bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–01–16
six papers selected by
Piotr Okupski,

  1. Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer.
  2. Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase.
  3. Vitiligo-Like Lesions in a Patient with Metastatic Breast Cancer Treated with Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor: A Case Report and Literature Review.
  4. Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer.
  5. Clinicopathological Features Related to the Efficacy of CDK4/6 Inhibitor-Based Treatments in Metastatic Breast Cancer.
  6. The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer.
  1. JCO Precis Oncol. 2022 Jan;6 e2100002
    Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer.
    Uzma S Asghar, Ruhi Kanani, Rebecca Roylance, Sibylle Mittnacht.
      Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.
    DOI:  https://doi.org/10.1200/PO.21.00002
  2. Cancers (Basel). 2022 Jan 01. pii: 210. [Epub ahead of print]14(1):
    Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase.
    Kamal Pandey, Nar Bahadur Katuwal, Nahee Park, Jin Hur, Young Bin Cho, Seung Ki Kim, Seung Ah Lee, Isaac Kim, Seung-Ryeol Lee, Yong Wha Moon.
      Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer.
    Keywords:  CDK4/6; PLK1; drug resistance; hormone receptor-positive breast cancer
    DOI:  https://doi.org/10.3390/cancers14010210
  3. Clin Cosmet Investig Dermatol. 2022 ;15 5-10
    Vitiligo-Like Lesions in a Patient with Metastatic Breast Cancer Treated with Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor: A Case Report and Literature Review.
    Baha' Sharaf, Rama AlMasri, Nayef Abdel-Razeq, Osama Salama, Ibrahim Hamad, Mahmoud Abunasser, Hikmat Abdel-Razeq.
       Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, with an impressive efficacy and safety profile. Cytopenia is the main adverse event, which is both predictable and manageable. Here, we report a case of CDK4/6 inhibitor-induced vitiligo-like lesions. Vitiligo or vitiligo-like lesions are a rare adverse event; only a few cases are reported in the literature.
    Case Presentation: A 71-year-old female patient was diagnosed initially with early-stage right breast cancer (HR+/HER2-) and was treated with breast-conserving surgery followed by chemotherapy, radiotherapy, and hormonal therapy. A few years later, she developed metastatic disease to the hilar lymph nodes, and to multiple skeletal sites, including the left scapula, left shoulder, left iliac bone, and dorsal vertebrae, for which she was treated with ribociclib and letrozole. While on treatment, she developed hypopigmented lesions involving both hands, feet, and face, which were described as vitiligo-like lesions.
    Conclusion: CDK4/6 inhibitor-induced vitiligo is a rare and unpredictable adverse event. This case report highlights the rarity of this adverse event, the dilemma related to the optimal treatment, and decisions related to continuation, holding, or switching CDK4/6 inhibitors.
    Keywords:  CDK4/6 inhibitors; breast cancer; ribociclib; skin adverse events; vitiligo; vitiligo-like
    DOI:  https://doi.org/10.2147/CCID.S344867
  4. NPJ Breast Cancer. 2022 Jan 10. 8(1): 1
    Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer.
    Luca Gianni, Marco Colleoni, Giancarlo Bisagni, Mauro Mansutti, Claudio Zamagni, Lucia Del Mastro, Stefania Zambelli, Giampaolo Bianchini, Antonio Frassoldati, Ilaria Maffeis, Pinuccia Valagussa, Giuseppe Viale.
      The crosstalk between estrogen and HER2 receptors and cell-cycle regulation sustains resistance to endocrine therapy of HER2- and hormone receptor-positive breast cancer. We earlier reported that women with HER2 and ER-positive breast cancer receiving neoadjuvant dual HER2-block and palbociclib in the NA-PHER2 trial had Ki67 decrease and 27% pathological complete responses (pCR). We extended NA-PHER2 to Cohort B using dual HER2-block and palbociclib without fulvestrant and report here Ki67 drops at week-2 (mean change -25.7), at surgery (after 16 weeks, mean change -9.5), high objective response (88.5%) and pCR (19.2%). In Cohort C [Ki67 > 20% and HER2low (IHC 1+/2+ without gene amplification)], women also received fulvestrant, had dramatic Ki67 drop at week 2 (-29.5) persisting at surgery (-19.3), and objective responses in 78.3%. In view of the favorable tolerability and of the efficacy-predictive value of Ki67 drop at week-2, the chemotherapy-free approach of NA-PHER2 deserves further investigation in HER2 and ER-positive breast cancer. The trial is registered with ClinicalTrials.gov, number NCT02530424.
    DOI:  https://doi.org/10.1038/s41523-021-00377-8
  5. Breast Cancer (Auckl). 2022 ;16 11782234211065148
    Clinicopathological Features Related to the Efficacy of CDK4/6 Inhibitor-Based Treatments in Metastatic Breast Cancer.
    Ayana Shikanai, Yoshiya Horimoto, Yumiko Ishizuka, Toshitaka Uomori, Katsuya Nakai, Atsushi Arakawa, Mitsue Saito.
       Background: Resistance to endocrine therapy has been a major obstacle in the management of hormone receptor (HR)-positive metastatic breast cancer (MBC). Meanwhile, a number of treatments are available to such patients, and physicians often encounter difficulties in choosing the most appropriate treatments for individual patients. The combination of CDK 4/6 inhibitors (CDKi) and endocrine therapy has now become a standard treatment for HR-positive and human epidermal growth factor receptor 2 (HER2)-negative MBC. However, no predictive markers for CDKi-based treatments have been established. Considering their side effects and the financial burden on patients, identifying such markers is crucial.
    Methods: Clinicopathological features of 107 patients with HR-positive HER2-negative MBC, who received CDKi-based treatments at our institution were retrospectively investigated. HR status in distant metastatic lesions and immunocompetent cells in peripheral blood were also studied.
    Results: Progression-free survival (PFS) was significantly shorter in patients whose primary tumour was high grade (P = 0.016) or high neutrophil-to-lymphocyte ratio (NLR) at baseline (P = 0.017). Meanwhile, there were no differences in other factors, such as expression levels of hormone receptors. Patients whose metastatic lesions were of low tumour grade or high Ki67 labelling index had longer PFS, and such trends were more obvious than primary lesions.
    Conclusion: Our data indicate that tumour grade in primary lesion and NLR are potential predictive factors for CDKi-based treatments. Moreover, pathological assessment of metastatic lesions might also be useful.
    Keywords:  Breast cancer; CDK 4/6 inhibitor; metastatic lesion; neutrophil-to-lymphocyte ratio; predictive marker
    DOI:  https://doi.org/10.1177/11782234211065148
  6. Cancers (Basel). 2021 Dec 29. pii: 153. [Epub ahead of print]14(1):
    The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer.
    Dorian V Ziegler, Katharina Huber, Lluis Fajas.
      In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy.
    Keywords:  CDKs; CKI; E2F; autophagy; cancer; cell cycle regulators
    DOI:  https://doi.org/10.3390/cancers14010153
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