The Use of CDK4/6 Inhibitors in the Treatment of High-Risk, HR-Positive, HER2-Negative, Early Breast Cancer

Professor Nadia Harbeck; Professor Giuseppe Curigliano; Dr Carlos Barrios


September 01, 2023


Funded through sponsorship by Eli Lilly. Medscape approached Eli Lilly to fund the production of this editorial article. Please see bottom of page for full disclaimer.



Treatment for breast cancer is highly effective, particularly when the disease is identified early, with >90% of early breast cancers potentially curable with modern treatments.[1–4] Standard of care for early breast cancer generally includes locoregional therapy with surgery and radiotherapy, and systemic treatment with neoadjuvant and/or adjuvant therapy.[1–4] The main aim is to prevent early recurrence and metastasis. Different subtypes and stages of presentation have different risk of recurrence. Most patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer do not experience recurrence on standard care.[3,4] However, up to 30% of those with high-risk clinical and/or pathological features may develop distant disease recurrence in the first 10 years,[3,4] with the risk highest during the first 3 years after surgery.[5]

Patients at high risk of recurrence are typically offered adjuvant chemotherapy, followed by extended adjuvant endocrine therapy for 5–10 years.[5] While chemotherapy has long been targeted to patients with breast cancers at high risk of progression, all patients receiving endocrine therapy have been treated with tamoxifen, aromatase inhibitors (AIs), and ovarian function suppression (OFS) independent of their recurrence risk. With recent developments in identification of patients at increased risk and in treatments to decrease this risk (see Box 1),[4] the importance of individualising treatment based on risk of recurrence has become clear. An expert group was brought together in a clinical forum to discuss the treatment of patients with HR-positive, HER2-negative early breast cancer based on their risk of recurrence.

Standard of care treatment options for HR-positive/HER-negative early breast cancer

Giuseppe Curigliano (GC): When deciding on the optimal treatment for ER-positive, HER-negative early breast cancer, we should take into account the risk of relapse and menopausal status. Risk should be defined according to clinical risk – that is, tumour stage and nodal involvement – and genomic risk.

The standard of care in premenopausal women should include endocrine therapy with or without ovarian function suppression (OFS) for patients with low risk. OFS plus tamoxifen may be considered for very low risk patients, and OFS plus an aromatase inhibitor (AI) may be used in intermediate-risk patients.

For postmenopausal women, the preference should be AIs. Even if the patient is at very low risk, use of tamoxifen alone may still be considered. In elderly patients with low risk disease you can propose tamoxifen or endocrine therapy with AI alone and avoid potentially radiotherapy.[13]

For patients at high risk, chemotherapy should be considered in addition to endocrine therapy. For patients with high risk in the post-chemotherapy setting, endocrine therapy should be combined with abemaciclib for at least 2 years according to the definition of risk in the monarchE study, which was based on clinical features: stage and size of the primary tumour, number of involved nodes, and ki67 ≥20%, which is prognostic but not predictive of activity.[3]

Data from the New Adjuvant TriAl with Ribociclib [LEE011] (NATALEE) were presented at the 2023 American Society of Clinical Oncology (ASCO) annual meeting.[11] The NATALEE phase III clinical trial included men and premenopausal or postmenopausal women from 20 different countries with stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer who were at risk for disease recurrence. Participants were randomly assigned to receive either 400 mg of adjuvant ribociclib for 3 years with hormonal therapy for at least 5 years (n = 2,549) or hormonal therapy alone for at least 5 years (n = 2,552). Men and premenopausal women also received goserelin. Prior hormonal therapy use was allowed if it was initiated no more than 12 months before randomisation. The study found that adding ribociclib to hormonal therapy led to a significant improvement in invasive disease–free survival compared with hormonal therapy alone. Researchers evaluated invasive disease–free survival after 426 invasive disease–free survival events occurred, a number that was prespecified for the interim analysis. Of those events, 189 occurred in the ribociclib group (7.4% of patients) vs 237 in the hormonal therapy alone group (9.2% of patients). The 3-year invasive disease–free survival rates were 90.4% in the ribociclib group compared with 87.1% in the hormonal therapy alone group.

Nadia Harbeck (NH): Bisphosphonates should also be used as an adjuvant agent where appropriate.

Recent developments in the use of CDK4/6 inhibitors for patients with HR+/HER– early breast cancer at high risk of recurrence

Carlos Barrios (CB): In view of the revolutionary results with the introduction of CDK4/6 inhibitors plus endocrine therapy in the metastatic setting,[14,15] it was only natural to try to move these combinations into the early setting. Trials addressing early breast cancer patients used similar strategies for each of the three CKD4/6 inhibitors – palbociclib, abemaciclib, and ribociclib (see Box 1) – but differ in terms of the high-risk patient populations enrolled.

Table 1 summarises the designs of completed and ongoing phase 3 trials with CKD 4/6 inhibitors as adjuvant therapy in HR-positive, HER2-negative early breast cancer.

Table 1. Phase 3 trials with adjuvant CDK4/6 inhibitor. Adapted from Harbeck et al (2021)[16]


Palbociclib was investigated in two trials of patients with high-risk breast cancer.[8,17] The PALbociclib CoLlaborative Adjuvant Study (PALLAS) was the first trial to investigate the effect of adding a CDK/6 inhibitor to adjuvant endocrine therapy in patients with HR-positive, HER-negative early breast cancer.[8] The trial enrolled more than 5,000 patients with stage II/III disease within 12 months of initial diagnosis. Notably, the trial had a significant discontinuation rate of about 40% for palbociclib. However, even in patients who were able to complete treatment with palbociclib, the overall results were negative, with the addition of palbociclib not improving invasive disease-free survival compared with adjuvant endocrine therapy alone. Subsequent multiple analyses were not able to identify any specific patient subgroups who would benefit from use of adjuvant palbociclib.[21,22]

The PENELOPE B study was an elegantly designed trial that compared 1 year of palbociclib plus endocrine therapy with endocrine therapy alone in patients who had residual disease after neoadjuvant chemotherapy.[17] This trial failed to show a significant benefit with the introduction of palbociclib. Of note, initial results showed an initial separation of the curves favouring the palbociclib combination, but further follow up failed to show any differences between the two arms.[17]

To date, the monarchE trial with abemaciclib is a study with positive results that has the longest follow up.[3,23] Patients were treated with 2 years of endocrine therapy and abemaciclib, followed by completion of endocrine therapy (5-10 years). The trial showed statistically significant results in its first presentation,[3] and 4-year follow-up data shows widening of the difference between the arms, suggesting a carry-over effect with the combination. Importantly, the curves continue to separate, even 2 years after stopping CKD4/6 treatment, which gives reassurance of the effectiveness of abemaciclib in this patient population.[23]

GC: PALLAS was clearly a negative trial and was designed when there was no experience with palbociclib, starting only when the first data on palbociclib in the metastatic setting became available. Patient characteristics were completely different to those in monarchE,[3] which precludes cross-trial comparisons. 

CB: Discussion among colleagues suggests that one way to address comparisons among the different risk populations in the CDK4/6 inhibitor trials is to consider the behaviour of the control arms. With this approach, the PALLAS trial seemed to include patients with a lower risk, as the recurrence rate in the control arm at 3 years was only 10.6%.[8] This was significantly higher in the monarchE trial with abemaciclib (15.6%)[3] and PENELOPE B trial with palbociclib (22.3%)[17] This potentially lower risk population may explain at least in part, the negative results of PALLAS.

NH: Only 40% of patients in PALLAS were lower risk,[8] while about 60% were about the same risk as in monarchE,[3] so this does not explain why PALLAS did not show any difference.

CB: I agree but is important for clinicians to understand that patients in trials may not have had the same risk. This prevents cross-trial comparison and is essential to consider for future analyses. The PALLAS trial was analysed in all possible ways, and none of the analyses identified a subgroup of patients that could derive benefit from palbociclib.[21,22,24] The PENELOPE B trial had the highest risk of recurrence in the control arms of all CDK4/6 trials reported to date, but even in this high-risk population, palbociclib did not show any benefit.[17] The duration of the CKD4/6 inhibitor treatment was also different these trials and this could further explain differences in results.

NH: The discontinuation criteria for PALLAS and the PENELOPE B trial were very strict,[8,17] and many patients at no risk of bodily harm had to leave the study because of blood values issues. Trial designs should therefore be amended during the study if it becomes apparent that discontinuation rates are unnecessarily high.

GC: Initial data from the NATALEE trial are encouraging.[10,11] Some features of NATALEE are noteworthy: enrolled patients were at stage II, N1, or N0 plus pT2/pT3 and G2 and G3, the dose of ribociclib was 400 mg (different from the 600mg dose used in the metastatic setting), the treatment duration of 3 years, and the genomic testing that was part of the inclusion criteria only for this trial.[10,11] If the results of NATALEE remain positive and ribociclib is licensed as adjuvant therapy for early breast cancer in the future, this will provide an alternative CKD4/6 inhibitor for use in this population and potentially in different patient populations. The NATALEE results may also help address the issue of treatment duration. Overall, the addition of ribociclib reduced the risk of disease recurrence by 25%. The invasive disease–free survival benefit seen in the ribociclib group was generally consistent across clinically relevant patient subgroups. Ribociclib also showed favourable outcomes in distant disease–free survival.

CB: We are currently uncertain whether the different trial results for the three CDK4/6 inhibitors mean that these agents have different profiles and effectiveness because they are different drugs or outcomes vary only due to differences in trial designs.

NH: Differences in trial designs may have influenced the results but these factors but do not completely explain why palbociclib did not reach the primary event outcome. Continuous and discontinuous use of these agents also may have played a role. In early breast cancer, it is mostly endocrine resistant disease that fails endocrine-based therapy in the first two years.[24] Abemaciclib has broader kinase inhibition properties than palbociclib or ribociclib,[25] which may also contribute to differences in results. We cannot currently pinpoint a single reason why different trials have different results, but ongoing translational research may help us understand these differences.

Disease management strategies with CDK4/6 inhibitors

Abemaciclib as neoadjuvant endocrine therapy

NH: If a clinician decides to use neoadjuvant chemotherapy, it is important to determine whether the patient will also meet the monarchE inclusion criteria for abemaciclib irrespective of the result of neoadjuvant chemotherapy.[3,23] Use of neoadjuvant abemaciclib requires verification of nodal involvement by biopsy (which is also used to guide targeted axillary dissections after neoadjuvant chemotherapy). Patients with tumour grade 3 or >5 cm on imaging also qualify for abemaciclib independent of the results of neoadjuvant chemotherapy. Ki67 and 1–3 lymph nodes are inclusion criteria only for countries with an indication for monarchE cohort 2, and it is important to bear in mind that some countries in Europe and Asia only have an indication for monarchE cohort 1.

GC: Genomic testing was a planned subgroup analysis in monarchE,[3,23] whereas genomic testing was one of the inclusion criteria for NATALEE.[18] In the future, we may consider patients at high risk according to genomics for abemaciclib in the adjuvant setting.

Management of axilla is another important consideration. Previously, efforts were made to deescalate locoregional treatment in these patients, but with the availability of trials that include patients with 1–3 or >4 nodes,[11] the question arises whether a patient with 1 of 1 positive node on sentinel biopsy should receive radiotherapy or lymphadenectomy if they may eventually be eligible for abemaciclib.

NH: With 1–3 nodes being an inclusion criteria for monarchE,[3,23] we sometimes have to perform additional axillary surgery, which we would normally try to avoid, in order to fulfil the criteria for abemaciclib. If NATALEE results remain positive and ribociclib is licensed, we will not have to count lymph nodes and the spectrum of patients will be broader. Clinicians will have more flexibility in terms of choice of CDK4/6 inhibitor following neoadjuvant or adjuvant chemotherapy and endocrine therapy if patients fulfil the inclusion criteria of more than one CDK4/6 inhibitor study and will also have the option to switch agent in case of toxicity.

Abemaciclib versus olaparib

NH: In patients with BRCA mutations, if both abemaciclib and olaparib are indicated, olaparib is preferred because of the overall survival benefit, although adding abemaciclib afterwards would still be within the time frame of the monarchE trial where some patients started about a year after primary diagnosis due to a late start of radiotherapy.

CB: Data are not yet available on sequencing of abemaciclib and olaparib in patients with germline BRCA1/2 mutations. Importantly, in patients with high risk that could be candidates for both adjuvant strategies it is not recommended to administer both agents concomitantly.

NH: Use of abemaciclib and olaparib in combination is contraindicated due to overlapping haematological toxicities.

Ovarian function suppression

CB: One important caveat to consider is that some the trials did not include OFS for all premenopausal patients.[3] With the available data, it seems sensible to consider optimising endocrine therapy with ovarian suppression, particularly in high-risk.[26]

Adverse events

CB: Although adverse events should be considered, most patients, particularly those in PENELOPE B and monarchE, seemed to be able to complete treatment without significant compromise of quality of life.[3,17,23]

GC: Patients should be educated about the risk of diarrhoea with abemaciclib. [6] Once diarrhoea appears, the patient should be started on loperamide to avoid Grade 1 diarrhoea progressing to Grade 2 or 3.[6] At the first sign of loose stools, patient should start loperamide, increase fluids, and notify medical team. After 24 hours, follow up with your patient. If the diarrhoea has not resolved within 24 hours to ≤Grade 1 with antidiarrheal medication, suspend abemaciclib until diarrhoea resolves. Box 2 shows management recommendations for diarrhoea induced by abemaciclib. More studies are needed to better understand which patients are at risk of diarrhoea and if dietary intervention may prevent its development.

CB: Recent data indicate that diarrhoea has no significant impact on quality of life in the adjuvant setting, with similar outcomes at study completion in terms of quality of life in both study arms.[27]

Box 2. Management recommendations for diarrhoea.[6]
  • Treatment with antidiarrhoeal agents, such as loperamide, should be started at the first sign of loose stools.

  • Grade 1A

    • No dose adjustment required.

  • Grade 2A

    • If toxicity does not resolve within 24 hours to Grade 1 or less, suspend dose until resolution.

    • Dose reduction is not required.

  • Grade 2A that persists or recurs after resuming the same dose despite maximal measures

    • Dose reduction is not required.

  • Grade 3 or 4A

    • Requires hospitalisation

    • Suspend dose until toxicity resolves to Grade 1 or less

    • Resume at next lower dose

(A)National Cancer Institute Common Terminology Criteria for Adverse Events.

GC: Haematological toxicity is another adverse event of note for abemaciclib. Neutropenia should be primarily managed with dose adjustment.[6] Recommendations include abemaciclib suspension for grade ≥3 neutropenia until resolution to grade ≤2.  Abemaciclib could be resumed with a dose reduction required for recurrent grade 3 or grade 4 neutropenia. Box 3 shows management recommendations for haematological toxicity induced by abemaciclib.

Box 3. Management recommendations for haematological malignancy.[6]
  • Grade 1 or 2A,B

    • No dose adjustment required.

  • Grade 3A,B

    • Suspend dose until toxicity resolves to Grade 1 or less

    • Dose reduction is not required.

  • Grade 3, recurrent or Grade 4A,B

    • Suspend dose until toxicity resolves to Grade 1 or less

    • Resume at next lower dose

  • Patient requires administration of blood cell growth factors

    • Suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factors was administered and until toxicity resolves to Grade 2 or less.

    • Resume at next lower dose unless the dose was already reduced for the toxicity that led to the use of the growth factor.

(A)National Cancer Institute Common Terminology Criteria for Adverse Events.
(B)Absolute neutrophil count: Grade 1 < LLN–1,500/mm3, Grade 2: 1,000–<1,500 mm3, Grade 3: 500–<1,000/mm3, Grade 4 <500/mm3.

NH: For ribociclib we will get the information on toxicity in early breast cancer from the ADAPTcycle study, in which ribociclib was used at the registered doe of 600 mg/d as it was compared to chemotherapy and from NATALEE where it was used at a reduced dose of 400 mg/d as it was added to standard of care.[19]

Acknowledgement: Jemma Lough, independent medical writer, helped draft this article.

Funded through sponsorship by Eli Lilly. Medscape approached Eli Lilly to fund the production of this editorial article. Eli Lilly has had no influence over the selection of the authors or the content of the article. The sponsorship fee included an honorarium for the authors, who were contracted and paid by Medscape Editorial. The views and opinions of the authors are not necessarily those of Eli Lilly, or of Medscape, its publisher, advisers, or advertisers. No part of this publication may be reproduced in any form without the permission of the publisher.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.