Although many patients with hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer can be successfully treated with endocrine therapy, a proportion are at risk of disease recurrence and death. Novel, effective treatments are needed to improve outcomes in this patient population, particularly for those at high risk of recurrence. Inhibitors of cyclin-dependent kinases (CDK) 4 and 6 have become standard of care for the adjuvant treatment of high-risk hormone receptor–positive/HER2-negative breast cancer.

High-Risk Hormone Receptor–Positive/HER2-Negative Early Breast Cancer

More than 90% of patients with breast cancer are diagnosed with early-stage disease, approximately 70% of whom have hormone receptor–positive/HER2-negative tumors.¹ Standard therapy for hormone receptor–positive/HER2-negative early breast cancer consists of adjuvant endocrine therapy (ie, aromatase inhibitors and/or antiestrogens) with or without ovarian suppression. Meta-analyses have indicated that up to 20% of such patients experience disease recurrence within the first 10 years of endocrine therapy, including some who present with distant metastases.² Risk of relapse is especially great for those with high-risk clinical or pathologic features. Clinicopathologic features predictive of relapse for hormone receptor–positive/HER2-negative early breast cancer include tumor size, grade, nodal status, increased Ki-67 expression level, residual cancer burden, and genomic signature.¹

CDK4/6 as a Therapeutic Target

CDK4 and CDK6 are involved in regulating cell cycle progression and controlling proliferation. CDK4/6 regulation is altered in many solid tumors, and CDK4/6 is often overexpressed in hormone receptor–positive breast cancers.³ CDK4/6 inhibitors target the ATP binding site of CDK4 and CDK6, blocking their phosphorylation of Rb and inducing cell cycle arrest and apoptosis.^4,5 These compounds differ in their structure and affinity for the ATP binding pocket of CDK4 and CDK6.⁶ CDK4/6 inhibitors act in concert with endocrine therapy to inhibit breast cancer growth, providing the clinical rationale for combination therapy.⁷

Three CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone receptor–positive/HER2-negative advanced or metastatic breast cancer (Table 1).^8-10 In phase III trials, treatment with these CDK4/6 inhibitors in combination with endocrine therapy demonstrated improved progression-free survival compared to endocrine therapy alone, leading to their approval in this setting.^11-18 In light of their benefit in advanced breast cancer, CDK4/6 inhibitors combined with endocrine therapy were subsequently evaluated as adjuvant therapy for hormone receptor–positive/HER2-negative early breast cancer.

Adjuvant Clinical Trials of CDK4/6 Inhibitors for Hormone Receptor–Positive/HER2-Negative Early Breast Cancer

Three CDK4/6 inhibitors have been evaluated in combination with endocrine therapy as adjuvant therapy for hormone receptor–positive/HER2-negative early breast cancer: palbociclib, ribociclib, and abemaciclib. To date, only abemaciclib has demonstrated a benefit in invasive disease–free survival compared with endocrine therapy alone and is the only CDK4/6 inhibitor currently approved as adjuvant therapy for patients with hormone receptor–positive/HER2–negative, node-positive early breast cancer who are at high risk of recurrence and have a Ki-67 level ≥ 20%. This section is intended to provide a summary of key clinical trials of CDK4/6 inhibitors for hormone receptor–positive/HER2-negative early breast cancer and is not intended to make any comparative conclusions about the products.

Palbociclib

Palbociclib therapy for hormone receptor–positive/HER2-negative early breast cancer has been studied in two phase III trials, although neither demonstrated a significant benefit from the addition of palbociclib to endocrine therapy. In the PALLAS study, patients received 2 years of palbociclib plus endocrine therapy or endocrine therapy alone as adjuvant therapy for hormone receptor–positive/HER2-negative high-risk breast cancer (with risk based on anatomic stage). No statistically significant benefit was seen with palbociclib for 4-year invasive disease–free survival or other survival endpoints, however (Table 2).^19,20 The most common adverse events with palbociclib plus endocrine therapy were leukopenia, fatigue, thrombocytopenia, anemia, upper respiratory tract infection, and alopecia, with a significantly higher rate of grade 3/4 neutropenia with palbociclib/endocrine therapy compared with endocrine therapy alone (61.3% vs 0.4%). Moreover, 42.2% of patients discontinued palbociclib prior to completion of the planned 2 years of therapy, mainly due to toxicity, based on protocol requirements.

Palbociclib in combination with endocrine therapy was also investigated in the PENELOPE-B trial in patients with hormone receptor–positive/HER2-negative breast cancer and residual invasive disease following resection and neoadjuvant chemotherapy who were at high risk of relapse (risk based on clinical pathologic staging–estrogen receptor grading). At a median follow-up of nearly 43 months, no significant increase was observed in estimated 3-year invasive disease–free survival or interim 3-year overall survival (Table 2).^21,22 The most common adverse events with palbociclib plus endocrine therapy were neutropenia, leukopenia, thrombocytopenia, anemia, hypocalcemia, fatigue, stomatitis, constipation, cough, and infection. The incidence of grade 3/4 neutropenia (70% vs 1%) and leukopenia (56% vs 1%) was significantly increased on the palbociclib arm.

Abemaciclib

The monarchE phase III trial compared treatment with abemaciclib plus endocrine therapy to endocrine therapy alone in patients with hormone receptor–positive/HER2-negative early breast cancer who were at high risk of recurrence (based on positive lymph node status, tumor size, histologic grade, and Ki-67 score ≥ 20%). At the 27-month and 42-month follow-up analyses, patients had a clinically meaningful improvement in invasive disease–free survival with abemaciclib-based therapy compared with the control treatment (Table 2).^23-25 According to Sara Tolaney, MD, MPH, Chief, Division of Breast Oncology at Dana-Farber Cancer Institute, the abemaciclib regimen reduced the relative risk of recurrence by about 30%. “Since these were mostly distant recurrences, we’re really preventing metastatic disease,” she noted. “With longer follow-up, we hope that it will also improve overall survival outcomes.”

The incidence of treatment-related adverse events was higher with abemaciclib (98.4% vs 88.8%), the most common of which were diarrhea, infections, neutropenia, fatigue, leukopenia, nausea, anemia, and headache. Grade 3/4 adverse events were also more frequent with abemaciclib (49.7% vs 16.3%), with a higher discontinuation rate during study treatment (18.5% vs 1.1%).²⁶ Results of the monarchE trial led to FDA approval of abemaciclib in combination with endocrine therapy as adjuvant therapy for high-risk patients with hormone receptor–positive/HER2-negative, node-positive early breast cancer and a Ki-67 score ≥ 20%.¹⁰

Both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network® (NCCN) guidelines indicate that abemaciclib plus endocrine therapy can be considered for treatment of patients with hormone receptor–positive/HER2-negative, node-positive early breast cancer with high risk of recurrence.^27,28 Since diarrhea (all grades) occurred in over 80% of patients on the abemaciclib arm in monarchE, patients should be educated on the risk of diarrhea and approaches for mitigation. Aditya Bardia, MD, MPH, Director, Breast Cancer Research, and attending physician at Mass General Cancer Center and Associate Professor, Harvard Medical School, noted that venous thromboembolism can also occur with abemaciclib therapy (2.3% incidence, all grades, in monarchE²⁴). “Caution should be exerted when combining abemaciclib with tamoxifen because both agents can increase risk of thromboembolism,” he pointed out. “If possible, an aromatase inhibitor with or without ovarian suppression should be used as the preferred endocrine partner with abemaciclib.”

Caution should be exerted when combining abemaciclib with tamoxifen because both agents can increase risk of thromboembolism. If possible, an aromatase inhibitor with or without ovarian suppression should be used as the preferred endocrine partner with abemaciclib. Aditya Bardia, MD, MPH

Ribociclib

While proven effective for hormone receptor–positive/HER2-negative advanced or metastatic breast cancer, ribociclib has not yet conclusively demonstrated efficacy in hormone receptor–positive/HER2-negative early breast cancer, although several trials are ongoing. The phase II LEADER trial (ClinicalTrials.gov identifier NCT03285412) evaluated 1 year of continuous or intermittent ribociclib in this setting. An interim safety analysis revealed that approximately one-third of patients discontinued ribociclib, largely within the first few months of treatment. The most common grade ≥ 3 adverse events resulting in study discontinuation were neutropenia, alanine aminotransferase increase, and aspartate aminotransferase increase.²⁹ Circulating tumor DNA (ctDNA) analysis revealed a strong association between detectable ctDNA and disease recurrence.³⁰ ADAPTcycle (NCT04055493) is a phase III trial comparing ribociclib plus endocrine therapy to chemotherapy in patients with intermediate-risk hormone receptor–positive/HER2-negative early breast cancer (with risk determined by Oncotype DX score and response to 3 weeks of preoperative endocrine therapy).³¹ Another phase III trial, NATALEE (NCT03701334), is evaluating adjuvant ribociclib and anastrozole in patients with hormone receptor–positive/HER2-negative early breast cancer.

It should be noted that approved dosing differs for these three CDK4/6 inhibitors (Table 1). The shorter half-life of abemaciclib (18.3 hours vs 29.0–32.0 hours for palbociclib and ribociclib) requires twice-daily dosing to maintain steady-state concentrations, whereas palbociclib and ribociclib are administered daily for 3 weeks followed by 1-week rest.^8-10 Dosing for palbociclib and ribociclib is based on trials in advanced or metastatic breast cancer since they are not currently approved for early breast cancer.

Ki-67 Expression

Expression of the nuclear protein Ki-67 is strongly correlated with breast cancer cell proliferation. In patients with hormone receptor–positive/HER2-negative early breast cancer, Ki-67 expression was prognostic for survival, with higher expression levels predicting lower 5-year disease-free survival rates.^32,33 Two large meta-analyses reported Ki-67 cutoffs of 19% and 25% as prognostic for poor survival, leading to consideration of a cutoff of ≥ 20% as prognostic for survival in patients with hormone receptor–positive breast cancer.^34,35 In monarchE, patients with high (≥ 20%) Ki-67 expression had a clinically meaningful increased risk of developing invasive disease within 2 years compared with those with low Ki-67, with 2-year invasive disease–free survival rates of 86.1% (95% confidence interval [CI] = 83.1%–88.7%) and 92.0% (95% CI = 89.7%–93.9%), respectively.³⁶ Because approval of abemaciclib as adjuvant therapy for hormone receptor–positive/HER2-negative early breast cancer was based in part on a Ki-67 score ≥ 20%, tumor Ki-67 expression level should be assessed when considering use of abemaciclib in this setting.¹⁰ Ki-67 expression should be measured using an FDA-approved test based on either immunohistochemistry (MIB-1 pharmDx) or molecular profiling (Oncotype DX 21-gene recurrence score).^10,37

Since benefit for abemaciclib was seen in patients with tumors having either low or high Ki-67, ASCO and NCCN guidelines (in contrast to the FDA indication) suggest that adjuvant abemaciclib may be considered for all patients with hormone receptor–positive/HER2-negative early breast cancer, based on monarchE intent-to-treat results (which included patients with low and high Ki-67 expression).^27,28 This is based in part, said Dr. Bardia, on the fact that laboratory assessment of Ki-67 can be quite variable because of differences in immunohistochemistry procedures and interpretation of scoring relative to the 20% cutoff level, which could result in some otherwise eligible patients being denied treatment.³⁸

Neoadjuvant Therapy With CDK4/6 Inhibitors

CDK4/6 inhibitors might also be effective as neoadjuvant therapy for hormone receptor–positive/HER2-negative early breast cancer. In a phase II trial, neoadjuvant therapy using a combination of abemaciclib and anastrozole resulted in cell cycle inhibition, enhanced immune activation, and clinical responses.³⁹ Improvements in invasive disease–free survival and distant relapse–free survival were also seen in the monarchE trial in patients who had received prior neoadjuvant chemotherapy.^23,24 Another study suggested that neoadjuvant palbociclib and letrozole may allow for a reduction in the use of chemotherapy in some patients, although no clear survival benefit was seen.⁴⁰ Neoadjuvant therapy with ribociclib plus letrozole might result in disease downstaging and/or a reduction in Ki-67 expression.⁴¹ Further study is needed to confirm the potential of CDK4/6 inhibitors in the breast cancer neoadjuvant setting.

Adherence

Since CDK4/6 inhibitors are administered orally, adherence is key to maximizing efficacy. In one study, the adherence rate to a CDK4/6 inhibitor plus fulvestrant for advanced breast cancer was 79% after 6 months of therapy but 32% by 24 months.⁴² Potential barriers to endocrine therapy adherence (which may also affect adherence to CDK4/6 inhibitors) include patient age, psychosocial factors such as depression, poor patient-provider communication, treatment-related adverse events, high comorbidity index, and financial or insurance issues (Figure 1).^43-45 Dr. Bardia noted that adherence in the real-world setting generally is lower than that seen in clinical trials, “and we do need data to evaluate real-world adherence related to endocrine therapy plus CDK4/6 inhibitors and potential strategies to improve adherence for patients with early breast cancer.”

Health-care providers should reinforce to patients the importance of maintaining adherence over the duration of CDK4/6 inhibitor therapy and the need for prompt reporting of adverse events. In the monarchE trial, most discontinuations occurred early in the course of treatment, highlighting the importance of close monitoring and dose adjustments as needed. “Dose modification with abemaciclib works quite well,” said Dr. Tolaney. “While most discontinuations happen within the first 3 months, subsequent discontinuation rates and rates of diarrhea are actually quite low, so that first month of treatment is really critical for monitoring patients,” she emphasized. Discontinuations due to treatment-related adverse events should also be distinguished from those based on protocol requirements specified in the clinical trial.

While most discontinuations happen within the first 3 months [of abemaciclib treatment], subsequent discontinuation rates and rates of diarrhea are actually quite low, so that first month of treatment is really critical for monitoring patients. Sara Tolaney, MD, MPH

Conclusion

Patients with high-risk hormone receptor–positive/HER2-negative early breast cancer represent a biologically and clinically distinct breast cancer subpopulation, requiring clinicians to tailor therapy to optimize outcomes. The improvement in invasive disease–free survival observed with abemaciclib plus endocrine therapy in the monarchE trial confirms its clinical benefit in this setting. Currently, abemaciclib is the only CDK4/6 inhibitor approved for adjuvant therapy of certain high-risk patients with early breast cancer and represents the first new adjuvant therapy approved for hormone receptor–positive/HER2-negative early breast cancer at high risk of recurrence and with a Ki-67 score ≥ 20% in more than 15 years.

The optimal timing and duration of CDK4/6 inhibitor therapy for hormone receptor–positive/HER2-negative early breast cancer remains to be determined. Abemaciclib, the only currently approved CDK4/6 inhibitor for hormone receptor–positive/HER2-negative early breast cancer, is approved for a treatment period of 2 years when given with endocrine therapy. Increasing the duration of therapy of adjuvant CDK4/6 inhibitors could be beneficial since half of all breast cancer recurrences occur more than 5 years after diagnosis; however, further study is required.⁴⁶ Additionally, because not all tumors respond to CDK4/6 inhibitors, predictive biomarkers other than hormone receptor status are needed that could inform patient selection and maximize the efficacy of such therapy.