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Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE study)

ABSTRACT: Biomarker studies for cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) are often limited by tissue availability and narrow genomic assessments. We conducted a multicenter prospective study to obtain an unbiased 'omics’ assessment of tumors derived from women commencing 1st line (1L) palbociclib plus letrozole for HR+ HER2- MBC. We generated RNA and DNA data from baseline and a subset of progression samples. Patient-derived xenograft models were established from 10 samples. Genome-wide analyses and semi-supervised assessments of RB1-genes were conducted using whole exome and RNA sequencing data from baseline and progression tumors. Genes (FAT1, MYC, CDK2, and AMBRA1) known to drive CDK4/6i response, were confirmed to be associated with progression free survival (PFS). Novel CDK4/6i response genes including TIMELESS, SAE1, CENPU, SPAG5, and EXO1, as well as copy alterations in cytobands 12q21.2; 11q24.2; 1p22.3; 11p15.1, and 4q22.2 were observed to be associated with PFS. Paired baseline/progression samples demonstrated enrichment of genes involved in lipid metabolic processes, particularly beta oxidation as well as frequent intrinsic subtype switching. An RB1 signature, associated with shorter PFS (HR=2.72, p=0.006) and lack of cell cycle arrest in the NeoPalana study, may identify a subgroup of patients with de novo endocrine resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317345 | GEO | 2026/01/28

REPOSITORIES: GEO

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	GSE317345_CQN_normalized_expression.txt.gz	Txt
	GSE317345_GeneCounts.txt.gz	Txt

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Similar Datasets

Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE study) paired

Project description:Biomarker studies for cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) are often limited by tissue availability and narrow genomic assessments. We conducted a multicenter prospective study to obtain an unbiased 'omics’ assessment of tumors derived from women commencing 1st line (1L) palbociclib plus letrozole for HR+ HER2- MBC. We generated RNA and DNA data from baseline and a subset of progression samples. Patient-derived xenograft models were established from 10 samples. Genome-wide analyses and semi-supervised assessments of RB1-genes were conducted using whole exome and RNA sequencing data from baseline and progression tumors. Genes (FAT1, MYC, CDK2, and AMBRA1) known to drive CDK4/6i response, were confirmed to be associated with progression free survival (PFS). Novel CDK4/6i response genes including TIMELESS, SAE1, CENPU, SPAG5, and EXO1, as well as copy alterations in cytobands 12q21.2; 11q24.2; 1p22.3; 11p15.1, and 4q22.2 were observed to be associated with PFS. Paired baseline/progression samples demonstrated enrichment of genes involved in lipid metabolic processes, particularly beta oxidation as well as frequent intrinsic subtype switching. An RB1 signature, associated with shorter PFS (HR=2.72, p=0.006) and lack of cell cycle arrest in the NeoPalana study, may identify a subgroup of patients with de novo endocrine resistance.

2026-01-28 | GSE317628 | GEO

Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Response to CDK4/6 Inhibition in Metastatic HR+/HER2- Breast Cancer

Project description:Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), combined with endocrine therapy, represent the standard treatment for metastatic HR+/HER2- breast cancer (mBC). Despite their established efficacy, intrinsic resistance affects approximately one-third of patients, posing a significant challenge and underscoring the importance of identifying reliable predictive biomarkers. This study utilizes single-cell RNA sequencing (scRNAseq) of metastatic site biopsies to unveil cellular and molecular biomarkers predictive of CDK4/6i response. Through this analysis, we have identified and validated the tumor-specific molecular biomarkers across two independent mBC patient cohorts using bulk RNAseq data from baseline fresh biopsies or FFPE slides of HR+/HER2- mBC patients prior to CDK4/6i treatment. Additionally, the data indicate that baseline predictors may include tumor-infiltrating cytotoxic NK and T lymphocytes, suggesting the potential utility of checkpoint inhibitors in CDK4/6i progressors. These potentially actionable insights underscore the importance of optimizing therapeutic strategies based on microenvironment-specific changes observed following disease progression.

2025-02-18 | GSE262288 | GEO

Characterizing of Breast Cancer translational PEARL clinical trial

Project description:Introduction In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed. Methods We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusion We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.

2023-01-26 | GSE223700 | GEO

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

Project description:The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has significantly improved outcomes for patients with hormone receptor-positive (HR+) metastatic breast cancer. However, most patients eventually develop resistance, leading to treatment discontinuation. The therapeutic benefits of maintaining CDK4/6i or transitioning to CDK2 inhibitors (CDK2i) beyond disease progression remain unclear. Here, we show that maintaining CDK4/6i and ET or combining them with CDK2i effectively suppresses the growth of drug-resistant HR+ breast cancer cells by prolonging G1-phase progression. CDK4/6i maintenance triggers a non-canonical pathway for Rb inactivation through post-translational degradation, resulting in attenuated E2F activity and slowed G1 progression. ET further augments this effect by inhibiting c-Myc-mediated E2F amplification. Although the maintenance of CDK4/6i and ET outperforms CDK2i with ET, the triple combination of CDK4/6i, CDK2i, and ET most effectively suppresses both E2F activity and tumor growth. Moreover, while overexpression of both cyclin E and A can promote resistance to the CDK4/6i and CDK2i combination, cyclin E plays a more pivotal role in developing resistance. These findings highlight the potential of sustained CDK4/6i therapy and the incorporation of CDK2i to mitigate resistance in HR+ breast cancer.

2024-10-10 | GSE279160 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive breast cancer cell lines: MCF-7 and T47D

Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.

2023-07-10 | GSE222367 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive organoids derived from patient derived xenografts from patients who progressed on palbociclib

2023-07-10 | GSE229146 | GEO

Microarray gene expression data from MCF-7 and LetR cells

Project description:Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.

2022-08-05 | GSE210399 | GEO

Using prognostic signatures and machine learning to identify core features associated with response to CDK4/6 inhibitor-based therapy in metastatic breast cancer

Project description:CDK4/6 inhibitors in combination with endocrine therapy are widely used to treat HR+/HER2- metastatic breast cancer leading to improved progression-free survival (PFS) compared to single agent endocrine therapy. Over 300 patients receiving standard-of-care CDK4/6 inhibitor combination therapy for metastatic disease were enrolled at a single institution. Clinical, pathological, and gene expression data were employed to define determinants for PFS duration. Visceral disease (HR 1.55, p=0.0013), prior endocrine therapy (HR 2.34, p<0.001), and the type of endocrine therapy (HR 2.16, p<0.001) were highly associated with PFS duration. Multiple pre-defined gene expression signatures were employed to determine association with response to CDK4/6 inhibitor-based therapy. Random survival forest was applied to define key gene expression and clinical features associated with PFS and develop a predictive model. The time to progression predicted by this model was related to the median PFS observed in PALOMA-2/3 and PEARL studies. Interrogating genes identified as highly significant across all studies indicated common enrichment of gene networks associated with cell cycle and estrogen receptor signaling. These findings indicate that there are common features from real-world use of CDK4/6 inhibitors that could be used to infer time to progression and better inform treatment.

2025-01-08 | GSE285861 | GEO

Dual targeting CDK4/6 and CDK7 augments tumor response and anti-tumor immunity in breast cancer

Project description:CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis for hormone-positive (HR+) breast cancer patients. However, the emergence of drug resistance severely limits their long-term efficacy, and CDK4/6i monotherapy remains largely ineffective against triple-negative breast cancer (TNBC). Here, we demonstrate that combining CDK4/6i with CDK7 inhibitors (CDK7i) offers a promising therapeutic strategy to overcome resistance in both HR+ breast cancer and TNBC. Kinetic analyses reveal that CDK7i primarily targets RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance by amplifying E2F activity following the degradation of the retinoblastoma protein. Consequently, the combination of CDK4/6i and CDK7i synergistically suppresses E2F activity and inhibits the growth of drug-resistant tumors. Furthermore, this combination stimulates immune response pathways and cytokine production in cancer cells, enhancing anti-tumor immunity. These findings provide critical insights into evolving CDK inhibition strategies and highlight the therapeutic application of CDK7i in breast cancer management.

2024-11-07 | GSE281158 | GEO

RNA sequencing of luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors

Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.

2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

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