bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022‒11‒13
ten papers selected by
Piotr Okupski
  1. The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.
  2. Rapid Capillary Electrophoresis Method for Simultaneous Determination of Abemaciclib, Ribociclib, and Palbociclib in Pharmaceutical Dosage Forms: A Green Approach.
  3. Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.
  4. New treatment options for hormone receptor positive breast cancer in 2023.
  5. Abemaciclib in combination with pembrolizumab for HR+, HER2- metastatic breast cancer: Phase 1b study.
  6. Systemic Treatment for Hormone Receptor-positive/HER2-negative Advanced/Metastatic Breast Cancer: A Review of European Real-world Evidence Studies.
  7. Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.
  8. Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.
  9. Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies.
  10. Adjuvant Abemaciclib Combined with Endocrine Therapy: Efficacy Results in monarchE Cohort 1.
  1. Cancers (Basel). 2022 Nov 01. pii: 5388. [Epub ahead of print]14(21):
    The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance.
    Mary Abdelmalak, Rajanbir Singh, Mohammed Anwer, Pavel Ivanchenko, Amritdeep Randhawa, Myra Ahmed, Anthony W Ashton, Yanming Du, Xuanmao Jiao, Richard Pestell.
      Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2-) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.
    Keywords:  CDK4/6 inhibitor; abemaciclib; advanced breast cancer; hormone receptor-positive; palbociclib; ribociclib
    DOI:  https://doi.org/10.3390/cancers14215388
  2. Molecules. 2022 Nov 06. pii: 7603. [Epub ahead of print]27(21):
    Rapid Capillary Electrophoresis Method for Simultaneous Determination of Abemaciclib, Ribociclib, and Palbociclib in Pharmaceutical Dosage Forms: A Green Approach.
    Zvonimir Mlinarić, Lu Turković, Iva Begović, Biljana Nigović, Miranda Sertić.
      Advances in the treatment of HR+/HER2- breast cancer phenotype have been made with the introduction of abemaciclib, ribociclib, and palbociclib, inhibitors of cyclin D dependent kinases 4 and 6 (CDK4/6). Here, a novel, fast, cheap, and green CE method for the simultaneous determination of these three CDK4/6 inhibitors in less than 4 min is proposed for the first time. Separation was achieved by capillary zone electrophoresis in an acidic medium, in accordance with the structures of the analytes and their pKa values. The optimal pH of the running buffer was found to be 2.9. The optimal method conditions were 27.5 kV separation voltage, 30 °C, 5 s injection time under 50 mbar pressure, and 50 mM phosphate background buffer with benzimidazole as an internal standard. The developed method was validated with respect to robustness, selectivity, accuracy, precision, linearity, and limits of detection. The method was shown to be linear in the range of 10 to 100 µg mL-1 with correlation coefficients higher than 0.9981. A greenness assessment of the proposed method was performed, and the method was shown to be green. The validated method was successfully applied to pharmaceutical dosage forms of all CDK4/6 inhibitors.
    Keywords:  CDK4/6 inhibitors; abemaciclib; breast cancer; capillary electrophoresis; green chemistry; palbociclib; ribociclib
    DOI:  https://doi.org/10.3390/molecules27217603
  3. Radiother Oncol. 2022 Oct 28. pii: S0167-8140(22)04518-2. [Epub ahead of print]177 40-45
    Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.
    Luca Visani, Lorenzo Livi, Ivica Ratosa, Miha Orazem, Domen Ribnikar, Calogero Saieva, Carlotta Becherini, Viola Salvestrini, Erika Scoccimarro, Marianna Valzano, Cecilia Cerbai, Isacco Desideri, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Andrea Morandi, Icro Meattini.
      PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting.METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate.
    RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55).
    CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.
    Keywords:  Breast cancer; CDK4/6 inhibitors; Concomitant treatment; Oligometastatic disease; Radiotherapy
    DOI:  https://doi.org/10.1016/j.radonc.2022.10.023
  4. Curr Opin Obstet Gynecol. 2022 Nov 08.
    New treatment options for hormone receptor positive breast cancer in 2023.
    Diana Lüftner.
      PURPOSE OF REVIEW: Hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer does respond to chemotherapy but can be addressed with a better therapeutic index by using biologically modified endocrine therapy. The most pronounced recent successes were reached by antibody drug conjugates (ADCs).RECENT FINDINGS: In early HR+/HER2- disease, adjuvant treatment escalations have taken place for high-risk patients using abemaciclib for the HR+ BRCA- subset and olaparib for HR+ BRCA+ patients. In metastatic spread, among all CDK (cyclin-dependent kinase) 4/6 inhibitors used for first-line therapy, only ribociclib improved overall survival in pre and postmenopausal patients. Palbociclib failed to demonstrate overall survival benefits. New options come up with oral selective oestrogen receptor degraders (SERDs) such as elacestrant, which will replace fulvestrant and is clinically important in combination therapies. ADCs, together with new patient categories such as HER2low or HER3+, enlarge the treatment portfolio and challenge the need of supportive care. The antitrophoblast antigen 2 (TROP2) ADC sacituzumab govitecan improves overall survival in heavily pretreated HR+/HER2- patients by 3.2 months. The best improvement of overall survival was shown bý trastuzumab deruxtecan in less pretreated HER2low (HER2 1+ or HER2 2+/no gene amplification) patients with a gained life span of 6 months.
    SUMMARY: Real-world data on the sequence of different ADCs with similar payloads are needed to establish best possible treatment algorithms. All these new agents will find their place after CDK4/6 inhibitor-based endocrine combination therapy.
    DOI:  https://doi.org/10.1097/GCO.0000000000000834
  5. NPJ Breast Cancer. 2022 Nov 05. 8(1): 118
    Abemaciclib in combination with pembrolizumab for HR+, HER2- metastatic breast cancer: Phase 1b study.
    Hope S Rugo, Peter Kabos, J Thad Beck, Guy Jerusalem, Hans Wildiers, Elena Sevillano, Luis Paz-Ares, Michael J Chisamore, Sonya C Chapman, Anwar M Hossain, Yanyun Chen, Sara M Tolaney.
      This nonrandomized, open-label, multi-cohort Phase 1b study (NCT02779751) investigated the safety and efficacy of abemaciclib plus pembrolizumab with/without anastrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) without prior CDK4 and 6 inhibitor exposure. Patients were divided into two cohorts: treatment naïve (cohort 1) and pretreated (cohort 2). Patients received abemaciclib plus pembrolizumab with (cohort 1) or without (cohort 2) anastrozole over 21-day cycles. The primary objective was safety, and secondary objectives included efficacy and pharmacokinetics (PK). Cohort 1/2 enrolled 26/28 patients, respectively. Neutropenia (30.8/28.6%), AST increase (34.6/17.9%), ALT increase (42.3/10.7%), and diarrhea (3.8/10.7%) were the most frequent grade ≥3 adverse events in cohort 1/2, respectively. A total of two deaths occurred, which investigators attributed to treatment-related adverse events (AEs), both in cohort 1. Higher rates of all grade and grade ≥3 interstitial lung disease (ILD)/pneumonitis were observed compared to previously reported with abemaciclib and pembrolizumab monotherapy. The PK profiles were consistent between cohorts and with previous monotherapy studies. In cohorts 1/2, the overall response rate and disease control rate were 23.1/28.6% and 84.6/82.1%, respectively. Median progression-free survival and overall survivals were 8.9 (95% CI: 3.9-11.1) and 26.3 months (95% CI: 20.0-31.0) for cohort 2; cohort 1 data are immature. Abemaciclib plus pembrolizumab demonstrated antitumor activity, but high rates of ILD/pneumonitis and severe transaminase elevations occurred with/without anastrozole compared to the previous reporting. Benefit/risk analysis does not support further evaluation of this combination in the treatment of HR+, HER2- MBC.
    DOI:  https://doi.org/10.1038/s41523-022-00482-2
  6. Crit Rev Oncol Hematol. 2022 Nov 03. pii: S1040-8428(22)00290-6. [Epub ahead of print] 103866
    Systemic Treatment for Hormone Receptor-positive/HER2-negative Advanced/Metastatic Breast Cancer: A Review of European Real-world Evidence Studies.
    Cláudia Vieira, Maria N Piperis, Alexandros Sagkriotis, Paul Cottu.
      This review examined patterns of systemic anticancer treatment in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice in Europe since 2016 to assess whether they reflect clinical guidelines and recent changes in available treatment options. We identified 30 publications for inclusion. In studies evaluating patients up to the end of 2017, endocrine therapy predominated, with endocrine monotherapy typically used in 45-65% of patients. More recent studies suggested that use of cyclin-dependent kinase 4/6 inhibitor therapy has gained ground since European approval in late 2016, with two studies reporting first-line use in over 55% of patients. Chemotherapy was typically used first line in 25-45% of patients, although current guidelines recommend endocrine therapy in the absence of a visceral crisis. In conclusion, our review suggests that the most recent treatment developments for patients with HR+/HER2- metastatic breast cancer are being reflected in the changing treatment patterns seen in real-world practice.
    Keywords:  Chemotherapy; Cyclin-dependent kinase 4/6; Endocrine; Human epidermal growth factor receptor 2; Metastatic breast cancer
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103866
  7. J Med Chem. 2022 Nov 09.
    Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.
    Weijiao Chen, Minghui Ji, Hao Cheng, Mingming Zheng, Fei Xia, Wenjian Min, Huanaoyu Yang, Xiao Wang, Liping Wang, Lijuan Cao, Kai Yuan, Peng Yang.
      Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD50 > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c00947
  8. Thorac Cancer. 2022 Nov 09.
    Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.
    Chunfang Hao, Xuedong Bai, Jie Zhang, Wenjing Meng, Zhongsheng Tong.
      OBJECTIVE: Our study evaluated the renal safety of abemaciclib plus endocrine therapy (ET) with bisphosphonate as a treatment option for hormone receptor positive, human epidermal growth factor receptor 2 (HER-2) negative (HR+/HER2-) advanced breast cancer (ABC), especially with bone metastasis.METHODS: Data were collected from HR+/HER2- ABC patients who received abemaciclib with ET between March 2021 and May 2022 in a single medical center in China. We performed an analysis of the change in serum creatine (Cr) and creatine clearance (CrCl), time to first abnormal Cr value, and Common Terminology Criteria for Adverse Events grade of increased creatinine.
    RESULTS: A total of 210 patients were included in the final analysis, with a median age of 56 years and a median weight of 65 kg. Any grade laboratory-assessing increased Cr occurred in 87.1% of patients, while CrCl rarely went down to 30 ml/min. Associations between start dose with grade of increased Cr and menopausal status with alert value, which is defined as creatinine clearance <30 ml/min, were indicated.
    CONCLUSION: This study shows that abemaciclib combined with bisphosphonate would be safe for renal function in HR+/HER2- ABC patients with bone metastases.
    Keywords:  HR+/HER2−; abemaciclib; bisphosphonate; breast cancer; renal safety
    DOI:  https://doi.org/10.1111/1759-7714.14715
  9. Cancers (Basel). 2022 Oct 24. pii: 5206. [Epub ahead of print]14(21):
    Molecular Mechanisms of Anti-Estrogen Therapy Resistance and Novel Targeted Therapies.
    Rumeysa Ozyurt, Bulent Ozpolat.
      Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.
    Keywords:  CDK4/6 inhibitors; RNAi; SERD; SERM; anti-estrogen therapy; aromatase inhibitors; estrogen receptor-positive breast cancer; resistance; targeted therapies
    DOI:  https://doi.org/10.3390/cancers14215206
  10. Oncologist. 2022 Nov 07. pii: oyac234. [Epub ahead of print]
    Adjuvant Abemaciclib Combined with Endocrine Therapy: Efficacy Results in monarchE Cohort 1.
    Masakazu Toi, Frances Boyle, Young-Hyuck Im, Mattea Reinisch, David Molthrop, Zefei Jiang, Ran Wei, Francisco Sapunar, Brenda R Grimes, Sarah Cassidy Nabinger, Stephen R D Johnston.
      The monarchE Cohort 1 patient population was enrolled based on high-risk clinicopathological features that can easily be identified as part of routine clinical breast cancer evaluation. Efficacy data from Cohort 1 demonstrate substantial evidence of benefit for adjuvant abemaciclib+ET in patients with HR+, HER2- early breast cancer at high risk of recurrence (ClinicalTrials.gov: NCT03155997 [monarchE]).
    Keywords:  CDK4/6; Ki-67; abemaciclib; adjuvant; early breast cancer
    DOI:  https://doi.org/10.1093/oncolo/oyac234
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