bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2021–12–12
nine papers selected by
Piotr Okupski,

  1. Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials.
  2. Targeted Therapy in HR+ HER2- Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options.
  3. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03).
  4. Gallium-68 Labeling of the Cyclin-Dependent Kinase 4/6 Inhibitors as Positron Emission Tomography Radiotracers for Tumor Imaging.
  5. Real-world effectiveness and sensitivity of palbociclib plus endocrine therapy in HR+/HER2- patients with metastatic breast cancer.
  6. Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib.
  7. Post-Progression Treatments after Palbociclib plus Endocrine Therapy in HR+/HER2- Metastatic Breast Cancer Patients: What Is the Better Choice?
  8. Trilaciclib prior to chemotherapy in patients with metastatic triple-negative breast cancer: final efficacy and subgroup analysis from a randomized phase II study.
  9. Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression.
  1. ESMO Open. 2021 Dec 01. pii: S2059-7029(21)00294-5. [Epub ahead of print]6(6): 100332
    Systematic review and meta-analysis of post-progression outcomes in ER+/HER2- metastatic breast cancer after CDK4/6 inhibitors within randomized clinical trials.
    E Munzone, E Pagan, V Bagnardi, E Montagna, G Cancello, S Dellapasqua, M Iorfida, M Mazza, M Colleoni.
       BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapy (ET) deeply transformed the treatment landscape of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer. Randomized clinical trials suggest that second progression-free survival (PFS2) was not compromised and time to subsequent chemotherapy (TTC) may be delayed. We carried out a meta-analysis to assess the benefit on PFS2 and on delaying the TTC.
    METHODS: We conducted a systematic literature search of randomized clinical trials with CDK4/6 inhibitors and ET reporting PFS2 or TTC of HR+/HER2- pre- or postmenopausal metastatic breast cancer. We also reviewed abstracts and presentations from all major conference proceedings. We calculated the pooled hazard ratios (HR) for PFS2 and TTC using random-effects models with 95% confidence intervals (CI). I2 was used to quantify heterogeneity between results of the studies.
    RESULTS: Eight studies (MONALEESA-2/3/7, MONARCH-2/3, PALOMA-1/2/3) were included in this analysis (N = 4580 patients). PFS2 benefit was observed in patients who received CDK4/6 inhibitors plus ET (pooled HR = 0.68, 95% CI = 0.62-0.74, I2 = 0%) and also a delay in subsequent TTC (pooled HR = 0.65, 95% CI = 0.60-0.71, I2 = 0%). A benefit in terms of PFS (pooled HR = 0.55, 95% CI = 0.51-0.59, I2 = 0%) and overall survival (pooled HR = 0.76, 95% CI = 0.69-0.84, I2 = 0%) was also observed.
    CONCLUSIONS: CDK4/6 inhibitors plus ET compared with ET alone improve PFS2 and TTC. The delay of chemotherapy may postpone the start of a more toxic treatment option, delaying related toxicities and potentially maintaining a better quality of life for patients, for a longer time. The benefit in PFS2 may postpone the onset of endocrine resistance and help further validate this treatment approach.
    Keywords:  CDK4/6 inhibitors; ER-positive/HER2-negative; PFS2; TTC; endocrine therapy; metastatic breast cancer
    DOI:  https://doi.org/10.1016/j.esmoop.2021.100332
  2. Cancers (Basel). 2021 Nov 29. pii: 5994. [Epub ahead of print]13(23):
    Targeted Therapy in HR+ HER2- Metastatic Breast Cancer: Current Clinical Trials and Their Implications for CDK4/6 Inhibitor Therapy and beyond Treatment Options.
    Constanze Elfgen, Vesna Bjelic-Radisic.
      A metastatic state of breast cancer (MBC) affects hundreds of thousands of women worldwide. In hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) MBC, cyclin-dependent kinase (CDK)4/6 inhibitors can improve the progression-free survival (PFS), as well as the overall survival (OS), in selected patients and have been established as first- and second-line therapies. However, as MBC remains uncurable, resistance to CDK4/6 inhibitors occurs and requires alternative treatment approaches. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. This review provides a summary and update on the clinical relevance, patient selection, ongoing trials of CDK4/6 inhibitors, and further targeted therapy options. It focuses on clinical aspects and practicability, as well as adverse events and patient-reported outcomes.
    Keywords:  CDK4/6 inhibitor; HR-positive breast cancer; PI3K inhibitor; metastatic breast cancer; quality of life in MBC; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13235994
  3. J Clin Oncol. 2021 Dec 07. JCO2102554
    Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03).
    PALLAS groups and investigators
       PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed.
    PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival.
    RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial.
    CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.
    DOI:  https://doi.org/10.1200/JCO.21.02554
  4. ACS Omega. 2021 Nov 30. 6(47): 32253-32261
    Gallium-68 Labeling of the Cyclin-Dependent Kinase 4/6 Inhibitors as Positron Emission Tomography Radiotracers for Tumor Imaging.
    Cheng Liu, Ziyi Yang, Mingyu Liu, Xiangwei Wang, Shaoli Song, Xiaoping Xu, Zhongyi Yang.
      Cyclin-dependent kinase 4 and 6 (CDK4/6) have emerged as interesting therapeutic drug targets with many potential applications in anti-tumors, especially in breast cancer. A novel CDK4/6 kinase-derived positron emission tomography (PET) imaging agent was designed based on palbociclib modified with a chelator DOTA. This new compound with a chelator DOTA-palbociclib was radiolabeled with gallium 68 (68Ga). After labeling, the purity and stability were evaluated, and the blood pharmacokinetics were carried out in normal healthy mice. Human breast cancer MCF-7 (ER+/HER2-) cells were used for in vitro cell uptake tests. PET imaging and ex vivo biodistribution were conducted in MCF-7 tumor-bearing mice. Specific binding of tumors was evaluated by the blocking assay. Furthermore, the uptake of 68Ga-DOTA-palbociclib in tumors was studied by autoradiography of tissue sections followed by immunofluorescence evaluation of CDK4 and CDK6. 68Ga-DOTA-palbociclib was synthesized very simply in a high labeling rate and radiochemical purity in 10 min. The labeling compound showed excellent stability both in vitro and in vivo and exhibited good pharmacokinetics, making it suitable for in vivo imaging. Cell uptake studies display that co-incubation with palbociclib can inhibit cellular uptake of 68Ga-DOTA-palbociclib. In vivo imaging and ex vivo biodistribution in mice bearing MCF-7 tumors both showed obvious radioactive uptake in the tumor and higher tumor-to-muscle ratios, while the tumor radioactivity accumulation was significantly decreased when prior administered with an excess of cold palbociclib, confirming CDK4/6 specific binding of 68Ga-DOTA-palbociclib in vivo. Autoradiography of the avid tumor section showed a high correlation between immunofluorescence with the CDK4/6 positive areas of the tumor, further demonstrating that 68Ga-DOTA-palbociclib specifically targeted CDK4/6 positive tumors. We synthesized 68Ga-DOTA-palbociclib, a new CDK4/6 kinase PET imaging agent, and validated its excellent stability, pharmacokinetics, and specific tumor binding. Based on our primary results, 68Ga-DOTA-palbociclib is a promising imaging agent with the potential to tailor a precise treatment program for CDK4/6 inhibitors.
    DOI:  https://doi.org/10.1021/acsomega.1c05073
  5. Medicine (Baltimore). 2021 Nov 05. 100(44): e27710
    Real-world effectiveness and sensitivity of palbociclib plus endocrine therapy in HR+/HER2- patients with metastatic breast cancer.
    Jingping Li, Xiangmei Zhang, Chao Yang, Yalei Lv, Hua Yang, Xiangshun Kong, Meng Han, Zunyi Wang, Jie Ma, Jianjun Han, Yunjiang Liu.
       ABSTRACT: Palbociclib has shown satisfactory outcomes when combined with endocrine therapy (ET) in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, data in Asia are currently scarce.This retrospective study aimed to evaluate the real-world effectiveness, sensitivity, and toxicity of palbociclib plus ET in HR+/HER2- MBC in North China. We recruited patients with HR+/HER2- MBC from August 2018 to July 2020 across 7 hospitals in North China. The primary endpoint was to evaluate progression-free survival (PFS) after initial progress on palbociclib therapy. The secondary endpoints included determining predictive biomarkers of palbociclib sensitivity and toxicity of palbociclib.A total of 54 patients were analyzed in this cohort with an estimated median follow-up time of 14.3 months. Patients who received palbociclib as a first-line treatment showed significantly prolonged PFS compared with those who received palbociclib as a second-line or beyond treatment (21.8 months vs 15.9 months vs 6.8 months) (P < .001). Besides, patients with Ki67 <30% (P = .024) and PR ≥20% (P = .041) in metastatic tumors had significantly longer PFS. The Cox proportional-hazards regression analyses proved that different lines (P = .001 in multivariate analysis), Ki67 <30% (P = .035 in multivariate analysis), and PR ≥20% (P = .045 in univariate analysis) in metastatic tumors affected PFS significantly. The most common adverse events were hematologic, with 31.48% of patients having neutropenia.Palbociclib plus ET significantly prolonged PFS for patients with HR+/HER2- MBC who received first-line therapy, with manageable toxicity. The values of Ki67 and PR in metastatic tumors may be potential predictive biomarkers of palbociclib sensitivity.
    DOI:  https://doi.org/10.1097/MD.0000000000027710
  6. Oncol Lett. 2022 Jan;23(1): 25
    Baseline lymphopenia as prognostic factor in patients with metastatic breast cancer treated with palbociclib.
    George Emile, Sarah Penager, Christelle Levy, Alison Johnson, Djelila Allouache, Justine Lequesne, Ioana Hrab, Carine Segura, Adeline Morel, Katarina Gunzer, Audrey Faveyrial, Francois Cherifi, Angelique Da Silva.
      Cyclin-dependent-kinase 4-6 inhibitors (CDK4/6i) have improved the management of hormone receptor (HR)+/human epidermal growth factor receptor (HER)2- metastatic breast cancer (mBC). Currently, there are no valid prognostic factors for response to CDK4/6i. Baseline lymphopenia is reported as a prognostic factor in several types of cancer. The present retrospective study aimed to evaluate the effect of baseline absolute lymphocyte count (ALC) on response to palbociclib. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival (OS), best response and safety. A total of 114 patients treated for mBC between 2016 and 2019 were included. Median baseline ALC was 1.4 g/l (range, 0.2-4.3 g/l). A total of 65 (57%) and 49 (43%) patients had baseline ALC values of <1.5 and ≥1.5 g/l, respectively. Patients with baseline lymphopenia exhibited significantly shorter PFS (6 vs. 10 months; P=0.004) and OS (20 vs. 33 months; P=0.02). ALC <1.5 g/l independently predicted worse survival, as indicated by multivariate analysis (P=0.04; hazard ratio, 1.76; 95% confidence interval, 1.02-3.02). Patients with baseline ALC <1.5 g/l had significantly less partial response (14 vs. 22%; P=0.016) and more disease progression (46 vs. 20%; P=0.016) than those with ALC ≥1.5 g/l. ALC is a strong and easy-to-use dosage with prognostic factor for patients with HR+/HER2- mBC treated with palbociclib and endocrine therapy. Lymphopenia may also be a predictive factor of early progression. These data need to be verified in a larger prospective study.
    Keywords:  cyclin dependant kinase inhibitor; lymphopenia; metastatic breast cancer; palbociclib; prognosis factor
    DOI:  https://doi.org/10.3892/ol.2021.13143
  7. Oncology. 2021 Dec 07.
    Post-Progression Treatments after Palbociclib plus Endocrine Therapy in HR+/HER2- Metastatic Breast Cancer Patients: What Is the Better Choice?
    Alessandra Fabi, Mariangela Ciccarese, Sinome Scagnoli, Michelangelo Russillo, Francesco Schettini, Giuseppe Buono, Vito Lorusso, Katia Cannita, Grazia Arpino, Simonetta Stani, Michela Palleschi, Rosalba Rossello, Giuseppina Sarobba, Agnese Fabbri, Marianna Giampaglia, Patrizia Pellegrini, Vincenzo Adamo, Francesca Morelli, Vittoria Barberi, Gianluigi Ferretti, Giovanna Catania, Simona Pisegna, Francesco Cognetti, Diana Giannarelli.
       BACKGROUND: To date, a consensus has not yet been reached about the therapy sequence after disease progression (PD) on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer (MBC).
    OBJECTIVES: The present study assesses, in a real-world setting, the activity of different subsequent therapies in patients who experienced a PD on palbociclib (P) + endocrine therapy (ET), to evaluate the best therapy sequence.
    METHODS: This is a multicenter retrospective observational study. Records of consecutive HR+/HER2- MBC patients from January 2017 to May 2019 were reviewed. The primary endpoint was the evaluation of progression-free survival (PFS) according to subsequent treatment lines after progression on P+ET. Toxicity data were also collected.
    RESULTS: The outcomes were analyzed in 89 MBC patients that had progressed on previous P+ET: 17 patients were on hormone therapy (HT) and 31 patients on chemotherapy (CT) as second-line treatments; seven patients were on HT and 34 on CT as third-line therapies. PFS of patients treated with HT as second-line therapy is significantly improved when compared with patients treated with CT (p=0.01). Considering third-line settings, the difference in PFS was not statistically different between HT and CT. A better outcome in terms of toxicity is observed among HT patients for both second- and third-line therapies.
    CONCLUSIONS: patients who were progressive on P+ET could still benefit from a subsequent ET. In patients who experienced a good efficacy from prior ET, without visceral metastatic sites, HT seems the most suitable option, when compared to CT, also in terms of safety.
    DOI:  https://doi.org/10.1159/000521252
  8. Clin Cancer Res. 2021 Dec 09. pii: clincanres.2272.2021. [Epub ahead of print]
    Trilaciclib prior to chemotherapy in patients with metastatic triple-negative breast cancer: final efficacy and subgroup analysis from a randomized phase II study.
    Antoinette R Tan, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica Sorrentino, Janet Horton, Joyce O'Shaughnessy.
       PURPOSE: We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).
    EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to group 1 (GCb [days 1, 8]; n = 34), group 2 (trilaciclib prior to GCb [days 1, 8]; n = 33), or group 3 (trilaciclib [days 1, 8] and trilaciclib prior to GCb [days 2, 9]; n = 35). Subgroup analyses were performed according to CDK4/6 dependence, level of PD-L1 expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCR β CDR3 at baseline and on treatment.
    RESULTS: Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (hazard ratio [HR] 0.31; P = 0.0016), 17.8 months in group 3 (HR 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population. T-cell activation was enhanced in patients receiving trilaciclib.
    CONCLUSIONS: Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2272
  9. Transl Oncol. 2021 Dec 07. pii: S1936-5233(21)00293-X. [Epub ahead of print]15(1): 101302
    Nafamostat mesylate overcomes endocrine resistance of breast cancer through epigenetic regulation of CDK4 and CDK6 expression.
    Yueh-Te Lin, Joseph Lin, Yi-En Liu, Kai-Wen Hsu, Chang-Chi Hsieh, Dar-Ren Chen, Han-Tsang Wu.
      Breast cancer is common worldwide, and the estrogen receptor-positive subtype accounts for approximately 70% of breast cancer in women. Tamoxifen and fulvestrant are drugs currently used for endocrinal therapy. Breast cancer exhibiting endocrine resistance can undergo metastasis and lead to the death of breast cancer patients. Drug repurposing is an active area of research in clinical medicine. We found that nafamostat mesylate, clinically used for patients with pancreatitis and disseminated intravascular coagulation, acts as an anti-cancer drug for endocrine-resistant estrogen receptor-positive breast cancer (ERPBC). Epigenetic repression of CDK4 and CDK6 by nafamostat mesylate induced apoptosis and suppressed the metastasis of ERPBC through the deacetylation of Histone 3 Lysine 27. A combination of nafamostat mesylate and CDK4/6 inhibitor synergistically overcame endocrine resistance in ERPBC. Nafamostat mesylate might be an essential adjuvant or alternative drug for the treatment of endocrine-resistant ERPBC due to the low cost-efficiency of the CDK4/6 inhibitor.
    Keywords:  CDK4/6; Endocrine resistance; Estrogen receptor-positive breast cancer; Nafamostat mesylate
    DOI:  https://doi.org/10.1016/j.tranon.2021.101302
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