bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2023–04–09
seven papers selected by
Piotr Okupski,

  1. Economic Evaluation for Palbociclib Plus Fulvestrant vs Ribociclib Plus Fulvestrant and Abemaciclib Plus Fulvestrant in Endocrine-Resistant Advanced or Metastatic Breast Cancer in Italy.
  2. A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor.
  3. A retrospective, non-interventional study of breast cancer patients diagnosed with ER+/HER2 negative, locally advanced or metastatic breast cancer treated with palbociclib in Denmark.
  4. Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial.
  5. Advances in Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer.
  6. Observational study of HR+/HER2- metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS).
  7. Palbociclib and Michael-acceptor hybrid compounds as CDK4/6 covalent inhibitors: Improved potency, broad anticancer spectrum and overcoming drug resistance.
  1. Ther Clin Risk Manag. 2023 ;19 301-312
    Economic Evaluation for Palbociclib Plus Fulvestrant vs Ribociclib Plus Fulvestrant and Abemaciclib Plus Fulvestrant in Endocrine-Resistant Advanced or Metastatic Breast Cancer in Italy.
    Giorgio Lorenzo Colombo, Maria Chiara Valentino, Alessandra Fabi, Maria Vittoria Dieci, Mauro Caruggi, Giacomo Matteo Bruno, Gloria Lombardi, Sergio Di Matteo.
       Background: To date, no study evaluated the cost-effectiveness of palbociclib (PAL) plus fulvestrant (FUL) vs ribociclib (RIB) plus FUL and abemaciclib (ABM) plus FUL in Italy. Cost-effectiveness analysis comparing the three cyclin-dependent 4/6 kinase inhibitors in combination with endocrine therapies for the management of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer in Italy was developed.
    Material and Methods: To assess the cost-effectiveness of PAL plus FUL vs RIB plus FUL and ABM plus FUL, a cost-minimization has been carried out with a conservative scenario considering three CDK4/6 inhibitors with equal effectiveness in terms of overall survival (OS) (MAIC, Rugo et al 2021). Adverse events (AEs) associated with all therapies were obtained from clinical trials. Ad-hoc analysis was performed to estimate the cost-effectiveness considering the quality-of-life (QoL) data (Lloyd et al 2006).
    Results: Cost-minimization inputs were drugs, visits and exams, AE monitoring and best supportive care (BSC) before the progression state, active and BSC in the progression and terminal phase of the last two weeks of life. Given the comparability of PAL, RIB and ABM in terms of efficacy, this analysis demonstrated slight economic savings over a lifetime for PAL. Results showed saving per patient of €305 (lifetime) when PAL is compared with RIB; for PAL vs ABM a saving of €243 (lifetime) in a conservative scenario. Results of a budget impact analysis showed a potential savings of €319,563 for PAL vs RIB and €297,544 for PAL vs ABM. When QoL data were considered, results may favor PAL due to the lower impact of AE with savings and improvement in the QoL related to fewer AE.
    Conclusion: From the Italian perspective, a cost-saving profile associated with the use of PAL+FUL for the management of advanced/metastatic HR+/HER2- breast cancer compared to RIB+FUL and ABM+FUL emerged.
    Keywords:  Italy; abemaciclib; cost effectiveness; cost-minimization; metastatic breast cancer; palbociclib; ribociclib; second-line endocrine therapy
    DOI:  https://doi.org/10.2147/TCRM.S391769
  2. Contemp Clin Trials Commun. 2023 Jun;33 101110
    A phase I trial of palbociclib and bosutinib with fulvestrant in patients with metastatic hormone receptor positive and HER2 negative (HR+ HER2-) breast cancer refractory to an aromatase inhibitor and a CDK4/6 inhibitor.
    Tina Roy, Elizabeth Barrows, Candace Mainor, Julie Collins, Filipa Lynce, Claudine Isaacs, Paula R Pohlmann.
      Standard treatment for metastatic hormone positive (HR+) breast cancer includes a combination of a CDK4/6 inhibitor and antiestrogen therapy. Despite durable responses, eventual endocrine resistance results in disease progression. The Src/Abl pathway has been shown to mediate endocrine resistance in breast cancer, thus providing a promising target for novel therapies. Bosutinib is a tyrosine kinase inhibitor that targets the Src/Abl pathway, which has been studied in hematologic malignancies. Preclinical data suggests that the addition of bosutinib to a CDK4/6 inhibitor and antiestrogen therapy has the potential to reverse endocrine resistance. This is a phase I, single arm, open-label clinical trial in which we evaluate the combination of palbociclib and fulvestrant with bosutinib in metastatic HR+ breast cancer. Patients with confirmed advanced HR+/HER2- breast cancer who have received no more than three lines of chemotherapy and have progressed on at least one aromatase inhibitor and one CDK4/6 inhibitor will be enrolled. Participants will be given a combination of palbociclib, fulvestrant and bosutinib over 28-day cycles. The primary objective of this study is to assess the safety and tolerability of bosutinib in combination with palbociclib and fulvestrant in the study population. Secondary objectives are to 1) determine the anti-tumor effect of this therapeutic combination by assessing overall response rate (ORR) and clinical benefit rate (CBR) after 6 months of treatment, 2) to determine the clinical pharmacology parameters of bosutinib in this regimen, and 3) to build a tissue repository at Georgetown Lombardi Comprehensive Cancer Center for further translational study.
    DOI:  https://doi.org/10.1016/j.conctc.2023.101110
  3. Acta Oncol. 2023 Apr 03. 1-8
    A retrospective, non-interventional study of breast cancer patients diagnosed with ER+/HER2 negative, locally advanced or metastatic breast cancer treated with palbociclib in Denmark.
    Rasmus Garly, Tobias Berg, Maj-Britt Jensen, Ann Knoop, Lone Volmer, Vesna Glavicic, Humma Khan, Peter Bo Poulsen, Jens Olsen, Iben Kümler.
       BACKGROUND: The recommended first-line treatment for advanced, ER+/HER2 negative breast cancer is a CDK 4/6 inhibitor in combination with an endocrine backbone. This study investigated the use of palbociclib, as first- or second-line therapy for advanced breast cancer patients in a real-world setting.
    MATERIAL AND METHODS: This retrospective, population-based study included all Danish, advanced breast cancer patients with ER+/HER2 negative disease who initiated first- or second-line treatment with palbociclib from January 1st, 2017, until December 31st, 2020. The primary outcomes were PFS and OS.
    RESULTS: The study included 1054 advanced breast cancer patients with a mean age of 66.8 years. Median OS was 51.7 months (95% CI, 44.9-54.6) for all patients in the first-line setting (n = 728) and median PFS was 24.3 months (95% CI, 21.7-27.8). Patients treated in second line (n = 326) had a median OS of 32.5 months (95% CI, 29.9-35.9) and a median PFS of 13.6 months (95% CI, 11.5-15.7). In first-line setting, the PFS and OS were significantly different for endocrine sensitive patients treated with AI (aromatase inhibitor) (n = 423) vs. fulvestrant (n = 158) as endocrine backbone to palbociclib (median PFS AI 31.3 months vs fulvestrant 19.9 months, p = 0.002 and median OS AI 56.9 months vs. fulvestrant 43.6 months, p = 0.001). In endocrine resistant patients (n = 145), no statistically significant difference in PFS was shown (median PFS AI 21.5 months vs. fulvestrant 12.0 months, p = 0.09), whereas OS was significantly different (median OS AI 43.5 months vs. fulvestrant 28.8 months, p = 0.02).
    CONCLUSION: In this real-world study, treatment with palbociclib combination therapy met the standards of efficacy set by the phase III trials, PALOMA-2 and PALOMA-3, and the standards set by real-world studies in other countries. The study showed significantly different outcomes in terms of PFS and OS in endocrine sensitive patients comparing AI vs. fulvestrant as endocrine backbone to palbociclib as first-line therapy.
    Keywords:  Breast cancer; advanced breast cancer; palbociclib; real-world evidence
    DOI:  https://doi.org/10.1080/0284186X.2023.2194030
  4. Eur J Cancer. 2023 Mar 08. pii: S0959-8049(23)00119-3. [Epub ahead of print]186 1-11
    Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial.
    Luca Malorni, Giampaolo Bianchini, Roberta Caputo, Alberto Zambelli, Fabio Puglisi, Giulia V Bianchi, Lucia Del Mastro, Ida Paris, Filippo Montemurro, Giacomo Allegrini, Marco Colleoni, Stefano Tamberi, Claudio Zamagni, Marina E Cazzaniga, Michele Orditura, Valentina Guarneri, Daniela Castelletti, Matteo Benelli, Mariacristina Di Marino, Grazia Arpino, Michelino De Laurentiis.
       BACKGROUND: Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumour cell proliferation.
    METHODS: The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging. Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models.
    RESULTS: Overall, 287 patients were enroled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (hazard ratio [HR], 2.21; 95% confidence interval [95% CI], 1.45, 3.37; P = 0.0002); similar results were observed for patients with high sTKa levels at C1D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression versus the pattern with low sTKa levels at both time points (HR, 2.89; 95% CI, 1.57, 5.31; P = 0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR, 5.65; CI: 2.84, 11.2; P < 0.0001). Baseline and dynamic sTKa changes provided independent information.
    CONCLUSIONS: sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2- ABC treated with ribociclib plus letrozole as first-line therapy.
    Keywords:  Advanced breast cancer; Biomarker; Letrozole; Ribociclib; Thymidine kinase
    DOI:  https://doi.org/10.1016/j.ejca.2023.03.001
  5. Curr Oncol Rep. 2023 Apr 01.
    Advances in Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer.
    Sharvina Ziyeh, Lauren Wong, Reva K Basho.
       PURPOSE OF REVIEW: To provide an overview of the current management of hormone receptor-positive (HR +) advanced breast cancer as well as highlight ongoing clinical investigation and novel therapies in development.
    RECENT FINDINGS: CDK4/6 inhibition plus endocrine therapy is standard front-line therapy for HR + advanced breast cancer. Continuation of CDK4/6 inhibitors in combination with alternative endocrine therapy has been evaluated in the second-line setting. Alternatively, endocrine therapy in combination with PI3K/AKT pathway targeting agents has been studied, particularly in patients with PI3K pathway alterations. The oral SERD elacestrant has also been evaluated in patients with ESR1 mutation. Many novel endocrine agents and targeted agents are in development. An improved understanding of combination therapies and sequencing of therapies is needed to optimize the treatment paradigm. Biomarker development is needed to guide treatment decisions. Advances in the treatment of HR + breast cancer have resulted in improved patient outcomes in recent years. Continued development efforts with identification of biomarkers to better understand response and resistance to therapy are needed.
    Keywords:  AKT inhibition; CDK4/6 inhibition; CERANs; Endocrine therapy; HER2 negative breast cancer; Hormone receptor-positive breast cancer; PI3K inhibition; PIK3CA mutation; PROTACs; SARMs; SERCAs; SERDs; SERMs
    DOI:  https://doi.org/10.1007/s11912-023-01393-6
  6. Clin Transl Oncol. 2023 Apr 07.
    Observational study of HR+/HER2- metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS).
    Salvador Blanch, Juan Miguel Gil-Gil, Miriam Arumí, Elena Aguirre, Miguel Ángel Seguí, Manuel Atienza, Silvia Díaz-Cerezo, Alberto Molero, José Manuel Cervera, Joaquín Gavilá.
       INTRODUCTION/OBJECTIVES: To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2-) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain.
    MATERIAL AND METHODS: This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan-Meier (KM) method.
    RESULTS: The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16-28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1-10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%).
    CONCLUSION: These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.
    Keywords:  Abemaciclib; Effectiveness; HR+/HER2− Spain; Metastatic breast cancer; Real world
    DOI:  https://doi.org/10.1007/s12094-023-03159-9
  7. Bioorg Med Chem. 2023 Mar 26. pii: S0968-0896(23)00111-6. [Epub ahead of print]84 117263
    Palbociclib and Michael-acceptor hybrid compounds as CDK4/6 covalent inhibitors: Improved potency, broad anticancer spectrum and overcoming drug resistance.
    Lei Fang, Mengqi Chu, Changhang Yan, Yilin Liu, Zimeng Zhao.
      To search for potent CDK4/6 covalent inhibitors, total 14 compounds have been designed and synthesized by connecting different Michael-acceptor to the piperazine moiety of palbociclib. All the compounds displayed good antiproliferative activity against human hepatoma cell (HepG2), non-small cell lung cancer (A549), and breast cancer (MDA-MB-231 and MCF-7) cell lines. In particular, compound A4 showed the highest inhibitory activity to MDA-MB-231 and MCF-7 cells with IC50 values of 0.51 μM and 0.48 μM, respectively. More importantly, A4 also showed strong inhibition against MDA-MB-231/palbociclib cells, indicating that A4 could effectively avoid the resistance of palbociclib. In the enzyme test, A4 showed selective inhibitory activity against CDK4/6, with the IC50 value of 18 nM and 13 nM, respectively. It was also found that A4 could efficiently induce apoptosis and arrest the cell cycle at G0/G1 phase. Moreover, A4 could significantly decrease the phosphorylation level of CDK4 and CDK6. HPLC and molecular modeling studies suggested that A4 could form a covalent bond with the target protein.
    Keywords:  Broad anticancer spectrum; CDK4/6 covalent inhibitors; Overcoming drug resistance; Palbociclib derivatives
    DOI:  https://doi.org/10.1016/j.bmc.2023.117263
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