bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–02–06
six papers selected by
Piotr Okupski,

  1. Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer.
  2. Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.
  3. Clinical Significance of PIK3CA and ESR1 Mutations in circulating tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib Plus Fulvestrant.
  4. [Updates in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in 2021].
  5. Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations.
  6. PROactively TACkling CDK4/6 therapy resistance.
  1. Anticancer Res. 2022 Feb;42(2): 1099-1106
    Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer.
    Hirohito Seki, Takashi Sakurai, Akihisa Sakurada, Tetsuhiko Kinoshita, Ken Shimizu.
       BACKGROUND/AIM: This study investigated the efficacy of continuing cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) after disease progression on prior-palbociclib combined with endocrine therapy (ET).
    PATIENTS AND METHODS: This retrospective study based on 25 ER+/HER2- MBC patients reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib.
    RESULTS: The overall response rate and clinical benefit rate were 16.0% and 44.0%, respectively. The median progression-free survival (PFS) was 5.3 months. In multivariate analysis, the best overall response (BOR) to prior-palbociclib was the only independent predictive factor for PFS (p=0.015). The median time to chemotherapy was 33.9 months. The median PFS in patients treated with next-line chemotherapy after progression on subsequent-abemaciclib was 6.2 months.
    CONCLUSION: BOR to prior-palbociclib was the only independent predictive factor for PFS in ER+/HER2- MBC patients undergoing subsequent-abemaciclib after disease progression on prior-palbociclib.
    Keywords:  CDK4/6 inhibitor resistance; ER+/HER2– metastatic breast cancer; abemaciclib; palbociclib
    DOI:  https://doi.org/10.21873/anticanres.15572
  2. Lancet Oncol. 2022 Feb;pii: S1470-2045(21)00708-7. [Epub ahead of print]23(2): 195-197
    Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic.
    Georg Pfeiler, Angela DeMichele, Amylou C Dueck, Christian Fesl, Michael Gnant, Erica L Mayer.
      
    DOI:  https://doi.org/10.1016/S1470-2045(21)00708-7
  3. Clin Cancer Res. 2022 Feb 04. pii: clincanres.3276.2021. [Epub ahead of print]
    Clinical Significance of PIK3CA and ESR1 Mutations in circulating tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib Plus Fulvestrant.
    Sara M Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Hong Wang, Sameera Wijayawardana, Valerie M Jansen, Lacey M Litchfield, George W Sledge.
       BACKGROUND: PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2- advanced breast cancer (ABC). Inhibition of CDK4&6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2.
    PATIENTS AND METHODS: MONARCH 2 was a global, randomized, double-blind Phase 3 trial of abemaciclib plus fulvestrant in women with HR+, HER2- ABC that had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA.
    RESULTS: Abemaciclib plus fulvestrant improved PFS compared to placebo plus fulvestrant in both PIK3CA-wild-type and PIK3CA-mutant subgroups, as well as both ESR1-wild-type and ESR1-mutant subgroups. Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status.
    CONCLUSION: Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA or ESR1-mutant tumors compared to the respective wild-type subgroups, in women with HR+, HER2- ABC that had progressed on ET.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3276
  4. Bull Cancer. 2022 Jan 31. pii: S0007-4551(22)00001-7. [Epub ahead of print]
    [Updates in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in 2021].
    Essia Mezni, Renaud Sabatier, Anthony Goncalves, Cécile Vicier.
      Overall, 2021 was marked by the confirmation of the major interest of cell cycle inhibitors for hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative advanced breast cancers with very high overall survival data exceeding five years for hormone-sensitive disease. Studies have also confirmed the efficacy and safety of this therapeutic class in the elderly population. New cell cycle inhibitors are under development (SHR6390). New combinations are also being evaluated, notably palbociclib with SAR439859 (a new selective estrogen receptor degrader: SERD). Targeting of the Phosphoinositide 3-kinases (PI3K) pathway by taselisib, in hormone-resistant disease with a Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutation, modestly improves progression-free survival but with a non-negligible toxicity of the treatment.
    Keywords:  Advanced breast cancer; CDK inhibitor; Cancer du sein métastatique; Hormone receptor-positive; Inhibiteur CDK; Inhibiteur PIK3CA; PIK3CA inhibitor; Récepteurs hormonaux positifs
    DOI:  https://doi.org/10.1016/j.bulcan.2021.12.009
  5. Nat Cancer. 2021 May;2(5): 498-502
    Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations.
    Priscilla K Brastianos, Albert E Kim, Nancy Wang, Eudocia Q Lee, Jennifer Ligibel, Justine V Cohen, Ugonma N Chukwueke, Maura Mahar, Kevin Oh, Michael D White, Helen A Shih, Deborah Forst, Justin F Gainor, Rebecca S Heist, Elizabeth R Gerstner, Tracy T Batchelor, Donald Lawrence, David P Ryan, A John Iafrate, Anita Giobbie-Hurder, Sandro Santagata, Scott L Carter, Daniel P Cahill, Ryan J Sullivan.
      Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy.
    DOI:  https://doi.org/10.1038/s43018-021-00198-5
  6. Nat Cancer. 2021 Apr;2(4): 372-373
    PROactively TACkling CDK4/6 therapy resistance.
    Signe Caksa, Andrew E Aplin.
      
    DOI:  https://doi.org/10.1038/s43018-021-00193-w
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