bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–05–15
nine papers selected by
Piotr Okupski,

  1. Cyclin-Dependent Kinase 4 and 6 Inhibitors: A Quantum Leap in the Treatment of Advanced Breast Cancers.
  2. Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting.
  3. Systemic Therapies Following Progression on First-line CDK4/6-inhibitor Treatment: Analysis of Real-world Data.
  4. Overall Survival With Palbociclib And Fulvestrant in Women With HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-Blind, Phase 3 Randomized Study.
  5. Cost Effectiveness of Ribociclib and Palbociclib in the Second-Line Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer in Post-Menopausal Indian Women.
  6. Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study.
  7. Abemaciclib in Patients with End-Stage Renal Disease and Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: A Report of 2 Cases.
  8. CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune surface molecules.
  9. Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib.
  1. Cureus. 2022 Apr;14(4): e23901
    Cyclin-Dependent Kinase 4 and 6 Inhibitors: A Quantum Leap in the Treatment of Advanced Breast Cancers.
    Sanjana Reddy, Zineb Barkhane, Jalal Elmadi, Lakshmi Satish Kumar, Lakshmi Sree Pugalenthi, Mahlika Ahmad.
      Breast cancer (BC) is defined as an uncontrolled growth of breast cells that affected 2.3 million women in 2020 alone. Until a few years earlier, radiotherapy and chemotherapy were the most commonly used treatments in treating BC; however, many trials and studies were conducted to test the competence of cyclin-dependent kinases 4/6 (CDK4/6) in arresting the cell cycle, and it was found that they were highly influential in halting the disease from progressing. Palbociclib, ribociclib, and abemaciclib are the three drugs that have been approved by the US Food and Drug Administration (FDA) and are even more efficient when used in combination with aromatase inhibitors and fulvestrant. This article aimed to explain the effect of CDK4/6 inhibitors on tumor cells and their efficacy in combination with other drugs. We further explored the development of resistance to these treatments and future possibilities.
    Keywords:  abemaciclib; cdk4/6 inhibitor; her2-positive breast cancer; palbociclib; ribociclib
    DOI:  https://doi.org/10.7759/cureus.23901
  2. Curr Med Res Opin. 2022 May 13. 1-13
    Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting.
    Gregory L Price, Lavanya Sudharshan, Paula Ryan, Jonathan Rajkumar, Kristin M Sheffield, Emily Nash Smyth, Claudia Morato Guimaraes, Sarah Rybowski, Gebra Cuyun Carter, Wambui Grace Gathirua-Mwangi, Yu-Jing Huang.
       OBJECTIVE: To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib).
    METHODS: This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported.
    RESULTS: Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall.
    CONCLUSIONS: This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.
    Keywords:  CDK4/CDK6 inhibitor; adverse events; metastatic breast cancer; real-world utilization
    DOI:  https://doi.org/10.1080/03007995.2022.2073122
  3. Oncologist. 2022 Apr 25. pii: oyac075. [Epub ahead of print]
    Systemic Therapies Following Progression on First-line CDK4/6-inhibitor Treatment: Analysis of Real-world Data.
    James M Martin, Elizabeth A Handorf, Alberto J Montero, Lori J Goldstein.
       BACKGROUND: Metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (Her2-) breast cancer remains a significant cause of cancer-related mortality. First-line treatment with endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i) has largely become the standard systemic therapy. Following progression, no prospective randomized data exist to help guide second-line treatment.
    MATERIALS AND METHODS: This study used a nationwide electronic health record (EHR)-derived de-identified database, specifically analyzing 1210 patients with HR+/Her2- metastatic breast cancer (MBC) who were treated in the first-line setting with a CDK4/6i from the years 2015-2020. The aim of this study was to assess what therapies were given after first-line progression on CDK4/6i and to observe treatment patterns over time. Determination of second-line treatment efficacy, specifically assessing real-world progression-free survival (rwPFS) and overall survival (OS) was performed.
    RESULTS: A total of 839 patients received a documented second-line therapy after progression on first-line CDK4/6i treatment. Chemotherapy was chosen for 29.7% of patients, and the use of chemotherapy decreased over time. Three hundred two (36.0%) of patients continued a CDK4/6i. Data were adjusted for age, race, Eastern Cooperative Oncology Group (ECOG) performance status, stage at breast cancer diagnosis, and insurance payer type. Continuation of the CDK4/6i was associated with improved rwPFS (HR 0.48, 95% CI 0.43-0.53, P < .0001) and OS (HR 0.30, 95% CI 0.26-0.35, P < .0001) compared to chemotherapy. A majority of these patients continued the same CDK4/6i in the second-line setting, as was given in the first-line setting.
    CONCLUSION: While prospective data are needed, analysis of real-world data suggests a survival benefit for continuation of a CDK4/6i beyond frontline progression for patients with HR+/Her2- MBC.
    Keywords:  CDK4/6 inhibitor; abemaciclib; everolimus; palbociclib; ribociclib
    DOI:  https://doi.org/10.1093/oncolo/oyac075
  4. Clin Cancer Res. 2022 May 12. pii: clincanres.0305.2022. [Epub ahead of print]
    Overall Survival With Palbociclib And Fulvestrant in Women With HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-Blind, Phase 3 Randomized Study.
    Massimo Cristofanilli, Hope S Rugo, Seock-Ah Im, Dennis J Slamon, Nadia Harbeck, Igor Bondarenko, Norikazu Masuda, Marco Colleoni, Angela DeMichele, Sherene Loi, Hiroji Iwata, Ben O'Leary, Fabrice André, Sibylle Loibl, Eustratios Bananis, Yuan Liu, Xin Huang, Sindy Kim, Maria Jose Lechuga Frean, Nicholas C Turner.
       PURPOSE: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).
    PATIENTS AND METHODS: Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/d; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.
    RESULTS: At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS (95% CI) was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC, low circulating tumor fraction, and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.
    CONCLUSIONS: The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.
    TRIAL REGISTRATION: ClinicalTrials.gov Identifer: NCT01942135.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0305
  5. Appl Health Econ Health Policy. 2022 May 10.
    Cost Effectiveness of Ribociclib and Palbociclib in the Second-Line Treatment of Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer in Post-Menopausal Indian Women.
    Nidhi Gupta, Dharna Gupta, Jyoti Dixit, Nikita Mehra, Ashish Singh, Manjunath Nookala Krishnamurthy, Gaurav Jyani, Kavitha Rajsekhar, Jayachandran Perumal Kalaiyarasi, Partha Sarathi Roy, Prabhat Singh Malik, Anisha Mathew, Pankaj Malhotra, Sudeep Gupta, Lalit Kumar, Amal Kataki, Shankar Prinja.
       BACKGROUND: In this study, we evaluate the cost and outcomes of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus fulvestrant, fulvestrant alone, and conventional chemotherapy as the second-line therapy for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in India.
    METHODS: Using a Markov model, the clinical effectiveness of managing HR+, HER2- MBC in postmenopausal women with either a CDK4/6i (either ribociclib or palbociclib) and fulvestrant, fulvestrant alone, and chemotherapy (single-agent paclitaxel or capecitabine) was measured in terms of quality-adjusted life-years (QALYs). The costs were estimated from two different points of view: scenario I, as per the prevailing market prices of the drugs; and scenario II, as per the reimbursement rates set up by the publicly financed national health insurance scheme. Incremental cost per QALY gained with a given treatment option was compared against the next best alternative and was assessed for cost effectiveness using a threshold of 1-time the per capita gross domestic product (GDP) in India from a societal perspective.
    RESULTS: In scenario I, an MBC patient was found to incur a lifetime cost of Indian Rupees (₹) 2.54 million ($34,644), ₹2.53 million ($34,496), ₹512,598 ($6,984), ₹326,026 ($4,442) and ₹237,115 ($3,230) for the ribociclib and palbociclib combination arms, fulvestrant monotherapy, single-agent paclitaxel and the single-agent capecitabine treatment arms, respectively. The lifetime cost for CDK4/6i (ribociclib and palbociclib) combination therapy, fulvestrant monotherapy, paclitaxel, and capecitabine arms was estimated to be ₹1.94 million ($26,459), ₹1.92 million ($26,220), ₹315,387 ($4,296), ₹187,392 ($2,553) and ₹153,263 ($2,088), respectively, in scenario II. The mean QALYs lived per MBC patient with CDK4/6i (either ribociclib or palbociclib) combination therapy, fulvestrant, paclitaxel and capecitabine were estimated to be 1.4, 1.0, 0.9 and 0.7, respectively. None of the treatment arms are cost effective at current prices and reimbursement rates at a threshold of 1-time the per capita GDP of India. However, a 78% reduction in the current market price or a 72% reduction in the reimbursement rate of fulvestrant in the government-funded insurance program will make it a cost-effective treatment option for HR+, HER2- MBC patients in India.
    CONCLUSION: CDK4/6i (ribociclib and palbociclib) therapy is not a cost-effective treatment option for MBC patients. A 72% reduction in the reimbursement rate for fulvestrant monotherapy will make it a cost-effective treatment option in the Indian context.
    DOI:  https://doi.org/10.1007/s40258-022-00731-2
  6. BMC Cancer. 2022 May 07. 22(1): 516
    Proton pump inhibitors may reduce the efficacy of ribociclib and palbociclib in metastatic breast cancer patients based on an observational study.
    Kadir Eser, Arif Hakan Önder, Emel Sezer, Timuçin Çil, Ali İnal, Banu Öztürk, Vehbi Erçolak, Berna Bozkurt Duman, Halil Çelik, Tolga Köşeci, Oğuzhan Kesen.
       INTRODUCTION: Approximately 20-33% of all cancer patients are treated with acid-reducing agents (ARAs), most commonly proton pump inhibitors (PPIs), to reduce gastroesophageal reflux disease symptoms. Palbociclib and ribociclib are weak bases so their solubility depends on different pH. The solubility of palbociclib dramatically decreases to < 0.5 mg/ml when pH is above 4,5 but ribociclibs' solubility decreases when pH increases above 6,5. In the current study, we aimed to investigate the effects of concurrent PPIs on palbociclib and ribociclib efficacy in terms of progression-free survival in metastatic breast cancer (mBC) patients.
    PATIENTS AND METHODS: We enrolled hormone receptor-positive, HER2-negative mBC patients treated with endocrine treatment (letrozole or fulvestrant) combined palbociclib or ribociclib alone or with PPI accompanying our observational study. During palbociclib/ribociclib therapy, patients should be treated with "concurrent PPIs" defined as all or more than half of treatment with palbociclib/ribociclib, If no PPI was applied, it was defined as 'no concurrent PPI', those who used PPI but less than half were excluded from the study. All data was collected from real-life retrospectively.
    RESULTS: Our study included 217 patients, 105 of whom received palbociclib and 112 received ribociclib treatment. In the study population CDK inhibitor treatment was added to fulvestrant 102 patients ( 47%), to letrozole 115 patients (53%). In the Palbociclib arm fulvestrant/letrozole ratio was 53.3/46.7%, in the ribociclib arm it was 41.07/58.93%. Of 105 patients who received palbociclib, 65 were on concomitant PPI therapy, 40 were not. Of the 112 patients who received ribociclib, 61 were on concomitant PPI therapy, 51 were not. In the palbociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (13.04 months vs. unreachable, p < 0.001). It was determined that taking PPIs was an independent predictor of shortening PFS (p < 0.001) in the multivariate analysis, In the ribociclib group, the PFS of the patients using PPIs was shorter than the PFS of the patients not using (12.64 months vs. unreachable, p = 0.003). It was determined that taking PPIs was single statistically independent predictor of shortening PFS (p = 0.003, univariate analysis).
    CONCLUSIONS: Our study demonstrated that concomitant usage of PPIs was associated with shorter PFS in mBC treated with both ribociclib and especially palbociclib. If it needs to be used, PPI selection should be made carefully and low-strength PPI or other ARAs (eg H2 antagonists, antacids) should be preferred.
    Keywords:  Breast cancer; PFS; Palbociclib; Proton pump inhibitors; Ribociclib
    DOI:  https://doi.org/10.1186/s12885-022-09624-y
  7. Case Rep Oncol. 2022 Jan-Apr;15(1):15(1): 305-311
    Abemaciclib in Patients with End-Stage Renal Disease and Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: A Report of 2 Cases.
    Vittorio Gebbia.
      Cyclin4/6-dependent kinase inhibitors (CDKIs) plus hormonotherapy currently represent the standard golden treatment for patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor-2-negative (her-2-) advanced breast carcinoma. Among CDKIs, abemaciclib is the most active. No data on the use of abemaciclib in patients with end-stage renal disease (ESRD) exist in the medical literature. Two women with ER+, her-2- metastatic breast cancer received standard hormonal therapy plus abemaciclib 100 mg b.i.d. under strict monitoring for toxicity. Although ESRD exposes patients to a higher risk of toxicity from antineoplastic agents, no unexpected or severe toxicity was recorded in both patients after 9 and 12 months of therapy. In 1 patient, grade 2 diarrhea started after 7 days of therapy and disappeared or was significantly reduced after using loperamide and dietary modifications. Both patients complained of grade 1 asthenia. Hematological parameters were in line with expected toxicity. No cardiovascular or hepatic side effects were observed. This report of two women with metastatic breast cancer suggests the potentially safe use of abemaciclib in ESRD, which should be confirmed in more extensive real-life studies.
    Keywords:  Abemaciclib; End-stage renal disease; Estrogen receptor; Metastatic breast cancer
    DOI:  https://doi.org/10.1159/000523856
  8. J Transl Med. 2022 May 13. 20(1): 217
    CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune surface molecules.
    Yiquan Wu, Prabha Shrestha, Natalie M Heape, Robert Yarchoan.
       BACKGROUND: The two oncogenic human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), both downregulate immune surface molecules, such as MHC-I, ICAM-1, and B7-2, enabling them to evade T-cell and natural killer cell immunity. Both also either encode for human cyclin homologues or promote cellular cyclin activity, and this has been shown to be important for proliferation and survival of gammaherpesvirus-induced tumors. CDK4/6 inhibitors, which are approved for certain breast cancers, have been shown to enhance expression of MHC-I in cell lines and murine models of breast cancer, and this was attributed to activation of interferons by endogenous retrovirus elements. However, it was not known if this would occur in gammaherpesvirus-induced tumors in which interferons are already activated.
    METHODS: Multiple KSHV/EBV-infected cell lines were treated with CDK4/6 inhibitors. The growth of viable cells and expression of surface markers was assessed. T cell activation stimulated by the treated cells was assayed by a T-cell activation bioassay. Both viral and host gene expression was surveyed using RT-qPCR.
    RESULTS: Three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, inhibited cell growth in KSHV-induced primary effusion lymphoma (PEL) and EBV positive Burkitt's lymphoma (BL) cell lines, and KSHV-infected human umbilical vein endothelial cells (HUVECs). Moreover, CDK4/6 inhibitors increased mRNA and surface expression of MHC-I in all three and prevented downregulation of MHC-I surface expression during lytic replication in KSHV-infected cells. CDK4/6 inhibitors also variably increased mRNA and surface expression of ICAM-1 and B7-2 in the tested lines. Abemaciclib also significantly enhanced T-cell activation induced by treated PEL and BL cells. Certain gammaherpesvirus genes as well as endogenous retrovirus (ERV) 3-1 genes were enhanced by CDK4/6 inhibitors in most PEL and BL lines and this enhancement was associated with expression of gamma interferon-induced genes including MHC-I.
    CONCLUSIONS: These observations provide evidence that CDK4/6 inhibitors can induce expression of surface immune markers MHC-I, B7-2, and ICAM-1 in gammaherpesvirus-infected cell lines and induce virus-specific immunity. They can thus thwart virus-induced immune evasion. These effects, along with their direct effects on KSHV- or EBV-induced tumors, provide a rational for the clinical testing of these drugs in these tumors.
    Keywords:  CDK inhibitor; Cyclin; EBV; Gammaherpesvirus; Immune evasion; KSHV; Kaposi sarcoma; Lymphoma; MHC-I; Viral malignancy
    DOI:  https://doi.org/10.1186/s12967-022-03400-z
  9. Eur J Clin Pharmacol. 2022 May 09.
    Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib.
    Akimitsu Maeda, Hitoshi Ando, Kei Irie, Naoya Hashimoto, Jun-Ichi Morishige, Shoji Fukushima, Akira Okada, Hiromichi Ebi, Masahide Matsuzaki, Hiroji Iwata, Masataka Sawaki.
       PURPOSE: Adverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib.
    METHODS: A total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms.
    RESULTS: The trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. For ABCB1 2677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5-295.8] ng/mL vs. 113.5 [23.6-355.2] ng/mL, P = 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86-20.7; P = 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms.
    CONCLUSION: ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.
    Keywords:  ABCB1; ABCG2; Abemaciclib; Pharmacokinetics; Polymorphisms
    DOI:  https://doi.org/10.1007/s00228-022-03331-0
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