HR, 0.77 [95% CI, 0.66 0.90]) OS 20% 0.80 0.67 0.95]); benefits seen ER-negative subsets, without significant between treatment arm ER status. Low status highly prognostic, but also predicted (interaction P = .0998 DFS; 0.027 OS), independent menopausal Specifically, low activity whereas tumor burden proliferation-driven signatures molecular subtype classification did not. CONCLUSION At follow-up, confirmed sustained adjuvant breast cancer. identified cancer who benefited specifically, cancer, rather than burden, subtype, or

Language: Английский

---