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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 | GSE317345 | GEO
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
Project description:Aim: To outline the demographic and clinical features, treatment approaches and clinical outcomes of patients treated with palbociclib as the initial therapy for HR+/HER2- advanced or metastatic breast cancer (aBC/mBC) in private healthcare facilities in Brazil.Materials & methods: This study involved a retrospective review conducted from June 2022 to May 2023.Results: The study included 121 patients, with an average age of 54.4 years, and 82 (67.7%) were menopausal at the time of diagnosis. Of these, 51 patients (42.1%) were treated with palbociclib and fulvestrant, while 67 patients (55.8%) received palbociclib and aromatase inhibitors. Most patients (65.3%) did not need to adjust their doses. The progression-free survival rates were 78% at 6 months and 60% at 12 months. Overall survival rates were 86% at 6 months and 70% at 12 months.Conclusion: Palbociclib combinations show promising effectiveness in managing HR+/HER2- advanced or metastatic breast cancer.
| S-EPMC11534102 | biostudies-literature
Project description:PurposeIn hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (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.Experimental designWe performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.ResultsNon-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); 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.ConclusionsWe 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.
| S-EPMC10102847 | biostudies-literature
Project description:PurposeTo overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC).Patients and methodsPhase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS).ResultsForty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year.ConclusionsTLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.
| S-EPMC10722138 | biostudies-literature
Project description:Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE_study)
| PRJNA1414632 | ENA
Project description:BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance.MethodsTissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival.ResultsNovel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C.ConclusionsWe identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET.Trial registrationClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
| S-EPMC10360358 | biostudies-literature
Project description:Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE study)
| PRJNA1406769 | ENA
Project description:Data on real-world effectiveness of cyclin-dependent kinase 4/6 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015-March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 [45.2-57.7] versus 43.2 [37.6-48.0] months; hazard ratio, 0.76 [95% CI, 0.65-0.87]; P < 0.0001). Progression-free survival (95% CI) is 19.3 (17.5-20.7) versus 13.9 (12.5-15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62-0.78]; P < 0.0001). These data support first-line palbociclib plus an AI treatment for HR+/HER2- MBC.(Trial number NCT05361655).
| S-EPMC9553912 | biostudies-literature
Project description:Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE study) paired
| PRJNA1414568 | ENA