Dataset Information

CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.

ABSTRACT:

Purpose

In 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 design

We 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.

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 2.4 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.

Conclusions

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.

SUBMITTER: Guerrero-Zotano A

PROVIDER: S-EPMC10102847 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.

Guerrero-Zotano Ángel Á Belli Stefania S Zielinski Christoph C Gil-Gil Miguel M Fernandez-Serra Antonio A Ruiz-Borrego Manuel M Ciruelos Gil Eva Maria EM Pascual Javier J Muñoz-Mateu Montserrat M Bermejo Begoña B Margeli Vila Mireia M Antón Antonio A Murillo Laura L Nissenbaum Bella B Liu Yuan Y Herranz Jesús J Fernández-García Daniel D Caballero Rosalía R López-Guerrero José Antonio JA Bianco Roberto R Formisano Luigi L Turner Nicholas N Martín Miguel M

Clinical cancer research : an official journal of the American Association for Cancer Research 20230401 8

<h4>Purpose</h4>In 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.<h4>Experimental design</h4>We performed mRNA gene expression profiling and correlation with progression ...[more]

PMID: 36749874

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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.

Project description:PurposeThis research designeded to: 1. Analyze the efficacy and safety of Palbociclib treatment in HR-positive and HER2-negative (HR + /HER2-) metastatic breast cancer(MBC) patients. 2. Establish and validate a nomogram model for predicting the progression-free survival (PFS) rates of 6 months, 12 months, and 18 months in HR + /HER2- MBC patients after receiving Palbociclib plus endocrine therapy (ET).Patients and methods1. This research retrospectively analyzed the efficacy and safety of Palbociclib combined with ET in 214 patients with HR + /HER2- MBC. 2. A nomogram was designed and constructed with the retrospective clinical data of 214 patients with HR + /HER2- MBC who received Palbociclib plus ET at Zhejiang Cancer Hospital in China from August 2018 to August 2022. Among these patients, 161 were randomly assigned to the training cohort, while 53 to the validation cohort. The predictive accuracy of the nomogram was assessed through the analysis the area under the receiver operating characteristic(ROC) curve, calibration curve, and decision curve analysis(DCA).Results1. Median PFS was 7.17 months (95% CI: 7.61-10.05 months), with an objective response rate (ORR) of 2.80% and a disease control rate (DCR) of 34.58%. The most prevalent grade 3-4 adverse event was neutropenia (38.79%). 2. Multiple variable analysis of the training set revealed that age < 60 years old, PR < 20%, Ki-67 ≥ 20%, luminal B molecular subtype, primary resistance to ET, receipt of late-stage chemotherapy, and presence of liver metastasis or ≥ 2 visceral metastases were independent prognostic factors associated with poor PFS (P < 0.05). Then, the predictive model underwent development and validation utilizing the aforementioned parameters. On the one hand, the area under the ROC curve (AUC) values of the training set at 6 months, 12 months, and 18 months were 0.771, 0.783, and 0.790, respectively, indicating a strong predictive ability of the developed model. On the other hand, the AUC of the validation set at 6 months, 12 months, and 18 months were 0.720, 0.766, and 0.754, respectively, suggesting the favorable discriminatory ability of the model. The calibration curves also exhibited a good fit with the ideal curves, and the DCA demonstrated the clinical applicability of the model. The nomogram's different scores could distinguish PFS.ConclusionThis retrospective study demonstrates the efficacy of Palbociclib in Chinese breast cancer patients. Moreover, the clinical parameters showed a significant association with the prognosis of HR + /HER2- MBC, and the prognostic models constructed based on these variables also displayed robust predictive power, which could offer more intuitive and convenient references for clinical doctors to formulate follow-up treatment plans.

Project description:IntroductionEndocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) are standard treatment options for hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of standard subsequent therapies after CDK4/6i-based treatment is unclear. This study aimed to examine physician practice patterns and treatment outcomes of subsequent therapies administered after progression on palbociclib therapy in clinical practice.MethodsThe study included 200 patients with HR+/HER2- MBC who underwent subsequent treatments after progressing on palbociclib-based regimens in five Chinese institutions between August 2017 and April 2020. The treatment pattern, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were reported.ResultsA total of 200 patients were included, of whom 147 (73.5%) and 53 (26.5%) received subsequent chemotherapy and endocrine therapy, respectively. The frequently used monochemotherapy regimens were taxane (n = 29), capecitabine (n = 21), and vinorelbine (n = 17), while the endocrine therapy regimens were chidamide plus exemestane (n = 16) and everolimus plus exemestane (n = 9). The overall median PFS (mPFS) was 5.5 months, with no significant difference in mPFS between the chemotherapy and endocrine therapy groups (p = 0.669). However, among patients not sensitive to prior palbociclib treatment, those administered chemotherapy had significantly longer PFS than those administered endocrine therapy (p = 0.006). The mPFS with endocrine therapy after first-, second-, and subsequent-line palbociclib was 13.4, 3.1, and 4.1 months, respectively (p = 0.233); in contrast, the mPFS with chemotherapy was 7.2, 6.5, and 4.9 months after first-, second-, and subsequent-line palbociclib, respectively (p = 0.364). The median OS was not achieved. The ORR was 10.6% among the 198 patients included in the analysis.ConclusionsPhysicians prefer chemotherapy over endocrine therapy for the treatment of patients with HR+/HER2- MBC who develop progression on palbociclib. Sensitivity to previous palbociclib treatment might be one of the indicators for predicting response to subsequent treatment.ClinicalTrials.gov identifier: NCT04517318.

Project description:PurposeThe aim of this study was to evaluate the cost-effectiveness of ribociclib compared to palbociclib, both in combination with letrozole, in the first-line treatment of postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC) from the perspective of the Spanish National Health System (NHS).Patients and methodsDisease progression was simulated with a partitioned survival model developed from the parameterization and extrapolation of survival curves of postmenopausal women with HR+/HER2- ABC from clinical trials with ribociclib or palbociclib, both in combination with letrozole. The model was structured on the basis of three health states (progression-free, progressed disease, and death), with a 1-month cycle length and inclusion of subsequent treatments administered for disease progression, over a time horizon of 15 years. Clinical, economic, and quality of life parameters were drawn from clinical trials and the literature. The use of resources and clinical practice in the Spanish setting was validated by a panel of experts. The Spanish NHS perspective was adopted, taking into account exclusively direct health costs from 2017 expressed in Euros. Drug prices used were the reported ex-factory prices. Uncertainty of the parameters and robustness of the results were evaluated using deterministic and probabilistic sensitivity analyses (2,000 iterations).ResultsThis cost-effectiveness analysis showed a greater benefit (0.437 and 0.285 life-years gained [LYGs] and quality-adjusted life years [QALYs] gained, respectively) and a slightly higher cost (€439.86) for ribociclib+letrozole compared to palbociclib+letrozole. The resulting incremental cost-effectiveness and cost-utility ratios were €1,007.69 per LYG and €1,543.62 per QALY gained, respectively. The results of the multiple sensitivity analyses showed limited dispersion of the outcomes, thus corroborating their robustness.ConclusionFrom the NHS perspective, considering the most commonly established willingness-to-pay thresholds in the Spanish setting, ribociclib+letrozole would represent a cost-effective therapeutic option compared to palbociclib+letrozole in the first-line treatment of HR+/HER2- ABC in postmenopausal women.

Dataset Information

CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.

Purpose

Experimental design

Results

Conclusions

Publications

CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.

Similar Datasets

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