bims-cyhorp 2022-04-24 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022‒04‒24
eight papers selected by
Piotr Okupski

Efficacy and safety of palbociclib plus endocrine therapy for patients with HR+/HER2- advanced breast cancer in real-world clinical practice.
Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study.
The efficacy and safety of alpelisib in breast cancer: A real-world analysis.
Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection.
Cost-Utility of the CDK 4/6 Inhibitors for Postmenopausal Women With Luminal Advanced Breast Cancer in Brazil.
Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug-Drug Interactions Are the Usual Suspects.
Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer.
Discovery of a Novel Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer.

Ann Transl Med. 2022 Mar;10(6): 362

Efficacy and safety of palbociclib plus endocrine therapy for patients with HR+/HER2- advanced breast cancer in real-world clinical practice.

Bingqian Zhong, Jie Zhang, Jing Wu, Langshuang Sun, Shuhong Li, Xiaohua Zeng, Lu Gan.

  Background: Palbociclib is the first cyclin dependent kinase 4/6 (CDK4/6) inhibitor approved in China to be combined with endocrine therapy (ET) for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. However, palbociclib has only been used in China for a short amount of time, and there is limited data on its real-world applications. This study observed the efficacy and safety of palbociclib plus ET in a real-world setting in southwest China and we hope to provide some references for the treatment of patients with breast cancer in China.Methods: This was an observational study of patients with HR+/HER2- advanced breast cancer (ABC) who received palbociclib plus ET. The primary endpoint of the study was progression-free survival (PFS) and the 6- and 12-month progression-free rates. The secondary endpoint included the objective response rate (ORR) and the clinical benefit rate (CBR).
Results: A total of 64 patients were enrolled in this study, and 54.7% of them received palbociclib plus ET as the first-line treatment for ABC. The median PFS was 21.6 months (95% CI: 11.2-32.0 months) after a median follow-up period of 13.8 months (95% CI: 11.9-15.7 months). The 6-month progression-free rate was 75.4%, and 48.9% of patients remained progression-free at 12 months. Overall, the ORR was 21.6% and the CBR was 76.5%. Patients with the molecular typing of Luminal A (P=0.035), a lower Ki67 level (P<0.001), sensitivity or acquired resistance to ET (P=0.003), less than 3 visceral metastases lesions (P=0.001), and those who received palbociclib plus ET as first-line or second-line of treatment for ABC (P=0.001) showed longer PFS. A total of 53.1% of patients had grade 3-4 adverse events (AEs), but only 4.7% of patients experienced permanent discontinuation of treatment due to intolerable AEs.
Conclusions: The efficacy of palbociclib plus ET is worthy of recognition and the toxicity was acceptable in this study, which is similar to previously reported data from randomized clinical trials and other real-world evidence. Treatment for ABC using palbociclib plus ET should be recommended more widely in China due to the efficacy and safety.

Keywords:  Palbociclib; advanced breast cancer (ABC); endocrine therapy (ET); hormone receptor-positive (HR+); human epidermal growth factor receptor 2-negative (HER2−)

DOI:  https://doi.org/10.21037/atm-22-1002
Eur J Cancer. 2022 Apr 13. pii: S0959-8049(22)00146-0. [Epub ahead of print]168 12-24

Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study.

Miguel Martín, Christoph Zielinski, Manuel Ruiz-Borrego, Eva Carrasco, Eva M Ciruelos, Montserrat Muñoz, Begoña Bermejo, Mireia Margelí, Tibor Csöszi, Antonio Antón, Nicholas Turner, María I Casas, Serafín Morales, Emilio Alba, Lourdes Calvo, Juan de la Haba-Rodríguez, Manuel Ramos, Laura Murillo, Ana Santaballa, José L Alonso-Romero, Pedro Sánchez-Rovira, Massimo Corsaro, Xin Huang, Christiane Thallinger, Zsuzsanna Kahan, Miguel Gil-Gil.

  BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis.METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death).
RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed.
CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors.
TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

Keywords:  CDK4/6 inhibitor; Capecitabine; Endocrine therapy; HER2–negative; Hormone receptor-positive metastatic breast cancer; Overall survival; Palbociclib

DOI:  https://doi.org/10.1016/j.ejca.2022.03.006
J Oncol Pharm Pract. 2022 Apr 22. 10781552221096413

The efficacy and safety of alpelisib in breast cancer: A real-world analysis.

Jenn Miller, Emily Armgardt, Alison Svoboda.

  Published trials of alpelisib + fulvestrant demonstrate efficacy and high rates of adverse effects as a first-line treatment option for metastatic breast cancer and as an option after cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i). The purpose of this analysis is to determine the real-world efficacy and safety of this regimen in heavily pretreated patients. This is a retrospective cohort analysis evaluating patients receiving alpelisib + fulvestrant for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer who previously received ≤ 2 lines of therapy in the metastatic setting and those who previously received ≥ 3 lines of therapy in the metastatic setting. Adverse effects, specifically hyperglycemia, rash, and diarrhea, were reported for the entire population. Thirty-three patients were included in this analysis. Progression-free survival (PFS), overall survival, time to change in therapy, and time to discontinuation were similar in the two groups. Forty-nine percent of patients discontinued alpelisib + fulvestrant due to progression of disease, and 27% of patients discontinued treatment due to adverse effects. Hyperglycemia, rash, and diarrhea occurred at high rates: 66.7%, 45.5%, and 72.7%, respectively. All three of these adverse effects required hospitalizations and pharmacological treatment. This analysis demonstrates that the outcomes of alpelisib + fulvestrant were worse in the real-world salvage setting in HR+, HER2- metastatic breast cancer as compared to the front-line setting. The real-world tolerability of this regimen is still of great concern.

Keywords:  Alpelisib; breast cancer; fulvestrant; metastatic

DOI:  https://doi.org/10.1177/10781552221096413
Breast Cancer (Dove Med Press). 2022 ;14 101-111

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection.

Maria Chiara Parati, Rebecca Pedersini, Gianluca Perego, Roberto Reduzzi, Tommaso Savio, Mary Cabiddu, Karen Borgonovo, Mara Ghilardi, Andrea Luciani, Fausto Petrelli.

  Among pre- and postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), combinations of an aromatase inhibitor (AI) or fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) have demonstrated improved progression-free survival (PFS) and overall survival (OS) compared to standard single-agent hormone therapy alone as first-line therapy for de novo metastatic disease or relapse during or after adjuvant therapy and no previous therapies in an advanced setting. We here reviewed clinical data about ribociclib in advanced and early BC. Also, we shed light on patient selection and special settings in which medical oncologists urgently await an advance in treatment. Ribociclib was FDA-approved in combination with letrozole based on a Phase III study in which 668 postmenopausal women with HR+, HER2-negative recurrent or metastatic BC were treated with first-line letrozole with or without ribociclib. For patients with metastatic disease at presentation or after a course of AIs, the results of the MONALEESA-3 trial suggest ribociclib's efficacy in combination with fulvestrant, and this combination is FDA-approved for initial- and subsequent-line endocrine therapy for postmenopausal women with metastatic hormone receptor-positive, HER2-negative BC. In adjuvant and neoadjuvant settings, the use of CDK 4/6 inhibitors may be useful to boost outcomes in high-risk patients with HR+ BC, but data contrast with those of a phase III study, which produced positive results. New combinations are being explored in upfront disease (neoadjuvant) or in association with other targeted agents in metastatic disease. Compared to other CDK 4/6 available, ribociclib has a higher incidence of liver function test abnormalities than the other agents and can cause QTc prolongation, and therefore may be prudently avoided in patients with cardiac morbidities or other risk factors for QTc prolongation (drugs, interactions). In these cases, different agents (palbociclib or abemaciclib) may be used. In conclusion, ribociclib with letrozole or with fulvestrant is effective for the entire spectrum of patients with HR+ BC in the advanced setting. Ribociclib has all the characteristics of an innovative drug able to change the clinical practice and most BC patients' prognoses.

Keywords:  CDK 4/6 inhibitors; breast cancer; review; ribociclib

DOI:  https://doi.org/10.2147/BCTT.S341857
Value Health Reg Issues. 2022 Apr 13. pii: S2212-1099(22)00099-1. [Epub ahead of print]31 47-52

Cost-Utility of the CDK 4/6 Inhibitors for Postmenopausal Women With Luminal Advanced Breast Cancer in Brazil.

Luana Schroeder Damico Nascimento Macedo, Aline Silveira Silva, Ana Cláudia Wekmuller França, Carlos Alberto da Silva Magliano, Isandra Meirelles, Matheus Piccin Padilla, Marisa da Silva Santos.

  OBJECTIVES: Several trials have demonstrated the benefit of the CDK 4/6 inhibitors for postmenopausal women with luminal advanced breast cancer. This research aims to compare the cost-utility of the CDK 4/6 inhibitors in patients with no history of resistance to endocrine therapy.METHODS: A Markov model was constructed to estimate the incremental cost per quality-adjusted life-years (QALYs) of treatments from the Brazilian public health system perspective over a lifetime horizon (30 years) with 5% annual discount rate for both benefits and costs. Efficacy parameters were extracted from the pivotal studies. Costs were based on open data from the Brazilian Ministry of Health. The utilities were calculated according to the overall population preferences from a British study. Deterministic and probabilistic sensitivity analyses evaluated the robustness of the results.
RESULTS: The most cost-effective drug was ribociclib (US$50 748/QALY), followed by abemaciclib (US$64 052/QALY) and palbociclib (US$65 289/QALY). The univariate analysis showed that the incremental cost-utility ratio (ICUR) was mainly sensitive to the overall survival hazard ratio. The one thousand-probabilistic simulation showed that all ICUR values were above classical thresholds such as 1 to 3 gross domestic product (GDP) per capita per QALY.
CONCLUSIONS: Even though there is no established willingness to pay threshold in Brazil, the estimated ICUR for CDK 4/6 inhibitors is >6 times the Brazilian GDP per capita (GDP per capita = US$5694.73), which might be a barrier to their inclusion in the Brazilian public health system.

Keywords:  CDK 4/6 inhibitors; advanced breast cancer; cost-utility analysis; economic models

DOI:  https://doi.org/10.1016/j.vhri.2022.02.006
Pharmaceutics. 2022 Apr 11. pii: 841. [Epub ahead of print]14(4):

Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug-Drug Interactions Are the Usual Suspects.

Fanny Leenhardt, Frédéric Fiteni, Ludovic Gauthier, Marie Alexandre, Séverine Guiu, Nelly Firmin, Stéphane Pouderoux, Marie Viala, Gerald Lossaint, Chloé Gautier, Caroline Mollevi, Matthieu Gracia, Celine Gongora, Litaty Mbatchi, Alexandre Evrard, William Jacot.

  Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure-toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug-drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.

Keywords:  clinical trial; drug–drug interaction; oncology breast cancer; therapeutic drug monitoring

DOI:  https://doi.org/10.3390/pharmaceutics14040841
Oncogene. 2022 Apr 18.

Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer.

Max A K Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Ignacio Viciano, Elvira R M Bakker, François Richard, Andrew Tutt, Lynda O'Leary, Amanda Fitzpatrick, Pere Roca-Cusachs, Paul J van Diest, Christine Desmedt, Juliet M Daniel, Clare M Isacke, Patrick W B Derksen.

Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs.

DOI: https://doi.org/10.1038/s41388-022-02314-w
J Med Chem. 2022 Apr 21.

Discovery of a Novel Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) and Cyclin-Dependent Kinase 4 (CDK4) Dual Inhibitor for the Treatment of Triple-Negative Breast Cancer.

Xiaoyu Chen, Chengxia Shu, Wenqiang Li, Qiangqiang Hou, Guangmei Luo, Kexin Yang, Xiaoxing Wu.

The treatment of triple-negative breast cancer (TNBC) remains a huge clinical challenge and dual-targeted small-molecule drugs might provide new therapeutic options for this type of breast cancer. In this work, we discovered a series of SHP2 and CDK4 dual inhibitors through a fused pharmacophore strategy and structural optimization. Notably, lead compound 10 with excellent SHP2 (IC50 = 4.3 nM) and CDK4 (IC50 = 18.2 nM) inhibitory activities effectively induced G0/G1 arrest to prevent the proliferation of TNBC cell lines. Furthermore, compound 10 showed great in vivo pharmacokinetic properties (F = 45.8%) and exerted significant antitumor efficacy in the EMT6 syngeneic mouse model. Western blotting and immunohistochemical analysis confirmed that 10 effectively targeted on both SHP2 and CDK4 and activated the immune response in tumors. These results indicate that lead compound 10, as the first SHP2 and CDK4 dual inhibitor, merits further development for treating TNBC.

DOI: https://doi.org/10.1021/acs.jmedchem.2c00063