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Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [tissue]

ABSTRACT: This study addresses the critical need for predictive biomarkers in patients with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) who have been treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is). Using single-cell RNA sequencing, we reveal differential mechanisms of early versus late progression, enhancing our understanding of resistance to CDK4/6is. We identify and validate tumor-specific molecular biomarkers and demonstrate that tumor-infiltrating cytotoxic natural killer and CD8+ T cells are predictive of therapeutic response. Additionally, increased immune activity suppression in late progressing tumors suggests that combining CDK4/6is with checkpoint inhibitors could be beneficial against drug resistance. Validation across 2 independent cohorts confirms the robustness and clinical relevance of our findings. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, offering a personalized and effective approach to managing HR+/HER2- mBC and improving patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274139 | GEO | 2025/02/18

REPOSITORIES: GEO

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Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [FFPE]

Project description:This study addresses the critical need for predictive biomarkers in patients with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) who have been treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is). Using single-cell RNA sequencing, we reveal differential mechanisms of early versus late progression, enhancing our understanding of resistance to CDK4/6is. We identify and validate tumor-specific molecular biomarkers and demonstrate that tumor-infiltrating cytotoxic natural killer and CD8+ T cells are predictive of therapeutic response. Additionally, increased immune activity suppression in late progressing tumors suggests that combining CDK4/6is with checkpoint inhibitors could be beneficial against drug resistance. Validation across 2 independent cohorts confirms the robustness and clinical relevance of our findings. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, offering a personalized and effective approach to managing HR+/HER2- mBC and improving patient outcomes.

2025-02-18 | GSE274141 | 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

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.

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

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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

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.

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Variants in cell-free DNA of hormone receptor positive, HER2 negative metastatic breast cancer assessed by targeted sequencing show monitoring and prognostic value

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| PRJEB29032 | ENA

Activation of the interferon signaling pathway is associated with resistance to CDK4/6 inhibitors and immune checkpoint activation in ER-positive breast cancer [RNA-seq]

Project description:CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may lead to the identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used in this study. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. We found that parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high Interferon (IFN) signaling and reduced sensitivity to CDK4/6 inhibitors, thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of a CDK4/6 inhibitor plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6 inhibition. PalboR derivatives displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Our study demonstrates that aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6 inhibitors. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, which warrants additional studies to clarify its involvement in resistance to CDK4/6 inhibitors.

2021-12-04 | GSE150997 | GEO

Single cell analysis of MCF7-derived multi-organ metastases

Project description:Bone metastases can disseminate to secondary sites and promote breast cancer progression creating additional clinical challenges. The mechanisms contributing to secondary metastasis are barely understood. Here, we evaluate the prediction power of Her2+ circulating tumor cells (CTCs) after analyzing over 13,000 CTCs from a cohort of 137 metastatic breast cancer (MBC) patients with initial HR+/Her2- status and employed preclinical models of bone metastasis (BM) to validate the role of Her2+ CTCs in multi-organ metastases. While Her2+ expression was higher in patients with bone metastasis, experimental analyses revealed that a majority of these Her2+ CTCs derived from bone lesions were more dependent on Her2 activity and more susceptible to anti-Her2 treatment. Targeting the bone-mediated Her2 induction reduces CTC detection and abrogates secondary metastasis from bone. Overall, we elucidate that Her2+ CTCs can serve as a non-invasive biomarker for BM formation with high therapeutic benefit for HR+ MBC patients.

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