bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2023–02–26
ten papers selected by
Piotr Okupski,

  1. Shifting Treatment Paradigms: Improvements in HR-Positive, HER-2- Negative Breast Cancer Care in Poland from a Clinical Perspective.
  2. CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients.
  3. Carboxypeptidase vitellogenic like facilitates resistance to CDK4/6 inhibitors in breast cancer.
  4. Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.
  5. p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer.
  6. Palbociclib impairs the proliferative capacity of activated T cells while retaining their cytotoxic efficacy.
  7. How I treat endocrine-dependent metastatic breast cancer.
  8. Cost-Effectiveness of Abemaciclib in Early Breast Cancer Patients: One Size Fits All or Tailoring to Patients' Needs?
  9. Utilizing Liquid Biopsy for Treatment Management in Bone-Dominant Metastatic Breast Cancer: A Case Report.
  10. [New treatment approaches for and ongoing trials in metastatic hormone-sensitive prostate cancer].
  1. Biomedicines. 2023 Feb 10. pii: 510. [Epub ahead of print]11(2):
    Shifting Treatment Paradigms: Improvements in HR-Positive, HER-2- Negative Breast Cancer Care in Poland from a Clinical Perspective.
    Marek Ziobro, Aleksandra Grela-Wojewoda.
      Patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer constitute about 70% of the breast cancer population. About 35% of these patients develop distant metastases and their treatment will be palliative. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors were shown to significantly improve the outcomes of these patients. In combination with endocrine therapy, they have become the standard first-line treatment for HR-positive, HER2-negative breast cancer. In Poland, treatment with CDK4/6 inhibitors is reimbursed only for patients participating in the drug program of the Ministry of Health. However, fulfilling the eligibility criteria for the program may be challenging both for patients and for clinicians. This may lead to a delay in treatment with CDK4/6 inhibitors or a decision to use older and less effective drugs that are more widely available. The aim of this review was to compare the efficacy of first-line therapies in patients with HR-positive, HER2-negative metastatic breast cancer depending on the use of CDK4/6 inhibitors. We compared the efficacy of previous standard therapies with that of ribociclib, a CDK4/6 inhibitor, based on the median progression-free survival (PFS) as an outcome. Median PFS is not affected by the efficacy of subsequent treatment lines and is easy to interpret both for clinicians and for patients. The first-line treatment with chemotherapy or endocrine therapy (without CDK4/6 inhibitors) prolongs median PFS by several months and even to over a dozen months. The first-line treatment with endocrine therapy plus CDK4/6 inhibitors provides an opportunity to achieve a median PFS of more than 25 months and to prolong it by about 9 to 14 months.
    Keywords:  CDK4/6 inhibitors; chemotherapy; endocrine therapy; metastatic breast cancer; ribociclib
    DOI:  https://doi.org/10.3390/biomedicines11020510
  2. Cancers (Basel). 2023 Feb 18. pii: 1306. [Epub ahead of print]15(4):
    CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients.
    Stefania Crucitta, Martina Ruglioni, Giulia Lorenzini, Irene Bargagna, Giovanna Irene Luculli, Irene Albanese, Diana Bilancio, Francesca Patanè, Andrea Fontana, Romano Danesi, Marzia Del Re.
      ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.
    Keywords:  CDK4/6 inhibitor; ESR1 mutation; ctDNA; liquid biopsy; metastatic breast cancer
    DOI:  https://doi.org/10.3390/cancers15041306
  3. Thorac Cancer. 2023 Feb 24.
    Carboxypeptidase vitellogenic like facilitates resistance to CDK4/6 inhibitors in breast cancer.
    Xiang Zhu, Xiaojie Xu, Lin Zhang, Xuhui Yang.
       OBJECTIVE: Inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6) are targeted therapeutic drugs for breast cancer treatment. The mechanism of resistance to these inhibitors requires further investigation.
    METHODS: We used bioinformatics to screen differentially expressed genes between cells that were susceptible and resistant to CDK4/6 inhibitors. Quantitative real-time PCR (qRT-PCR) was used to identify gene expressions in different cell lines. Cell viability, colony formation, cell cycle, and apoptosis assays were used to evaluate the effect of carboxypeptidase vitellogenic like (CPVL) on breast cancer cells under the condition of CDK4/6 inhibitors. Gene set enrichment analysis (GSEA) suggested the potential regulatory pathway of CPVL in breast cancer. Xenograft formation assay was conducted in nude mice to study the role of CPVL in vivo.
    RESULTS: Based on bioinformatics analysis and qRT-PCR, CPVL was identified more abundantly in cells that were resistant than sensitive to CDK4/6 inhibitors. Overexpressed or knocked down CPVL regulated the effects of CDK4/6 inhibitors in resistant cell lines. GSEA showed that resistance might be induced by CPVL through altered phosphatase and tensin homolog (PTEN)-related pathways. Our findings showed that CPVL negatively regulates PTEN to impact the anticancer effects of CDK4/6 inhibitors in vitro and in vivo.
    CONCLUSION: CPVL might be a key factor in regulating breast cancer resistance to CDK4/6 inhibitors.
    Keywords:  CDK4/6 inhibitor; CPVL; breast cancer; resistance
    DOI:  https://doi.org/10.1111/1759-7714.14829
  4. Target Oncol. 2023 Feb 24.
    Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence.
    Simon Fung, Hannah A Blair.
      Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.
    DOI:  https://doi.org/10.1007/s11523-023-00952-y
  5. JNCI Cancer Spectr. 2023 Feb 20. pii: pkad014. [Epub ahead of print]
    p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer.
    Silvana Mouron, Maria J Bueno, Manuel Muñoz, Raul Torres, Sandra Rodríguez, Juan V Apala, Jorge Silva, Rodrigo Sánchez-Bayona, Luis Manso, Juan Guerra, Laura Rodriguez-Lajusticia, Diego Malon, Marcos Malumbres, Miguel Quintela-Fandino.
      CDK4/6 inhibitors benefit a minority of patients that receive them in the breast cancer adjuvant setting. p27Kip1 is a protein that inhibits CDK/Cyclin complexes. We hypothesized that SNPs that impaired p27Kip1 function could render patients refractory to endocrine therapy but responsive to CDK4/6 inhibitors, narrowing-down the patient sub-population that requires CDK4/6 inhibitors. We found that the p27Kip1 V109G SNP is homozygous in ∼15% of hormone-positive breast cancer patients. Polymorphic patients experience rapid failure in response to endocrine monotherapy compared to wild-type/heterozygous patients in the first-line metastatic setting (progression-free survival: 92 versus 485 days; P < 0.001); when CDK4/6 inhibitors are added, the differences disappear (progression-free survival: 658 versus 761 days; P = 0.92). As opposed to wild-type p27Kip1, p27Kip1 V109G is unable to suppress the kinase activity of CDK4 in presence of endocrine inhibitors; however, palbociclib blocks CDK4 kinase activity regardless of the p27Kip1 status. p27Kip1 genotyping could constitute a tool for treatment selection.
    DOI:  https://doi.org/10.1093/jncics/pkad014
  6. Front Pharmacol. 2023 ;14 970457
    Palbociclib impairs the proliferative capacity of activated T cells while retaining their cytotoxic efficacy.
    Claudia Arndt, Antje Tunger, Rebekka Wehner, Rebecca Rothe, Eleni Kourtellari, Stephanie Luttosch, Katharina Hannemann, Stefanie Koristka, Liliana R Loureiro, Anja Feldmann, Torsten Tonn, Theresa Link, Jan Dominik Kuhlmann, Pauline Wimberger, Michael Philipp Bachmann, Marc Schmitz.
      The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib is an emerging cancer therapeutic that just recently gained Food and Drug Administration approval for treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor (Her)2-negative breast cancer in combination with the ER degrader fulvestrant. However, CDK4/6 inhibitors are not cancer-specific and may affect also other proliferating cells. Given the importance of T cells in antitumor defense, we studied the influence of palbociclib/fulvestrant on human CD3+ T cells and novel emerging T cell-based cancer immunotherapies. Palbociclib considerably inhibited the proliferation of activated T cells by mediating G0/G1 cell cycle arrest. However, after stopping the drug supply this suppression was fully reversible. In light of combination approaches, we further investigated the effect of palbociclib/fulvestrant on T cell-based immunotherapies by using a CD3-PSCA bispecific antibody or universal chimeric antigen receptor (UniCAR) T cells. Thereby, we observed that palbociclib clearly impaired T cell expansion. This effect resulted in a lower total concentration of interferon-γ and tumor necrosis factor, while palbociclib did not inhibit the average cytokine release per cell. In addition, the cytotoxic potential of the redirected T cells was unaffected by palbociclib and fulvestrant. Overall, these novel findings may have implications for the design of treatment modalities combining CDK4/6 inhibition and T cell-based cancer immunotherapeutic strategies.
    Keywords:  CAR T cell; CDK4/6; adoptive T cell therapy; bispecific antibody; cancer immunotherapy; fulvestrant; palbociclib
    DOI:  https://doi.org/10.3389/fphar.2023.970457
  7. ESMO Open. 2023 Feb 17. pii: S2059-7029(23)00102-3. [Epub ahead of print]8(2): 100882
    How I treat endocrine-dependent metastatic breast cancer.
    A Gombos, A Goncalves, G Curigliano, R Bartsch, J A Kyte, M Ignatiadis, A Awada.
      Estrogen receptor-positive (ER+)/HER2-negative (HER2-), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody-drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease. This review paper provides an overview of currently available treatment options in ER+/HER2- metastatic breast cancer and extensively discusses new approaches in late clinical development.
    Keywords:  CDK 4/6; PIK3CA; SERD; antibody–drug conjugate (ADC); luminal breast cancer
    DOI:  https://doi.org/10.1016/j.esmoop.2023.100882
  8. Breast Cancer (Dove Med Press). 2023 ;15 147-161
    Cost-Effectiveness of Abemaciclib in Early Breast Cancer Patients: One Size Fits All or Tailoring to Patients' Needs?
    Elisabeth M Jongbloed, Hedwig M Blommestein, Hannah M van Schoubroeck, John W M Martens, Saskia M Wilting, Carin A Uyl-de Groot, Agnes Jager.
       Purpose: The addition of two years of abemaciclib treatment to standard adjuvant endocrine therapy in all patients with high risk ER+, HER2- early breast cancer (EBC) has been approved by the US Food and Drug Administration (FDA). Pre-selection of patients with an immediate risk of recurrence within the group of clinically high risk patients using detection of minimal residual disease (MRD) using patient-informed circulating tumor DNA assays during follow-up could enhance efficacy. Here, we investigate the cost-effectiveness of the addition of two years abemaciclib in all high risk HR+, HER2- patients and in MRD-guided high risk patients only.
    Methods: Two semi-Markov models were developed to evaluate the cost-effectiveness of adding two years of abemaciclib compared to "standard treatment": 1) "abemaciclib all" and 2) "MRD-guided abemaciclib" using MRD-guidance. Data of the MonarchE trial were used to model the invasive disease-free survival (iDFS). Since iDFS and overall survival (OS) data of abemaciclib were currently limited, abemaciclib effects were extrapolated using a favorable, intermediate and unfavorable effect scenario.
    Results: The addition of abemaciclib in all high-risk EBC patients prolonged iDFS slightly (0.04 additional quality adjusted life years (QALYs)) and led to higher costs compared to standard ET, leading to a high incremental cost effectiveness ratio (ICER) of €1,551,876/QALY. Neither the favorable effect scenario (additional 1.09 QALYs) was cost-effective (ICER €62,935/QALY), using a willingness-to-pay threshold of €50,000/QALY. The "MRD-guided abemaciclib" strategy resulted in lower costs and an increase in QALYs (1.27) compared to "standard treatment" in the unfavorable effect scenario.
    Conclusion: The addition of abemaciclib to adjuvant endocrine therapy in all high-risk ER+, HER2- EBC patients is not cost-effective. However, using MRD detection to justify the addition of abemaciclib treatment dominates standard treatment in this cost-effectiveness analysis. Further evaluation of MRD detection in EBC by means of prospective clinical trials assessing clinical utility is recommended and promising in terms of cost-effectiveness.
    Keywords:  abemaciclib; breast cancer; circulating tumor DNA; cost-effectiveness; minimal residual disease
    DOI:  https://doi.org/10.2147/BCTT.S387375
  9. Case Rep Oncol. 2022 Sep-Dec;15(3):15(3): 854-860
    Utilizing Liquid Biopsy for Treatment Management in Bone-Dominant Metastatic Breast Cancer: A Case Report.
    Shirley Cheng, Edward Tri Nguyen, Jami Aya Fukui.
      Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. In clinical practice, the standard method to confirm metastatic disease and tailor treatment is to biopsy a metastatic site. Bone is the most common metastatic site, occurring in up to 70% of patients with advanced breast cancer. Standard-of-care management includes a needle biopsy with histopathological analysis to confirm tumor status and to evaluate for mutations. However, bone biopsies can be technically challenging and are oftentimes painful for patients. Given the challenges in acquisition and analysis of bone samples in metastatic breast cancer (mBC), a liquid biopsy is a less invasive alternative that can reveal clinically relevant alterations. Here, we report two cases of bone-dominant hormone-positive (HR+) mBC, in which circulating tumor DNA (ctDNA) was extracted from blood samples using two different next-generation sequencing (NGS) platforms to identify molecular targets for FDA approved treatment. In both patients, PIK3CA mutations were detected and subsequently started on alpelisib along with aromatase inhibitor or fulvestrant treatment. These cases demonstrate a feasible real-world clinical application to liquid biopsies.
    Keywords:  Bone metastasis; Bone-dominant; Breast cancer; Liquid biopsy; PIK3CA
    DOI:  https://doi.org/10.1159/000526642
  10. Urologie. 2023 Feb 23.
    [New treatment approaches for and ongoing trials in metastatic hormone-sensitive prostate cancer].
    A Isgandarov, C Darr, P Posdzich, K Hermann, B A Hadaschik, V Grünwald.
       BACKGROUND: For many years, therapy for metastatic hormone-sensitive prostate cancer (mHSPC) was dominated by monotherapy using androgen deprivation therapy (ADT). With the demonstration of survival benefit with intensified systemic therapy from the CHAARTED and STAMPEDE trials, this has fundamentally changed. We analyzed the phase III trials that led to the change in therapy in mHSPC. In addition, we summarized ongoing trials in mHSPC.
    OBJECTIVES: The ongoing studies and current data on systemic therapy in mHSPC were analyzed.
    RESULTS: Monotherapy with ADT is no longer considered the standard therapy for mHSPC. Combination therapy with ADT and novel androgen receptor targeting agents (ARTAs: abiraterone, apalutamide, enzalutamide) is now the established standard option. The added value of further intensification of therapy was demonstrated in the first trials of triple therapy with ADT + docetaxel + darolutamide or abiraterone in mHSPC. Current studies are also investigating new forms of therapy. Lutetium177-PSMA radioligand therapy is an established standard in metastatic castration-resistant prostate cancer (mCRPC) and is currently being evaluated in combination with ADT + ARTA in mHSPC. The use of PARP inhibitors (PARPi) have been established in mCRPC. Current studies are showing early evidence of benefit from novel combination therapies of PARPi + ARTA, which represent a further expansion of the therapeutic landscape. Experimental therapies are testing another combination, such as an AKT inhibitor with ARTA in patients with PTEN (phosphatase and tensin homolog) loss. Based on the proof of principle in mCRPC, this combination is now being evaluated in earlier stage mHSPC. Other experimental therapies in clinical testing include inhibitors of cyclin dependent kinases (CDK).
    CONCLUSIONS: Combination therapies are the current standard of care for mHSPC, with the combination of ADT + ARTA dominating. Preliminary results underline the importance of further intensification of therapy by means of triple therapy. However, novel combinations with radioligand therapy or PARP inhibitors are also promising in the treatment of mHSPC. Preliminary results show the principle efficacy of AKT inhibitors in patients with PTEN loss, which similar to therapy with CDK4/6 inhibitors still have to prove their clinical relevance in randomized trials.
    Keywords:  AKT; Androgen receptor; CDK4/6; PARP; Radioligand therapy
    DOI:  https://doi.org/10.1007/s00120-023-02046-z
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