bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2021–10–17
two papers selected by
Piotr Okupski,



  1. Breast. 2021 Oct 09. pii: S0960-9776(21)00471-9. [Epub ahead of print]60 163-167
       INTRODUCTION: Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition.
    METHODS: We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging.
    RESULTS: Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8-40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months.
    CONCLUSIONS: The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.
    Keywords:  CDK4/6 inhibitor; Metastatic breast cancer; Palliation; Radiotherapy; Safety
    DOI:  https://doi.org/10.1016/j.breast.2021.10.001
  2. Clin Cancer Res. 2021 Oct 13. pii: clincanres.1628.2021. [Epub ahead of print]
      Purpose: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER+/HER2- breast cancer; (ii) the pharmacodynamic effect of the agents on the biomarkers. Experimental design: 307 postmenopausal women with ER+/HER2- primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1 and CCND1. Results: Higher baseline ER and PgR were significantly associated with a greater chance of Complete Cell Cycle Arrest (CCCA: Ki67 <2.7%) at 14 weeks and higher baseline Ki67, c-PARP and CCNE1 with a lower chance. The interaction with treatment was significant only for c-PARP. CCND1 levels were decreased c.20% by letrozole at 2 and 14 weeks but showed a tendency to increase with palbociclib. CCNE1 levels fell 82% (median) in tumours showing CCCA but were unchanged in those with no CCCA. Only 2/9 tumours showed CCCA 3-9 days after stopping palbociclib. ESR1 mutations were found in 2/4 tumours for which surgery took place {greater than or equal to}6 months after starting treatment. Conclusion: High CCNE1 levels were confirmed as a biomarker of resistance to letrozole+palbociclib. Ki67 recovery within 3-9 days of discontinuing palbociclib indicates incomplete suppression of proliferation during the "off" week of its schedule.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1628