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CDK4/6 inhibitors in breast cancer

Publication digest

Read time: 50 mins
Last updated:5th Dec 2022
Published:12th Aug 2022

View our publication digests to learn key findings on the use of CDK4/6 inhibitors for treatment of HR+/HER2−, node-positive, high-risk early breast cancer.

  • Review data comparing clinical outcomes for various CDK4/6 inhibitors
  • Learn the long-term benefits of adjuvant abemaciclib combined with endocrine therapy
  • Consider the safety and tolerability profile of this combination therapy for breast cancer

A look at current and potential treatment approaches for hormone receptor-positive, HER2-negative early breast cancer

Harbeck et al. A look at current and potential treatment approaches for hormone receptor-positive, HER2-negative early breast cancer. Cancer. 2022;128: 2209-2223.

Despite the efficacy of current treatment approaches for hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) early breast cancer (EBC), approximately 20% of patients will still experience disease recurrence within the first 10 years1. Factors that increase this risk include large tumour size, tumour grade, nodal involvement, rate of proliferation (high Ki67 index) and vascular invasion2. Persistent risk for recurrence has driven investigation into the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant endocrine therapy (ET)3. CDK4/6 inhibitors abemaciclib, palbociclib and ribociclib have shown efficacy in treatment of advanced HR+/HER2-breast cancer, however clinical studies investigating the efficacy in early breast cancer have demonstrated varying results, with only abemaciclib receiving approval for treatment4-7.

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Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study

Harbeck et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571‒1581.

Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER-), node-positive, high-risk early breast cancer (EBC)1. However, follow-up from this study was limited to 24 months, necessitating further investigation. An additional 3-year follow up analysis was therefore performed, which found that adjuvant abemaciclib combined with ET improved IDFS and DRFS, and that the benefit observed in the initial monarchE study extended beyond the 2-year treatment period with a similar safety and tolerability profile2.

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CDK4/6 inhibitors in combination with endocrine therapy as potential therapies for treating high-risk early breast cancer patients

Does addition of abemaciclib to endocrine therapy (ET) as an adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer patients provide additional benefits versus treatment with ET alone?

Johnston S, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020:JCO2002514.

  • Up to 30% of patients with high-risk clinical and/or pathological features of HR+/HER2- early breast cancer (EBC) may experience recurrence8
  • Superior treatment options are required to prevent early recurrence and development of metastases for these patients8
  • Abemaciclib in combination with endocrine therapy is the first CDK4/6 inhibitor to demonstrate significant improvement in invasive disease-free survival (IDFS) patients8

Almost all patients (90%) with breast cancer are diagnosed at an early stage, of whom approximately 70% have HR+, HER2- cancers10,11. Adjuvant endocrine therapy (ET) which is the standard treatment for HR+/HER2- early breast cancer (EBC) has been linked to reducing the risk of recurrence and death12. However, recurrence for patients with high-risk features is high and it is therefore very important to optimise therapy to prevent early recurrences and metastases for these patients8,13.

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References

  1. Early Breast Cancer Trialists' Collaborative G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352.
  2. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66.
  3. Harbeck N, Burstein HJ, Hurvitz SA, Johnston S, Vidal GA. A look at current and potential treatment approaches for hormone receptor-positive, HER2-negative early breast cancer. Cancer. 2022;128 Suppl 11:2209-2223.
  4. Loibl S, Marme F, Martin M, Untch M, Bonnefoi H, Kim SB, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021;39(14):1518-1530.
  5. Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212-222.
  6. O'Shaughnessy J, Rastogi P, Harbeck N, Toi M, Hegg R, Sohn J, et al. VP8-2021: Adjuvant abemaciclib combined with endocrine therapy (ET): Updated results from monarchE. Annals of Oncology. 2021;32(12):1646-1649.
  7. O'Shaughnessy JA, Johnston S, Harbeck N, Toi M, Im Y-H, Reinisch M, et al. Abstract GS1-01: Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Cancer Research. 2021;81(4_Supplement):GS1-01-GS01-01.
  8. Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998.
  9. Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581.
  10. Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J, et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). Breast. 2018;39:131-138.
  11. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5).
  12. Lerebours F, Pulido M, Fourme E, Debled M, Becette V, Bonnefoi H, et al. Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials. Br J Cancer. 2020;122(6):759-765.
  13. Mamounas EP, Tang G, Paik S, Baehner FL, Liu Q, Jeong JH, et al. 21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology. Breast Cancer Res Treat. 2018;168(1):69-77.
  14. Shah M, Nunes MR, Stearns V. CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor-Positive Advanced Breast Cancer? Oncology (Williston Park). 2018;32(5):216-222.

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