bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–09–25
ten papers selected by
Piotr Okupski,

  1. Clinico-Immunological Effects of a Single-Agent CDK4/6 Inhibitor in Advanced HR+/HER2- Breast Cancer Based on a Window of Opportunity Study.
  2. Prospective Cohort Study of Combination Therapy With Abemaciclib and Hormonal Therapy for Chemotherapy-Treated Patients With Hormone Receptor-Positive Metastatic Breast Cancer.
  3. Prospective Cohort Study of Palbociclib Treatment in Postmenopausal Patients With Unresectable and Metastatic Hormone Receptor-Positive Breast Cancer: Study Protocol for a CSPOR-BC Palbociclib Cohort Trial.
  4. Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.
  5. Design, synthesis and biological evaluation of pteridine-7(8H)-one derivatives as potent and selective CDK4/6 inhibitors.
  6. The prognostic role of variations in tumour markers (CEA, CA15.3) in patients with metastatic breast cancer treated with CDK4/6 inhibitors.
  7. PFKFB4 facilitates palbociclib resistance in oestrogen receptor-positive breast cancer by enhancing stemness.
  8. Real-World Clinical Outcomes of Ribociclib in Combination with a Non-Steroidal Aromatase Inhibitor and a Luteinizing Hormone-Releasing Hormone Agonist in Premenopausal HR+/HER2- Advanced Breast Cancer Patients: An Italian Managed Access Program.
  9. Cost-effectiveness of palbociclib in early breast cancer patients with a high risk of relapse: Results from the PENELOPE-B trial.
  10. Trilaciclib prior to gemcitabine plus carboplatin for metastatic triple-negative breast cancer: phase III PRESERVE 2.
  1. Curr Issues Mol Biol. 2022 Sep 15. 44(9): 4255-4267
    Clinico-Immunological Effects of a Single-Agent CDK4/6 Inhibitor in Advanced HR+/HER2- Breast Cancer Based on a Window of Opportunity Study.
    Alberto D'Angelo, Fabiola Giudici, Robert Chapman, Jacob Darlow, Huseyin Kilili, Navid Sobhani, Mattia Cinelli, Maria Rosa Cappelletti, Carla Strina, Manuela Milani, Daniele Generali.
      Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 i), abemaciclib, palbociclib, and ribociclib, have been FDA-approved for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (aBC). This targeted therapy has revived hope in those aBC patients who did not respond to standard therapies. Interestingly, when administered as a single agent, CDK4/6 modulated several peripheral blood cells after a short-course treatment of 28 days. However, the impact of these immune effects has yet to be thoroughly investigated. Methods: We administered abemaciclib, palbociclib, and ribociclib monotherapy to 23 patients with HR+/HER2- metastatic breast cancer. The aim is to investigate the impact of on-treatment modifications on peripheral blood cells and their composite scores in patients after a 28-day course of CDK4/6 i alone. Results: In the current study, we observed a significant decrease in neutrophils (p-value < 0.001) for patients treated with abemaciclib, palbociclib, and ribociclib. An overall decrease of Tregs was observed and potentially linked to palbociclib treatment. The neutrophile to lymphocyte (N/L) ratio was also decreased overall and potentially linked to abemaciclib and palbociclib treatment. Platelets were decreased in patients administered with abemaciclib. Notably, the radiometabolic response was available only for those patients treated with ribociclib and abemaciclib, and only those lesions treated with ribociclib reached statistical relevance. Conclusions: Our study strongly supports the notion that CDK4/6 inhibitors induce tumour immune modulation. N/L ratio and platelet levels decreased due to treatment. Future studies should test whether patients would benefit from immunomodulators in association with CDK4/6 agents in a larger clinical trial. Moreover, the CDK4/6-induced immune modulation could also be considered a potential predictive clinical factor in HR+/HER2- advanced breast cancer.
    Keywords:  CDK4/6 inhibitors; breast cancer; immunomodulation; metastasis
    DOI:  https://doi.org/10.3390/cimb44090292
  2. World J Oncol. 2022 Aug;13(4): 216-221
    Prospective Cohort Study of Combination Therapy With Abemaciclib and Hormonal Therapy for Chemotherapy-Treated Patients With Hormone Receptor-Positive Metastatic Breast Cancer.
    Kana Miyahara, Kazutaka Narui, Yukari Uemura, Akimitsu Yamada, Kazuhiro Araki, Fumie Fujisawa, Takahiro Nakayama, Takashi Ishikawa, Naruto Taira, Yuichiro Kikawa, Tomohiko Aihara, Hirofumi Mukai.
       Background: Combination therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and hormonal therapy as the first-line and second-line treatments has already been shown to be effective in patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in clinical trials. On the other hand, in clinical practice, CDK4/6 inhibitors are used not only as first-/second-line but also as later-line hormonal therapies, or for patients receiving prior chemotherapy in metastatic setting. However, the efficacy and safety of combination therapy in these patients remain unclear. In this study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC.
    Methods: This multi-institutional prospective cohort study will involve a total of 300 chemotherapy-treated patients with HR+ HER2- MBC. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, clinical benefit rate, and adverse events. The preplanned subpopulation analysis is the number of chemotherapy regimens for HR+ HER2- MBC (two or less vs. three or more), prior treatment history with CDK4/6 inhibitors other than abemaciclib (presence vs. absence) and menopausal status (pre vs. post). We also planned to determine PFS of the subpopulation treated with abemaciclib as maintenance therapy after chemotherapy.
    Discussion: In this multi-institutional prospective cohort study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. We also evaluate this combination therapy as maintenance therapy in patients who respond to early-line chemotherapy.
    Keywords:  Abemaciclib; Chemotherapy-treated; Hormone receptor-positive metastatic breast cancer; Overall survival; Prospective cohort study; Real-world evidence
    DOI:  https://doi.org/10.14740/wjon1511
  3. World J Oncol. 2022 Aug;13(4): 190-194
    Prospective Cohort Study of Palbociclib Treatment in Postmenopausal Patients With Unresectable and Metastatic Hormone Receptor-Positive Breast Cancer: Study Protocol for a CSPOR-BC Palbociclib Cohort Trial.
    Kazutaka Narui, Takashi Ishikawa, Naruto Taira, Yukari Uemura, Hirofumi Mukai.
       Background: Combining palbociclib with letrozole or fulvestrant improved progression-free survival in hormone receptor (HR)-positive and human epidermal growth factor receptor-negative metastatic breast cancer. However, combining palbociclib to endocrine treatment increases toxicity and cost compared with the endocrine treatment alone. Moreover, palbociclib treatment may affect the outcome of the subsequent treatment because its benefit in terms of overall survival has not been observed yet. Therefore, it is crucial to examine whether palbociclib can improve clinical outcomes and quality of life (QoL) of patients in the real world.
    Methods: A prospective observational study with palbociclib is planned in 3 cohorts (A, B, and C) as per the line of endocrine treatment (i.e., first-line, second-line, or third-line or later-line treatment) for postmenopausal metastatic or unresectable breast cancer. The primary endpoint is progression-free survival in each treatment line, the most commonly used endpoint for global phase 3 studies. As per the results of these studies, the planned sample size is 700 cases: cohort A, 340 cases; cohort B, 200 cases; and cohort C, 130 cases. The secondary endpoints are overall survival, clinical benefit rate, time to chemotherapy, adverse events (AEs), patient-reported outcomes (PROs), and health-related QoL (HRQoL). These endpoints are evaluated again during the subsequent treatment. This study will examine whether the efficacy, safety, and QoL effects of palbociclib treatment in daily clinical practice are not inferior compared to those in clinical trials and whether palbociclib treatment affects the efficacy and safety of the subsequent treatment. Moreover, this study would provide information on the most effective time of adding palbociclib to endocrine treatment.
    Discussion: The reproducibility of randomized clinical trials (RCTs) using real-world data must be confirmed to evaluate whether real-world treatment benefits are similar to those observed in RCTs. Although the efficacy of palbociclib has been confirmed in RCTs, Aes of this drug, including its toxicities and cost, are not comparable to those of mono-hormone therapies. Thus, PROs/HRQoL is an important element of this study because several patients with HR-positive metastatic breast cancer have diseases for which sequential hormone therapy is preferential.
    Keywords:  Breast cancer; Palbociclib; Prospective cohort
    DOI:  https://doi.org/10.14740/wjon1507
  4. Target Oncol. 2022 Sep 24.
    Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.
    Michelino De Laurentiis, Roberta Caputo, Manuelita Mazza, Mauro Mansutti, Riccardo Masetti, Zelmira Ballatore, Rosalba Torrisi, Andrea Michelotti, Alberto Zambelli, Antonella Ferro, Daniele Generali, Patrizia Vici, Luigi Coltelli, Alessandra Fabi, Paolo Marchetti, Alberto Ballestrero, Simon Spazzapan, Antonio Frassoldati, Maria Giuseppina Sarobba, Donatella Grasso, Claudio Zamagni.
       BACKGROUND: Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial.
    OBJECTIVE: To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial.
    PATIENTS AND METHODS: Patients with HR+, HER2- ABC received ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day) while men and premenopausal women additionally received goserelin. Patients were allowed with ≤ 1 line of prior chemotherapy and an Eastern Cooperative Oncology Group performance status of ≤ 2. The primary outcome included safety and tolerability.
    RESULTS: Of the 554 Italian patients, 246 (44.4 %) patients completed treatment. The reasons for treatment discontinuation included progressive disease (PD; 36.6 %), adverse events (AEs; 11.9 %), and death (1.6 %). All-grade AEs and grade ≥ 3 AEs occurred in 98.9 % and 77.8 % patients, respectively. The most common treatment-related AEs were neutropenia (73.6 %), followed by leukopenia (32.1 %), and nausea (25.3 %). The overall response rate was 28.2 % (95 % confidence interval [CI], 24.4-32.1); clinical benefit rate was 71.7 % (95 % CI, 67.7-75.4); and median time to progression was 26.7 months (95 % CI, 24.8-non-estimable). Health-related quality of life scores were maintained during treatment.
    CONCLUSION: The safety and efficacy profiles of ribociclib plus letrozole in the Italian subpopulation was found to be consistent with the CompLEEment-1 global population result, MONALEESA-2, and MONALEESA-7 outcomes, which reaffirm ribociclib plus letrozole as the frontline treatment option in patients with HR+, HER2- ABC.
    TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT02941926 (30 November 2016).
    DOI:  https://doi.org/10.1007/s11523-022-00913-x
  5. Bioorg Med Chem Lett. 2022 Sep 18. pii: S0960-894X(22)00467-X. [Epub ahead of print] 128991
    Design, synthesis and biological evaluation of pteridine-7(8H)-one derivatives as potent and selective CDK4/6 inhibitors.
    Huan He, Qi Liu, Lu Chen, Jie Wang, Yuan Yuan, Honglin Li, Xuhong Qian, Zhenjiang Zhao, Zhuo Chen.
      Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC50 values of 16.7 nM and 30.5 nM respectively and showed excellent selectivity to CDK1/2/7/9. Moreover, compound L2 displayed potent antiproliferative activities at low digital micromolar range via inducing apoptosis in breast and colon cancer cells. In all, we developed a new series of pteridine-7(8H)-one derivatives which exhibited promising antitumor activities as selective CDK4/6 inhibitors.
    Keywords:  CDK4/6 inhibitors; Scaffold hopping; Structure-activity relationships
    DOI:  https://doi.org/10.1016/j.bmcl.2022.128991
  6. Drugs Context. 2022 ;pii: 2022-1-3. [Epub ahead of print]11
    The prognostic role of variations in tumour markers (CEA, CA15.3) in patients with metastatic breast cancer treated with CDK4/6 inhibitors.
    Federico Sottotetti, Elisa Ferraris, Barbara Tagliaferri, Raffaella Palumbo, Erica Quaquarini, Cristina Teragni, Emanuela Balletti, Claudia Leli, Andrea Premoli, Ludovica Mollica, Silvia Puglisi, Silvia Sardi, Alberto Malovini, Paolo Pedrazzoli, Antonio Bernardo.
      Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.
    Keywords:  CDK4/6 inhibitors; breast cancer; tumour markers
    DOI:  https://doi.org/10.7573/dic.2022-1-3
  7. Cell Prolif. 2022 Sep 20. e13337
    PFKFB4 facilitates palbociclib resistance in oestrogen receptor-positive breast cancer by enhancing stemness.
    Sijie Wang, Yuncheng Bei, Qiang Tian, Jian He, Rui Wang, Qiuping Wang, Luchen Sun, Jiangqiong Ke, Congying Xie, Pingping Shen.
       BACKGROUND: ER+ breast cancer (ER+ BC) is the most common subtype of BC. Recently, CDK4/6 inhibitors combined with aromatase inhibitors have been approved by FDA as the first-line therapy for patients with ER+ BC, and showed promising therapeutic efficacy in clinical treatment. However, resistance to CDK4/6 inhibitors is frequently observed. A better understanding of the drug resistance mechanism is beneficial to improving therapeutic strategies by identifying optimal combinational treatments.
    METHODS: Western blotting, qPCR, flow cytometry and a series of cell experiments were performed to evaluate the phenotype of MCF-7/R cells. RNA sequencing, non-targeted metabolomics, shRNA knockdown and tumour cell-bearing mouse models were used to clarify the drug resistance mechanism.
    RESULTS: Here, we found that ER+ BC cells have shown an adaptive resistance to palbociclib-induced cell cycle arrest by activating an alternative signal pathway, independent of the CDK4/6-RB signal transduction. Continuing treatment of palbociclib evoked cellular senescence of ER+ BC cells. Subsequently, the senescence-like phenotype promoted stemness of ER+ BC cells, accompanied by increased chemoresistance and tumour-initiating potential. Based on transcriptome analysis, we found that PFKFB4 played an important role in stemness transformation and drug resistance. A close correlation was determined between PFKFB4 expression by ER+ BC cells and cell senescence and stemness. Mechanistically, metabolomic profiling revealed that PFKFB4 reprogramed glucose metabolism and promoted cell stemness by enhancing glycolysis. Strikingly, diminishing PFKFB4 levels improved drug sensitivity and overcame chemoresistance during palbociclib treatment in ER+ BC.
    CONCLUSIONS: These findings not only demonstrated the novel mechanism underlying which ER+ BC cells resisted to palbociclib, but also provided a possible therapeutic strategy in the intervention of ER+ BC to overcome drug resistance.
    DOI:  https://doi.org/10.1111/cpr.13337
  8. Curr Oncol. 2022 Sep 17. 29(9): 6635-6641
    Real-World Clinical Outcomes of Ribociclib in Combination with a Non-Steroidal Aromatase Inhibitor and a Luteinizing Hormone-Releasing Hormone Agonist in Premenopausal HR+/HER2- Advanced Breast Cancer Patients: An Italian Managed Access Program.
    Nicoletta Staropoli, Elena Geuna, Gaetana Rinaldi, Giancarlo Bisagni, Vieri Scotti, Giovanni Faggioni, Laura Vannini, Carlo Arcara, Gabriella Moretti, Marco Gunnellini, Luigi Coltelli, Francesco Verderame, Lorenzo Livi, Giuseppina Sanna, Donatella Grasso, Giulia Abbinante, Francesca Ragni.
      Ribociclib plus an aromatase inhibitor and ovarian function suppression is the preferred first-line option for pre-/perimenopausal women with hormone receptor-positive/human epidermal growth factor receptor-2-negative advanced or metastatic breast cancer. We opened an italian managed access program (MAP) that permitted access to ribociclib to selected patients and allowed to collect informative results on the clinical impact of the therapy. The MAP (April 2018-May 2020) included 64 premenopausal patients, with characteristics similar to those of the MONALEESA-7 trial. Of 57 patients with a known response, 48 (84.2%) achieved a clinical benefit (i.e., complete response, N = 7 (12.3%); partial response, N = 17 (29.8%); stable disease, N = 24 (42.1%)), while 9 (15.8%) experienced tumor progression. Some patients (N = 15-23.4%) needed ribociclib dose reduction because of adverse events. Thereafter, the treatment was well tolerated, and no new safety signals emerged. Our study is the first reported Italian real-world evidence of ribociclib effectiveness in premenopausal HR+/HER2- advanced breast cancer patients. Response and clinical benefit rates were particularly encouraging compared with those of the ribociclib group of MONALEESA-7. Our work confirms that ribociclib in combination with endocrine therapy is highly effective in the treatment of premenopausal HR+/HER2- advanced breast cancer patients with an expected safety profile.
    Keywords:  MAP; MONALEESA-7; advanced breast cancer; premenopausal; ribociclib; young breast cancer
    DOI:  https://doi.org/10.3390/curroncol29090521
  9. Front Oncol. 2022 ;12 886831
    Cost-effectiveness of palbociclib in early breast cancer patients with a high risk of relapse: Results from the PENELOPE-B trial.
    Katya Galactionova, Sibylle Loibl, Paola Salari, Frederik Marmé, Miguel Martin, Michael Untch, Hervé R Bonnefoi, Sung-Bae Kim, Harry D Bear, Nicole McCarthy, Karen A Gelmon, José A García-Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Michael Gnant, Andreas Makris, Nicole Burchardi, Matthias Schwenkglenks.
       Background: Patients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL.
    Methods: We performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices.
    Results: The effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: -0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated.
    Conclusions: One year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany.
    Keywords:  (postneo)adjuvant; CDKi; Germany; Palbociclib; Penelope-B; cost-effectiveness; early breast cancer
    DOI:  https://doi.org/10.3389/fonc.2022.886831
  10. Future Oncol. 2022 Sep 22.
    Trilaciclib prior to gemcitabine plus carboplatin for metastatic triple-negative breast cancer: phase III PRESERVE 2.
    Shom Goel, Antoinette R Tan, Hope S Rugo, Philippe Aftimos, Zoran Andrić, Andrew Beelen, Jingshan Zhang, John S Yi, Rajesh Malik, Joyce O'Shaughnessy.
      Triple-negative breast cancer (TNBC) is an aggressive malignancy for which cytotoxic chemotherapy remains the backbone of treatment. Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor that induces transient cell cycle arrest of hematopoietic stem and progenitor cells and immune cells during chemotherapy exposure, protecting them from chemotherapy-induced damage and enhancing immune activity. Administration of trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly improved overall survival (OS) compared with GCb alone in an open-label phase II trial in patients with metastatic TNBC, potentially through protection and direct activation of immune function. The randomized, double-blind, placebo-controlled, phase III PRESERVE 2 trial will evaluate the efficacy and safety of trilaciclib administered prior to GCb in patients with locally advanced unresectable or metastatic TNBC. Clinical Trial Registration: NCT04799249 (ClinicalTrials.gov).
    Keywords:  CDK4/6 inhibitor; carboplatin; gemcitabine; immunotherapy; metastatic; overall survival; patient-reported outcome; phase III; trilaciclib; triple-negative breast cancer
    DOI:  https://doi.org/10.2217/fon-2022-0773
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