bims-cyhorp 2021-11-28 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021–11–28
eight papers selected by
Piotr Okupski,

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.
Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer.
Observational real world data with palbociclib associated to hormone therapy for advanced breast carcinoma.
[Clinical observation of palbociclib combined with endocrine therapy in hormone receptor positive and HER2 negative advanced breast cancer].
FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells.
Risk of venous and arterial thromboembolic events in women with advanced breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta-analysis.
Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer.
Bioequivalence Study of Palbociclib Capsules in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Front Oncol. 2021 ;11 777867

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer.

Neil Portman, Julia Chen, Elgene Lim.

  With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.

Keywords:  CDK4/6 inhibitor; MDM2; breast cancer; endocrine resistance; estrogen receptor

DOI:  https://doi.org/10.3389/fonc.2021.777867
Int J Mol Sci. 2021 Nov 14. pii: 12292. [Epub ahead of print]22(22):

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer.

Erin R Scheidemann, Ayesha N Shajahan-Haq.

  Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

Keywords:  CDK4/6 inhibitors; ER+ breast cancer; abemaciclib; antiestrogens; palbociclib; ribociclib

DOI:  https://doi.org/10.3390/ijms222212292
Farm Hosp. 2021 Sep 02. 45(6): 329-334

Observational real world data with palbociclib associated to hormone therapy for advanced breast carcinoma.

Teresa Sampedro, Rubén Pampín, Javier Barbazán, Virginia Reguero, Virginia Galeazzi, Ignacio Peláez.

OBJECTIVE: Cyclin-dependent kinase 4/6 inhibitors have a synergistic effect in combination with endocrine therapy. This combination is used as first and subsequent-line treatment for advanced luminal breast carcinoma because it increases progression-free survival. We analysed clinical course and toxicity in patients treated with palbociclib in our hospital and determined potential associations between these variables and clinicopathological variables.
METHOD: Observational retrospective study including patients with advanced or metastatic breast cancer treated with palbociclib plus endocrine therapy at the Hospital Universitario de Cabueñes between 2017 and 2020. We analysed clinicopathological variables, toxicity, and survival. Results: In total, 72 women and 1 man (median age: 63 years) received palbociclib plus an aromatase inhibitor or fulvestrant. When used as firstline treatment, progression-free survival was 22 months, and as second and subsequent-line treatment, progression-free survival was 13 months. Adverse effects (mainly haematological) were experienced by nearly all any patient, although delays and dose adjustments were common (61.7% and 42.7%, respectively). Performance status alone had a significant impact on progression-free survival (22 months in patients with ECOG 0 vs 12 months in patients with ECOG ≥ 1; P = 0.021).
CONCLUSIONS: Disease stage, age, and performance status do not limit the use of treatment with palbociclib, nor its combination with aromatase inhibitors or fulvestrant for first or subsequent-line treatment. Toxicity is easily managed. Real-world results are equivalent to those published to date.
Zhonghua Yi Xue Za Zhi. 2021 Nov 30. 101(44): 3625-3630

[Clinical observation of palbociclib combined with endocrine therapy in hormone receptor positive and HER2 negative advanced breast cancer].

H M Lyu, L M Niu, M W Zhang, H A Zeng, S N Zhao, Z Z Liu, M Yan.

Objective: To analyze the application, efficacy, and safety of palbociclib in hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer in the real world. Methods: The information of patients who received palbociclib treatment from September 2018 to September 2020 was collected, and the general medical history data and disease characteristics were summarized. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and safety were analyzed. Results: A total of 55 patients with HR+/HER2-advanced breast cancer who received a treatment regimen containing palbociclib were enrolled. The ORR was 48.8%, and DCR was 88.4%. The median PFS was 12.0 months (95%CI, 11.1-13.0 months), and the median TTF was 8.50 months (95%CI, 2.5-14.5 months). Among them, palbociclib was superior to multi-line therapy in the first line (P=0.000 1). The prognosis of patients with non-liver metastases was better (P=0.01). Hematological toxicity was the focus of observation of adverse events, including leukopenia, neutropenia, and thrombocytopenia. The incidence rates of them were 78.2%, 85.5%, and 34.5%, respectively. No other grade 3-4 nonhematological toxicity was found. Conclusions: Palbociclib combined with endocrine therapy in patients with HR+/HER2-advanced breast cancer has good efficacy and controllable adverse reactions. It can be used as a first-line or multi-line treatment option for HR+/HER2-advanced breast cancer.

DOI: https://doi.org/10.3760/cma.j.cn112137-20210416-00912
Cells. 2021 Nov 04. pii: 3008. [Epub ahead of print]10(11):

FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells.

Qiong Cheng, Zhikun Ma, Yujie Shi, Amanda B Parris, Lingfei Kong, Xiaohe Yang.

  Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.

Keywords:  CDK4/6 inhibitor resistance; FGFR1; breast cancer; cancer stem cells; cyclins/CDKs; palbociclib

DOI:  https://doi.org/10.3390/cells10113008
Thromb Res. 2021 Nov 17. pii: S0049-3848(21)00514-4. [Epub ahead of print]208 190-197

Risk of venous and arterial thromboembolic events in women with advanced breast cancer treated with CDK 4/6 inhibitors: A systematic review and meta-analysis.

Elena Bolzacchini, Fulvio Pomero, Martina Fazio, Chiara Civitelli, Giulia Fabro, Domenico Pellegrino, Monica Giordano, Alessandro Squizzato.

   BACKGROUND: Cyclin-dependent kinase inhibitors (CDKIs) may increase the risk of thrombotic events of endocrine therapy (ET) in women with hormone-sensitive, HER2-negative advanced breast cancer (BC). Aim of our systematic review is the estimate of the risk of venous and arterial thromboembolism in women with advanced BC treated with CDKIs in phase III randomized controlled trials (RCTs).
METHODS: Studies were identified by electronic search of MEDLINE, EMBASE and CENTRAL database until October 2021. Risk of bias was assessed according to Cochrane criteria. Differences in thrombotic outcomes among groups were expressed as pooled odds ratio (OR) and corresponding 95% confidence interval (CI), which were calculated using both a fixed-effects and a random-effects model. Statistical heterogeneity was evaluated using the I2 statistic.
RESULTS: We included 7 phase III RCTs (4415 patients) for a total of 15 papers (7 were the first published paper and 8 the follow-up papers). Reporting of thrombotic events was at high risk of bias. Women with advanced BC treated with CDKIs and ET had a two to threefold increased risk of venous thromboembolic event (VTE) compared to ET plus placebo arm [OR 2.90 (95% CI 1.32, 6.37; I2 = 0%) in the main papers and OR 2.20 (95% CI 0.93, 5.20; I2 = 49%) in the follow-up papers]. Women with advanced BC treated with CDKIs and ET had a non-significant mild increased risk of arterial thromboembolic event compared to ET plus placebo arm [OR 1.22 (95% CI 0.47, 3.18 I2 = 0%)].
CONCLUSIONS: CDKIs in combination with endocrine therapy are associated with a two to threefold higher risk of VTE in comparison to endocrine therapy alone in women with advanced breast cancer, while the risk of arterial events is still to be defined.

Keywords:  Arterial thromboembolism; Breast cancer; CDK 4/6 inhibitors; Venous thromboembolism

DOI:  https://doi.org/10.1016/j.thromres.2021.11.009
Breast. 2021 Nov 17. pii: S0960-9776(21)00995-4. [Epub ahead of print]60 263-271

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer.

R K Ismail, J van Breeschoten, M W J M Wouters, M van Dartel, S van der Flier, A K L Reyners, P de Graeff, A M G Pasmooij, A de Boer, K E Broekman, D L Hilarius.

   BACKGROUND: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC).
PATIENTS AND METHODS: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations).
RESULTS: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051).
CONCLUSION: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS.

Keywords:  Breast cancer; Clinical outcomes; Dose reductions; Older patients; Palbociclib

DOI:  https://doi.org/10.1016/j.breast.2021.11.013
Clin Drug Investig. 2021 Nov 26.

Bioequivalence Study of Palbociclib Capsules in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Nan-Nan Chu, Lin Zhang, Jiakun Wang, Xianghong Gu, Ying Ding, Kai Huang, Lin-Ling Que, Qing He.

BACKGROUND AND OBJECTIVE: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinase 4/6 used for the treatment of advanced breast cancer. This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of palbociclib capsules in healthy Chinese subjects under fasting and fed conditions and evaluated the bioequivalence of two palbociclib products to obtain sufficient evidence for the marketing approval of the new generic drug.
METHODS: A randomized, open-label, two-period crossover study was conducted in healthy Chinese volunteers under both fasting and fed conditions (30 subjects/condition). Eligible healthy subjects received a single 125-mg dose of the palbociclib test or reference formulation followed by a 14-day washout period. Serial blood samples were collected at scheduled timepoints, and plasma concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. A non-compartment method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC0-t), the AUC from time 0 to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration, and the elimination half-life. The geometric mean ratios and the corresponding 90% confidence intervals of palbociclib were acquired for the bioequivalence analysis. Safety and tolerability were assessed by monitoring adverse events, laboratory assessments, vital signs, physical examinations, and 12-lead electrocardiograms.
RESULTS: Under the fasting condition, the pharmacokinetic parameter values of the test formulation were similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 94.35-103.82% for Cmax, 94.79-103.26% for AUC0-t, and 94.82-103.38% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. Meanwhile, under the fed condition, the pharmacokinetic parameter values of the test formulation were also similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 96.65-103.56% for Cmax, 98.06-103.61% for AUC0-t, and 97.88-103.46% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. The test and reference products were well tolerated, and no serious adverse events occurred during the study.
CONCLUSIONS: Pharmacokinetic bioequivalence of palbociclib in healthy subjects was established between the palbociclib test formulation and the reference formulation under fasting and fed conditions according to predetermined regulatory criteria. The two formulations were safe and well tolerated.

DOI: https://doi.org/10.1007/s40261-021-01103-9