bims-cyhorp Biomed News
on Cyclin-dependent kinases in Hormone Receptor positive Breast Cancer
Issue of 2021‒08‒29
ten papers selected by
Piotr Okupski

  1. Nat Commun. 2021 08 25. 12(1): 5112
      CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.
  2. Breast Cancer Res. 2021 Aug 23. 23(1): 87
      BACKGROUND: In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR] 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial.METHODS: The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n = 72; placebo plus fulvestrant, n = 42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS).
    RESULTS: At the primary objective cutoff (February 14, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR 0.415; 95% CI 0.246-0.698). At the pre-specified OS interim cutoff (20-June-2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR 0.477; 95% CI 0.302-0.755). A numerical OS benefit was observed with abemaciclib plus fulvestrant compared to fulvestrant alone (HR 0.689; 95% CI 0.379-1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR 0.599), TTC (HR 0.674), and CFS (HR 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously.
    CONCLUSIONS: Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant.
    CLINICAL TRIAL REGISTRATION: NCT02107703. Registered April 08, 2014- Retrospectively registered, .
    Keywords:  Abemaciclib; Advanced breast cancer; CDK4 and 6 inhibitor; Fulvestrant; Premenopausal women
  3. Mol Cancer Res. 2021 Aug 26. pii: molcanres.0081.2021. [Epub ahead of print]
      Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) represents an unmet clinical need and is frequently caused by compensatory CDK2 activity. Here we describe a novel strategy to prevent CDK4i resistance by using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. We find that NP-ALT blocks proliferation in HR+ breast cancer (BC) cells, as well as CDK4i-resistant cell types, including Triple Negative (TN) BC. The peptide ALT is not as stable in primary mammary epithelium, suggesting that NP-ALT has little effect in non-tumor tissues. In HR+ BC cells specifically, NP-ALT treatment induces ROS and RIPK1-dependent necroptosis. Estrogen signaling and ER alpha appear required. Significantly, NP-ALT induces necroptosis in MCF7 ESRY537S cells, which contain an ER gain of function mutation frequently detected in metastatic patients, which renders them resistant to endocrine therapy. Here we show that NP-ALT causes necroptosis and tumor regression in treatment naïve, palbociclib-resistant and endocrine-resistant BC cells and xenograft models, demonstrating that p27 is a viable therapeutic target to combat drug resistance. Implications: This study reveals that blocking p27 tyrosine phosphorylation inhibits CDK4 and CDK2 activity and induces ROS-dependent necroptosis, suggesting a novel therapeutic option for endocrine and CDK4 inhibitor-resistant HR+ tumors.
  4. Biochem Biophys Rep. 2021 Sep;27 101099
      One of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) is t(8;21). Although patients with t(8;21) AML have a more favorable prognosis than other cytogenetic subgroups, relapse is still common and novel therapeutic approaches are needed. A recent study showed that t(8;21) AML is characterized by CCND2 deregulation and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells. In this study, we examined the in vivo effects of co-inhibiting CDK4/6 and autophagy. We used a mouse model in which t(8;21)-positive Kasumi-1 cells were subcutaneously inoculated into NOD/Shi-scid IL2Rgnull mice. The mice were treated with the autophagy inhibitor chloroquine (CQ), a CDK4/6 inhibitor (either abemaciclib or palbociclib), or a CDK4/6 inhibitor plus CQ. After 20 days of treatment, tumor volume was measured, and immunostaining and transmission electron microscopy observations were performed. There was no change in tumor growth in CQ-treated mice. However, mice treated with a CDK4/6 inhibitor plus CQ had significantly less tumor growth than mice treated with a CDK4/6 inhibitor alone. CDK4/6 inhibitor treatment increased the formation of autophagosomes. The number of single-strand DNA-positive (apoptotic) cells was significantly higher in the tumors of mice treated with a CDK4/6 inhibitor plus CQ than in mice treated with either CQ or a CDK4/6 inhibitor. These results show that CDK4/6 inhibition induces autophagy, and that co-inhibition of CDK4/6 and autophagy induces apoptosis in t(8;21) AML cells in vivo. The results suggest that inhibiting CDK4/6 and autophagy could be a novel and promising therapeutic strategy in t(8;21) AML.
    Keywords:  Apoptosis; Autophagy; CDK4/6; Leukemia; t(8;21)
  5. Clin Cancer Res. 2021 Aug 25. pii: clincanres.1095.2021. [Epub ahead of print]
      PURPOSE: Data are sparse for oral selective estrogen receptor (ER) degraders (SERDs) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study.MATERIALS AND METHODS: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n=77) or with ribociclib (arm B; n=78) or alpelisib (arm C; n=43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLTs) in the first 28-day treatment cycle, adverse events (AEs), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1).
    RESULTS: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C (10/43 [23%]). DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose-proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose-response. Objective response rates (95% CI) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively.
    CONCLUSIONS: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.
  6. Clin Breast Cancer. 2021 Jul 27. pii: S1526-8209(21)00202-0. [Epub ahead of print]
      BACKGROUND: Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor with a primary toxicity of myelosuppression, especially neutropenia, due to cytostatic CDK6 inhibition on bone marrow. Preclinical studies suggest palbociclib may enhance radiation toxicity, but this was only evaluated in limited case series of palliative radiotherapy and not specific to radiation targeting bony metastases.PATIENTS AND METHODS: This was a single institution retrospective cohort study. We included female patients who initiated palbociclib for advanced breast cancer between 2015 and 2019. The primary exposure was receipt of palliative radiation to bony metastases within 1 year prior to starting palbociclib. The primary outcome was the incidence and severity of myelosuppression during cycle one. Secondary outcomes include treatment interruptions and cycle 2 dose reductions, with subgroup analysis of radiation timing, type, dose, and location.
    RESULTS: Of the 247 patients, 47 received radiation to bone metastases. Only absolute lymphocyte count (ALC) after cycle one of palbociclib was significantly lower in the group receiving radiation (median ALC 0.84 vs. 1.10 K/mm3, P < .001), with similar rates of neutropenia, anemia, and thrombocytopenia. Patients who received ≥10 fractions radiation were more likely to have cycle one interrupted than those receiving shorter radiation courses (42.9% vs. 11.1%, P = .03). No radiation characteristics were associated with other hematologic toxicities or dose reduction.
    CONCLUSION: Palliative bone radiation within 1 year prior to palbociclib initiation was associated with greater lymphopenia during the first cycle than patients unexposed to radiation, but not neutropenia, anemia, or thrombocytopenia that would modify treatment.
    Keywords:  CDK inhibitors; Endocrine therapy; Hormone receptor-positive; Human epidermal growth factor receptor 2-negative; Metastatic breast cancer
  7. Acta Radiol Open. 2021 Aug;10(8): 20584601211030660
      Background: Neoadjuvant endocrine therapy is an alternative to neoadjuvant chemotherapy in women with inoperable luminal-like breast cancers. Neoadjuvant cyclin-dependent kinase 4/6 inhibitor treatment combined with endocrine treatment (CDK4/6I + E) is interesting given the combination's utility in the treatment of metastatic breast cancer. Currently, the literature on the radiological response evaluation of patients treated with neoadjuvant CDK4/6I + E in a real-life setting is scarce.Purpose: To conduct a radiological response evaluation of patients treated with neoadjuvant CDK4/6I + E in a real-life setting.
    Material and methods: We retrospectively reviewed clinical, pathological, and radiological findings of six patients with luminal-like breast cancers treated with neoadjuvant CDK4/6I + E treatment. The radiological neoadjuvant CDK4/6I + E response was evaluated with the RECIST 1.1 criteria and the pathological residual disease was assessed using the Residual Cancer Burden (RBC) criteria.
    Results: None of the patients achieved a complete radiological magnetic resonance imaging (MRI)-determined response or a complete pathological response; three (50%) patients had a partial radiological response; in the three others, the disease remained stable radiologically. All of the tumors were rendered susceptible to surgical treatment. Two out of six (33.3%) patients had a moderate response (RBC-II); four (66.7%) had an extensive residual disease (RBC-III) in the final surgical sample.
    Conclusion: Although none of the patients achieved a pathologically complete response, neoadjuvant CDK4/6I + E treatment rendered all tumors operable. MRI appears to be reliable in the assessment of the neoadjuvant CDK4/6I + E treatment response in a real-life setting. Larger studies are warranted to confirm these results.
    Keywords:  cyclin-dependent kinase; magnetic resonance imaging; response
  8. Cureus. 2021 Jul;13(7): e16604
      Palbociclib (Ibrance™) has been marketed since 2015 for patients with metastatic hormone-receptor-positive breast cancer. We report here the case of a patient who presented with a posterior reversible encephalopathy syndrome (PRES) during treatment with this new targeted therapy. The 67-year-old woman presented prodromal headaches followed by occurrences of two episodes of generalized convulsive seizures. The brain MRI revealed a bilateral, globally symmetrical, sub-cortical parietooccipital fluid-attenuated inversion recovery (FLAIR) hypersignal of the white matter. The patient recovered after palbociclib discontinuation with no further neurological signs. A follow-up MRI performed one month upon palbociclib discontinuation showed a decrease in the FLAIR signal abnormalities. Altogether, the clinical presentation was consistent with PRES. This case report aims to encourage physicians whom patients are treated with cyclin-dependent kinase 4/6 inhibitors to cautiously monitor symptoms suggesting PRES in contexts known to promote its occurrence such as that of arterial hypertension, immunosuppression, and/or autoimmune disease. PRES should be considered in the event of seizure, headache, and/or visual disturbances.
    Keywords:  cdk inhibitor; ibrance; palbociclib; posterior reversible encephalopathy syndrome; pres
  9. Eur J Cancer. 2021 Aug 20. pii: S0959-8049(21)00440-8. [Epub ahead of print]156 70-82
      BACKGROUND: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes.PATIENTS AND METHODS: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively.
    RESULTS: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale.
    CONCLUSION: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated.
    EUDRACT STUDY NUMBER: 2013-003170-27.
    Keywords:  CDK4/6 inhibitor; Endocrine therapy; Health-related quality of life; Hormone receptor–positive metastatic breast cancer; Palbociclib
  10. Curr Treat Options Oncol. 2021 Aug 23. 22(10): 94
      OPINION STATEMENT: Oligometastatic breast cancer, typically defined as the presence of 1-5 metastases, represents an intermediate state between locally advanced and widely metastatic disease. Emerging research suggests that oligometastatic cancer has a unique molecular signature distinct from widely metastatic disease, and that it carries a superior prognosis. Owing to its more limited capacity for widespread progression, oligometastatic disease may benefit from aggressive ablative therapy to known metastases. Options for ablation include surgical excision, radiofrequency ablation, and hypofractionated image-guided radiotherapy (HIGRT). The phase II SABR-COMET trial, which enrolled patients with oligometastatic disease of multiple histologies and randomized them to HIGRT vs. standard of care, found a notable survival advantage in favor of HIGRT. Other data suggest that HIGRT may synergize with immunotherapy by releasing powerful cytokines that increase anti-tumor immune surveillance and by recruiting tumor infiltrating lymphocytes, helping to overcome resistance to therapy. There are many ongoing trials exploring the role of ablative therapy, most notably HIGRT, with or without immunotherapy, for the treatment of oligometastatic breast cancer.We believe that patients with oligometastatic breast cancer should be offered enrollment on prospective clinical trials when possible. Outside the context of a clinical trial, we recommend that select patients with oligometastatic breast cancer be offered treatment with a curative approach, including ablative therapy to all sites of disease if it can be safely accomplished. Currently, selection criteria to consider for ablative therapy include longer disease-free interval from diagnosis to metastasis (>2 years), fewer metastases, and fewer involved organs. Undoubtedly, new data will refine or even upend our understanding of the definition and optimal management of oligometastatic disease.
    Keywords:  Ablative therapies; Breast cancer; Oligometastasis; Radiosurgery; SABR; SBRT