bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–03–27
eleven papers selected by
Piotr Okupski,

  1. Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting.
  2. The Impact of Real-World Alternative Dosing Strategies of Palbociclib on Progression-Free Survival in Patients with Metastatic Breast Cancer.
  3. Targeting CDK4/6 for Anticancer Therapy.
  4. AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer.
  5. How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story.
  6. Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study.
  7. Adjuvant Abemaciclib Combined with Endocrine Therapy for High Risk Early Breast Cancer: Safety and Patient-Reported Outcomes From the monarchE Study.
  8. Real-world treatment patterns of palbociclib and blood count monitoring in patients with advanced breast cancer in Japan.
  9. A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis.
  10. Feasibility of Adjuvant Treatment with Abemaciclib-Real-World Data from a Large German Breast Center.
  11. Unilateral lower-limb vasculopathy: A rare adverse event of CDK4/6 inhibitor in breast cancer.
  1. Drug Des Devel Ther. 2022 ;16 727-735
    Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting.
    Hikmat Abdel-Razeq, Baha' Sharaf.
      More than two-thirds of patients with breast cancer present with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease at their initial diagnosis. HR-positive breast cancer's growth depends on Cyclin D1, a direct transcriptional target of estrogen receptors (ER). The recent introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, ribociclib, and abemaciclib) has revolutionized the treatment of metastatic HR-positive, HER2-negative breast cancer in both endocrine-sensitive and endocrine-resistant settings and in both pre-and post-menopausal women. Multiple large randomized clinical trials had demonstrated improvement in progression-free survival (PFS) and, more recently, in overall survival (OS). Adjuvant endocrine therapy (ET) significantly reduces the risk of recurrence and death among patients with HR-positive early-stage breast cancer (EBC). However, up to 20% of these patients will experience local, regional or distal recurrences in the first ten years. Such resistance to ET motivated researchers to try CDK4/6 inhibitors in EBC, both in adjuvant and neoadjuvant settings. While many clinical trials are still ongoing, at least one study and two meta-analyses had shown beneficial results, based on which the US Food and Drug Administration had recently approved the use of one of these agents, abemaciclib, in combination with ET for the adjuvant therapy of patients with high-risk EBC. In this paper, we review the recently published and ongoing landmark clinical trials attempting to expand the use of CDK4/6 inhibitors, in combination with ET, in the adjuvant setting of EBC.
    Keywords:  CDK4/6 inhibitors; abemaciclib; adjuvant; early-stage breast cancer; palbociclib; ribociclib
    DOI:  https://doi.org/10.2147/DDDT.S356757
  2. Curr Oncol. 2022 Mar 07. 29(3): 1761-1772
    The Impact of Real-World Alternative Dosing Strategies of Palbociclib on Progression-Free Survival in Patients with Metastatic Breast Cancer.
    Fulbert Fu, Jessica Kano, Julia Ma, Mera Guindy.
       BACKGROUND: Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, in combination with letrozole or fulvestrant has been demonstrated to prolong the progression-free survival (PFS) in patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) metastatic breast cancer. In efforts to mitigate neutropenic toxicities, oncologists in real-world practice have prescribed alternative dosing strategies with palbociclib, yet the implication on PFS is unknown.
    METHODS: We conducted a retrospective, observational chart review of all female patients at our clinics with HR+, HER2- metastatic breast cancer receiving palbociclib in combination with either letrozole or fulvestrant with a first dose initiated between June 2016 and December 2018 and followed their disease course until 30 April 2020.
    RESULTS: The median PFS for all clinic patients receiving palbociclib and letrozole (n = 63) was 40.8 months (95% confidence interval (CI) 25.6-not estimable) and 16.97 months (95% CI 8.57-not estimable) for patients receiving palbociclib and fulvestrant (n = 11). We identified seven alternative dosing strategies prescribed by oncologists, the most prevalent being prescribing palbociclib for three weeks on and two weeks off (n = 8). The Kaplan-Meier curves for PFS in patients receiving letrozole and palbociclib prescribed alternative dosing strategies appear to diverge from monograph dosing early in the treatment. Many patients prescribed palbociclib using alternative dosing strategies continued to be observed even by the 18-month timepoint. The prevalence of grade 4 neutropenia was lower for patients on palbociclib with letrozole, suggesting a possible mitigation of severe neutropenia with alternative dosing strategies.
    CONCLUSIONS: We conclude that alternative dosing strategies used by oncologists such as prescribing palbociclib for three weeks on, two weeks off may achieve comparable disease control while mitigating neutropenic toxicities when compared to standard monograph dosing recommendations, prolonging treatment tolerability and adherence. Further large-scale studies are needed to confirm these results for future clinical adoption.
    Keywords:  alternative dosing strategies; fulvestrant; letrozole; metastatic breast cancer; neutropenia; palbociclib; progression-free survival
    DOI:  https://doi.org/10.3390/curroncol29030145
  3. Biomedicines. 2022 Mar 16. pii: 685. [Epub ahead of print]10(3):
    Targeting CDK4/6 for Anticancer Therapy.
    Jiating Qi, Zhuqing Ouyang.
      Cyclin-dependent kinase 4/6 (CDK4/6) are key regulators of the cell cycle and are deemed as critical therapeutic targets of multiple cancers. Various approaches have been applied to silence CDK4/6 at different levels, i.e., CRISPR to knock out at the DNA level, siRNA to inhibit translation, and drugs that target the protein of interest. Here we summarize the current status in this field, highlighting the mechanisms of small molecular inhibitors treatment and drug resistance. We describe approaches to combat drug resistance, including combination therapy and PROTACs drugs that degrade the kinases. Finally, critical issues and perspectives in the field are outlined.
    Keywords:  CDK4/6; PROTAC; abemaciclib; cancer; drug resistance; palbociclib; ribociclib; small molecular inhibitor; trilaciclib
    DOI:  https://doi.org/10.3390/biomedicines10030685
  4. Ther Adv Med Oncol. 2022 ;14 17588359221083956
    AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2- advanced breast cancer.
    Aditya Bardia, Javier Cortes, Sara A Hurvitz, Suzette Delaloge, Hiroji Iwata, Zhi-Ming Shao, Dheepak Kanagavel, Patrick Cohen, Qianying Liu, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Joyce O'Shaughnessy.
       Background: For estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), the current standard first-line treatment includes an aromatase inhibitor in combination with a cyclin-dependent kinase 4/6 inhibitor. When resistance occurs, often related to the occurrence of ESR1 mutations, selective estrogen receptor modulators or degraders (SERDs) may be used, alone or in combination regimens. Amcenestrant (SAR439859), an optimized oral SERD, has shown clinical antitumor activity in combination with palbociclib in patients with ER+/HER2- ABC and, as monotherapy, in patients with and without ESR1 mutations. Here, we describe the study design of AMEERA-5, an ongoing, prospective, phase 3, randomized, double-blind, multinational study comparing the efficacy and safety of amcenestrant plus palbociclib versus letrozole plus palbociclib in patients with advanced (locoregional recurrent or metastatic) ER+/HER2- breast cancer.
    Methods: Patients are pre-/postmenopausal women and men with no prior systemic therapy for ABC. The planned enrollment is 1066 patients. Patients are randomized 1:1 to either amcenestrant 200 mg plus palbociclib 125 mg or letrozole 2.5 mg plus palbociclib 125 mg. Amcenestrant, letrozole, and their matching placebos are taken once daily continuously; palbociclib is taken once daily for 21 days, followed by 7 days off-treatment for a 28-day cycle. Treatment continues until disease progression, unacceptable toxicity, or decision to stop treatment. Pre-/perimenopausal women and men receive goserelin subcutaneously. Randomization is stratified by de novo metastatic disease, menopausal status, and visceral metastases. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival; others are safety, pharmacokinetics, and quality of life.
    Conclusions: AMEERA-5 is evaluating the efficacy and safety of amcenestrant in combination with palbociclib as first-line therapy in pre-/postmenopausal women and men with ER+/HER2- ABC.
    ClinicalTrials Identifier: NCT04478266.
    Keywords:  ER-positive/HER2-negative; amcenestrant; endocrine therapy; metastatic breast cancer; selective estrogen receptor degrader
    DOI:  https://doi.org/10.1177/17588359221083956
  5. Life (Basel). 2022 Mar 05. pii: 378. [Epub ahead of print]12(3):
    How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story.
    Viola Cogliati, Serena Capici, Francesca Fulvia Pepe, Pierluigi di Mauro, Francesca Riva, Federica Cicchiello, Claudia Maggioni, Nicoletta Cordani, Maria Grazia Cerrito, Marina Elena Cazzaniga.
      CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.
    Keywords:  CDK4/6 inhibitors; metastatic breast cancer; therapy resistance; treatment sequencing
    DOI:  https://doi.org/10.3390/life12030378
  6. Front Oncol. 2022 ;12 775081
    Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study.
    Jian Zhang, Yanchun Meng, Biyun Wang, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Wenqing Yao, Xichun Hu.
       Purpose: The LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting.
    Patients and Methods: Postmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination.
    Results: A total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months).
    Conclusions: The fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing.
    Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03772353.
    Keywords:  CDK4/6 inhibitor; HER2-positive; endocrine therapy; hormone receptor-positive; metastatic breast cancer; pyrotinib
    DOI:  https://doi.org/10.3389/fonc.2022.775081
  7. Ann Oncol. 2022 Mar 22. pii: S0923-7534(22)00383-0. [Epub ahead of print]
    Adjuvant Abemaciclib Combined with Endocrine Therapy for High Risk Early Breast Cancer: Safety and Patient-Reported Outcomes From the monarchE Study.
    monarchE Committee Members
       BACKGROUND: In monarchE, abemaciclib plus endocrine therapy (ET) as adjuvant treatment of hormone receptor-positive, human epidermal growth factor 2-negative, high risk, early breast cancer demonstrated a clinically meaningful improvement in invasive disease-free survival versus ET alone. Detailed safety analyses conducted at a median follow-up of 27 months and key patient-reported outcomes (PRO) are presented.
    PATIENTS AND METHODS: The safety population included all patients who received at least one dose of study treatment (n=5591). Safety analyses included incidence, management, and outcomes of common and clinically relevant adverse events (AEs). Patient-reported health-related quality-of-life, ET symptoms, fatigue, and side effect burden were assessed.
    RESULTS: The addition of abemaciclib to ET resulted in higher incidence of Grade≥3 AEs (49.7% vs 16.3% with ET alone), predominantly laboratory cytopenias (e.g., neutropenia [19.6%]) without clinical complications. Abemaciclib-treated patients experienced more serious adverse events (SAEs; 13.3% vs 7.8%). Discontinuation of abemaciclib and/or ET due to AEs occurred in 18.5% of patients, mainly due to Grade1/2 AEs (66.8%). AEs were managed with comedications (e.g., antidiarrheals), abemaciclib dose holds (61.7%), and/or dose reductions (43.4%). Diarrhea was generally low grade (Grade1/2: 77%); Grade2/3 events were highest in the first month (20.5%), most short-lived (≤7 days) and did not recur. Venous thromboembolic events (VTE) were higher with abemaciclib+ET (2.5%) vs ET (0.6%); in the abemaciclib arm, increased VTE risk was observed with tamoxifen vs AIs (4.3% vs 1.8%). PROs were similar between arms, including being 'bothered by side effects of treatment', except for diarrhea. At ≥3 months, most patients reporting diarrhea reported "a little bit" or "somewhat".
    CONCLUSION: In patients with high risk EBC, adjuvant abemaciclib+ET has an acceptable safety profile and tolerability is supported by PRO findings. Most AEs were reversible and manageable with comedications and/or dose modifications, consistent with the known abemaciclib toxicity profile.
    Keywords:  HER2-negative; HR-positive; abemaciclib; early breast cancer; monarchE; safety
    DOI:  https://doi.org/10.1016/j.annonc.2022.03.006
  8. Future Oncol. 2022 Mar 21.
    Real-world treatment patterns of palbociclib and blood count monitoring in patients with advanced breast cancer in Japan.
    Masataka Sawaki, Yasuaki Muramatsu, Kanae Togo, Thomas Laurent, Hiroji Iwata.
      Aim: To reveal the treatment patterns of palbociclib and complete blood count (CBC) monitoring in a Japanese real-world setting. Materials & methods: Deidentified data of patients with advanced breast cancer who received palbociclib from 2017 to 2020 were examined from a Japanese claims database. Results & conclusion: We identified 1074 patients. Palbociclib was commonly prescribed as second- or later-line treatment in 2017/2018; thereafter its first-line treatment increased. Regardless of treatment lines, fulvestrant was most commonly prescribed in combination with palbociclib (57-66% in the first-third-line), and this finding differed from that in the USA. Most patients initiated palbociclib at 125 mg/day; however, over a half of patients reduced doses within the first 8 weeks. Although CBC was regularly monitored, some patients did not undergo blood tests. Early dose reduction and CBC monitoring should be performed cautiously to minimize safety concern and prevent early treatment discontinuation.
    Keywords:  advanced breast cancer; complete blood count; dose reduction; endocrine therapy; palbociclib; real-world data
    DOI:  https://doi.org/10.2217/fon-2021-1448
  9. NPJ Breast Cancer. 2022 Mar 21. 8(1): 35
    A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis.
    Jairam Krishnamurthy, Jingqin Luo, Rama Suresh, Foluso Ademuyiwa, Caron Rigden, Timothy Rearden, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Anna Roshal, Pavan K Tandra, Mathew Cherian, Tracy Summa, Brittney Haas, Shana Thomas, Leonel Hernandez-Aya, Mattias Bergqvist, Lindsey Peterson, Cynthia X Ma.
      Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase 1 (sTK1) activity. At data-cutoff, fifty-four patients received a median of 13 cycles (range 2.6-43.5). The rate of G3 + ANC was 21.3% (95% CI: 11.2-36.1%) without G4 in C1, and 40.7% (95% CI: 27.9-54.9%), including 38.9% G3 and 1.8% G4, in all cycles. The clinical benefit rate was 80.4% (95% CI: 66.5-89.7%). The median progression-free survival (mPFS) (95% CI) was 19.75 (12.11-34.89), 33.5 (17.25-not reached [NR]), and 11.96 (10.43-NR) months, in the overall, endocrine sensitive or resistant population, respectively. High sTK1 at baseline, C1 day 15 (C1D15), and C2D1 were independently prognostic for shorter PFS (p = 9.91 × 10-4, 0.001, 0.007, respectively). sTK1 decreased on C1D15 (p = 4.03 × 10-7), indicating target inhibition. Rise in sTK1 predicted progression, with the median lead time of 59.5 (inter-quartile range: -206.25-0) days. Palbociclib, 5-days-on/2-days-off weekly, met its primary endpoint with reduced G3 + ANC, without compromising efficacy. sTK1 is prognostic and shows promise in monitoring the palbociclib response. ClinicalTrials.gov#: NCT3007979.
    DOI:  https://doi.org/10.1038/s41523-022-00399-w
  10. J Pers Med. 2022 Mar 02. pii: 382. [Epub ahead of print]12(3):
    Feasibility of Adjuvant Treatment with Abemaciclib-Real-World Data from a Large German Breast Center.
    Dominik Dannehl, Lea L Volmer, Martin Weiss, Sabine Matovina, Eva-Maria Grischke, Ernst Oberlechner, Anna Seller, Christina B Walter, Markus Hahn, Tobias Engler, Sara Y Brucker, Andreas D Hartkopf.
      Abemaciclib significantly improves invasive disease-free survival when combined with endocrine therapy in clinical high-risk patients with HR+/Her2- early breast cancer (eBC). The objective of the following study was to model how many patients with eBC would be available for adjuvant treatment with abemaciclib in a real-world setting. Patients that underwent complete surgical treatment for eBC between January 2018 and December 2020 in a large single-center university hospital in Germany were eligible. Descriptive statistics were used to describe the patient population that could benefit from abemaciclib according to the inclusion criteria of monarchE. Of 1474 patients with eBC, 1121 (76.1%) had a HR+/Her2- subtype. Of these, 217 (19.4%) fulfilled the monarchE inclusion criteria. Within patients that fulfilled the monarchE inclusion criteria, 48.9% received no adjuvant or neoadjuvant chemotherapy. Thus, in a real-world situation, fewer patients will be pretreated with chemotherapy than was the case in monarchE. Breast care units are facing a significant patient burden, since the 2-year abemaciclib therapy requires regular monitoring of toxicities. Specific care concepts to strengthen therapy adherence as well as further studies to deescalate adjuvant systemic treatment and individualize CDK 4/6 inhibitor therapy are therefore needed.
    Keywords:  CDK 4/6; abemaciclib; breast cancer; monarchE; oncology; systemic therapy
    DOI:  https://doi.org/10.3390/jpm12030382
  11. Kaohsiung J Med Sci. 2022 Mar 23.
    Unilateral lower-limb vasculopathy: A rare adverse event of CDK4/6 inhibitor in breast cancer.
    Chih-Ching Chin, Jun-Ping Shiau, Chi-Wen Luo, Ming-Feng Hou.
      
    DOI:  https://doi.org/10.1002/kjm2.12526
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