bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–10–02
eight papers selected by
Piotr Okupski,

  1. Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4.
  2. Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer.
  3. Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer.
  4. Abemaciclib plus fulvestrant in East Asian women with HR+, HER2- advanced breast cancer: Overall Survival from MONARCH 2.
  5. Palbociclib Rechallenge for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial.
  6. A Likely Case of Abemaciclib-Induced Hyperpigmentation in a Patient With Metastatic Breast Cancer.
  7. A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer.
  8. Cost-effectiveness of Ribociclib in HER2- negative breast cancer: A synthesis of current evidence.
  1. Eur J Cancer. 2022 Sep 22. pii: S0959-8049(22)00489-0. [Epub ahead of print]175 236-245
    Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4.
    Binghe Xu, Xichun Hu, Wei Li, Tao Sun, Kunwei Shen, Shusen Wang, Ying Cheng, Qingyuan Zhang, Shude Cui, Zhongsheng Tong, Cuizhi Geng, Erwei Song, Chiun-Sheng Huang, Virote Sriuranpong, Roger K C Ngan, Yee H Chia, Xinwei Wang, Huadong Zhao.
       BACKGROUND: The cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2- ABC.
    METHODS: Postmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety.
    RESULTS: Median (95% CI) PFS was 21.5 (16.6-24.9) months with palbociclib plus letrozole and 13.9 (13.7-16.6) months with placebo plus letrozole (hazard ratio, 0.68 [95% CI, 0.53-0.87]; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported.
    CONCLUSIONS: Findings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2- ABC. No new safety concerns of palbociclib plus letrozole were identified.
    TRIAL REGISTRATION: Clinicaltrials. gov, NCT02297438.
    Keywords:  Advanced breast cancer; Asian; Letrozole; Oestrogen receptor–positive; Palbociclib
    DOI:  https://doi.org/10.1016/j.ejca.2022.08.012
  2. NPJ Precis Oncol. 2022 Sep 24. 6(1): 68
    Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer.
    Abeer J Al-Qasem, Carla L Alves, Sidse Ehmsen, Martina Tuttolomondo, Mikkel G Terp, Lene E Johansen, Henriette Vever, Luna V A Hoeg, Daniel Elias, Martin Bak, Henrik J Ditzel.
      Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.
    DOI:  https://doi.org/10.1038/s41698-022-00311-6
  3. Cancer Drug Resist. 2022 ;5(3): 727-748
    Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer.
    Sasha C Main, David W Cescon, Scott V Bratman.
      Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some patients do not respond to this treatment, and patients inevitably develop resistance, such that novel biomarkers are needed to predict primary resistance, monitor treatment response for acquired resistance, and personalize treatment strategies. Circumventing the spatial and temporal limitations of tissue biopsy, newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test. Studies on circulating tumor DNA (ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers, but emerging epigenetic ctDNA methodologies hold promise for further discovery. The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
    Keywords:  Breast cancer; CDK4/6 inhibitors; cell-free DNA; circulating biomarkers; circulating tumor DNA; liquid biopsy; predictive biomarkers; resistance mechanisms
    DOI:  https://doi.org/10.20517/cdr.2022.37
  4. Cancer Sci. 2022 Sep 28.
    Abemaciclib plus fulvestrant in East Asian women with HR+, HER2- advanced breast cancer: Overall Survival from MONARCH 2.
    Masakazu Toi, Chiun-Sheng Huang, Young-Hyuck Im, Joohyuk Sohn, Wei Zhang, Sachi Sakaguchi, Nadine Haddad, Gertjan van Hal, George W Sledge.
      MONARCH 2 is a global, randomized, double-blind, phase 3 study of abemaciclib/placebo + fulvestrant in patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat population in the MONARCH 2 trial. Consistent with the primary analysis, this subpopulation analysis of East Asian patients indicated PFS benefit in the abemaciclib arm. The median overall survival was not reached in the abemaciclib arm and was 48.9 months in the placebo arm (HR 0.80; 95% CI 0.52 - 1.24; p=0.377). Also, other efficacy endpoints including time to chemotherapy, chemotherapy free survival, and time to second disease progression indicated benefit in the abemaciclib arm. This analysis found no new safety concerns with longer follow-up. These findings support the positive benefit-risk balance of the MONARCH 2 regimen in East Asian patients with hormone receptor positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
    Keywords:  East Asia; abemaciclib; breast cancer; cyclin-dependent kinase inhibitor; metastatic
    DOI:  https://doi.org/10.1111/cas.15600
  5. Clin Cancer Res. 2022 Sep 27. pii: CCR-22-1281. [Epub ahead of print]
    Palbociclib Rechallenge for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial.
    Joan Albanell, José Manuel Peréz-García, Miguel Gil-Gil, Giuseppe Curigliano, Manuel Ruíz Borrego, Laura Comerma, Joan Gibert, Meritxell Bellet, Begoña Bermejo, Lourdes Calvo, Juan de la Haba, Enrique Espinosa, Alessandro Marco Marco Minisini, Vanesa Quiroga, Ana Santaballa Bertran, Leonardo Mina, Beatriz Bellosillo, Federico Rojo, Silvia Menéndez, Miguel Sampayo-Cordero, Crina Popa, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac.
       PURPOSE: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).
    PATIENTS AND METHODS: The multicenter, open-label, phase II BioPER trial included women who had experienced progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125mg, 100mg, or 75mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Co-primary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis.
    RESULTS: Among 33 patients enrolled, CBR was 34.4% (95%CI, 18.6-53.2; P<0.001) and 13.0% of tumors (95%CI, 5.2-27.5) showed loss of Rb protein expression, meeting both co-primary endpoints. Median progression-free survival was 2.6 months (95%CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (hazard ratio, 22.0; 95%CI, 1.71-282.9; P=0.018).
    CONCLUSIONS: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1281
  6. Cureus. 2022 Sep;14(9): e28948
    A Likely Case of Abemaciclib-Induced Hyperpigmentation in a Patient With Metastatic Breast Cancer.
    Michela Salusti-Simpson, Hannah Porter, Keith Morley.
      We report a case of a 64-year-old female with a past medical history of invasive right breast adenocarcinoma presented with diffuse hyperpigmentation of her skin after admission to the hospital for an infected breast implant. She had no recollection of a similar cutaneous reaction in her past. The patient had been on a chronic regimen of anastrozole and abemaciclib for her metastatic breast cancer. A punch biopsy revealed results were highly suspicious for a drug-induced hyperpigmentation reaction. After a thorough review of the patient's current and past medication lists, it was determined that her abemaciclib was the most likely culprit of her hyperpigmentation. This case is significant because of the rarity of this possible specific cutaneous reaction to abemaciclib. The literature that exists on cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6) is minimal. And so, the importance of shedding light on its possible cutaneous side effects is not only helpful for clinician diagnosis but also essential for patients to make informed decisions. To our knowledge, there is no other published literature on likely abemaciclib-induced hyperpigmentation.
    Keywords:  abemaciclib; adverse cutaneous drug reaction; breast cancer research; cutaneous adverse drug reaction; cutaneous hyperpigmentation; drug-reaction; to illustrate this rarely described cutaneous adverse effect of the drug
    DOI:  https://doi.org/10.7759/cureus.28948
  7. J Clin Oncol. 2022 Sep 29. JCO2200628
    A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor-Positive Recurrent Endometrial Cancer.
    Panagiotis A Konstantinopoulos, Elizabeth K Lee, Niya Xiong, Carolyn Krasner, Susana Campos, David L Kolin, Joyce F Liu, Neil Horowitz, Alexi A Wright, Sara Bouberhan, Richard T Penson, Oladapo Yeku, Brittany Bowes, Hope Needham, Martin Hayes, Hannah Sawyer, Madeline Polak, Meghan Shea, Su-Chun Cheng, Cesar Castro, Ursula A Matulonis.
       PURPOSE: Estrogen receptor (ER)-positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting.
    METHODS: We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months.
    RESULTS: At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response (CTNNB1, KRAS, and CDKN2A mutations) or absence of response (TP53 mutations), which require independent validation.
    CONCLUSION: Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.
    DOI:  https://doi.org/10.1200/JCO.22.00628
  8. Saudi Pharm J. 2022 Aug;30(8): 1113-1119
    Cost-effectiveness of Ribociclib in HER2- negative breast cancer: A synthesis of current evidence.
    Wedad H Alotaibi, Majd M Alhamdan, Bander Balkhi.
       Background: The main aim of this study was to investigate the cost-effectiveness of Ribociclib in the treatment of patients with breast cancer by assessing the published evidence.
    Method: A systematic review of the published literature was conducted to identify the economic evaluations/cost-effectiveness study of Ribociclib. In this study, several databases were inspected, including PubMed, NHS Economic Evaluation, Cochran, and Scopus. Studies were eligible if they assessed the cost-effectiveness of Ribociclib and reported incremental cost-effectiveness ratio (ICER). The study was performed and conducted following the PRISMA reporting guidelines.
    Results: Of 70 studies identified, 8 articles meet our inclusion criteria. The cost-effectiveness threshold varied from $24,144.18 in Spain to $198,000/QALY in the USA. Moreover, the result demonstrated that the mean ICER varied across different countries $1,863.47/QALY in Spain and $813,132/QALY in the USA.
    Conclusion: Among all CDK4/6 inhibitors medications, current evidence indicated that the use of Ribociclib for HER2- negative breast cancer management was beneficial and considered to be cost-effective. Future research is needed to investigate the role of Ribociclib in long-term treatment.
    Keywords:  Breast cancer; CDK4/6 inhibitors; Cost-effectiveness; Economics evaluation; Ribociclib; Systematic review
    DOI:  https://doi.org/10.1016/j.jsps.2022.06.002
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