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Risk Assessment and Ki-67 Testing in HR-Positive/HER2-Negative EBC for Adjuvant Abemaciclib
  • CME
  • CE

Yara Abdou, MD
Released: May 12, 2022

Risk Assessment and Ki-67 Testing in HR+/HER2- EBC for Adjuvant Abemaciclib

Guideline-Recommended Biomarker Testing for Breast Cancer

The diagnostic workup for newly diagnosed or recurrent EBC should include HER2 status by immunohistochemistry (IHC) with in situ hybridization if indicated and hormone receptor status, including estrogen receptors (ER) and progesterone receptors (PR).1-3

Several gene expression assays are available to help predict the risk of recurrence and response to systemic therapy. More recently, germline mutation testing is being incorporated into EBC management to specifically identify BRCA mutations and guide adjuvant therapy decisions for HER2- breast cancer.2 In addition, Ki-67 expression levels can be helpful when considering specific adjuvant targeted therapies such as the CDK4/6 inhibitor abemaciclib.

Background: Ki-67 in Breast Cancer

Uncontrolled cell proliferation is a hallmark of cancer and an established predictor of disease prognosis.4 Cell proliferation can be measured by determining the levels of Ki-67 expression. Ki-67 expression has prognostic value in EBC.5,6 HR+/HER2- patients with higher proportions of Ki-67 expressing tumor cells have a lower 5-year disease-free survival (DFS) rate than those with tumors that express lower Ki-67 levels.5

The International Ki-67 in Breast Cancer Working Group recognizes Ki-67 as a clinically valid prognostic marker for EBC and as an important exploratory marker for predicting and monitoring outcomes in clinical trials.6 Currently, Ki-67 as a biomarker is being investigated in several ongoing EBC trials (NCT02918084, NCT05180006, NCT04305236).

Ki-67 Testing

Ki-67 expression in tumor cells is assessed using IHC. Similar to ER testing and HER2 testing by IHC, variability exists in testing methodology and data interpretation, and efforts to standardize the measurement of Ki-67 levels are ongoing.6,7 Analytical validity of IHC for Ki-67 can be achieved in most labs when careful attention is given to preanalytical issues, staining protocols, and the use of a standardized and validated visual scoring protocol.

Development of Standardized Ki-67 Assay for the Phase III monarchE Trial of Adjuvant Abemaciclib

The phase III monarchE trial used a central, standardized testing protocol for Ki-67 levels with the MIB-1 monoclonal antibody on formalin-fixed paraffin-embedded tissue.8,9 The Ki-67 IHC MIB-1 pharmDX assay has been approved by the FDA as a companion diagnostic for the evaluation of Ki-67 expression in patients with high-risk EBC who may be eligible for treatment with abemaciclib combined with standard endocrine therapy (ET).10

Rationale for Ki-67 ≥20% Cutoff in monarchE

The analytical and prognostic value of Ki-67 cutoff levels differs according to application and intended use.6 In the monarchE trial, a Ki-67 cutoff value of 20% was used to describe patients with high Ki-67 expressing tumors.8 Currently, there is no clear consensus on a Ki-67 score that would differentiate patients with a higher or lower risk of disease recurrence.6 However, a cutoff of approximately 20% is generally considered appropriate to identify a high-risk population.

West German Study Group Phase III PlanB Trial: Concordance of Prognostic Markers With 21-Gene Assay

The West German Study Group phase III PlanB trial reported prospective outcome data for the concordance of prognostic markers with the 21-gene recurrence score (RS) assay, which assesses genomic risk in HR+/HER2- breast cancer.11 The study showed that RS had a weak to moderate positive correlation with Ki-67. An analysis of RS distribution by Ki-67 and PR levels found that very few patients (<5%) with Ki-67 levels <20% and PR >20% had a high RS. All patients with a Ki-67 ≥40% and PR ≤20% had a RS >25.

Ki-67 score as a continuous variable was a prognostic factor for DFS in a univariate analysis but not in a multivariate analysis.

Is There a Role for CDK4/6 Inhibition in Early-Stage HR+ Disease?

Currently, there are 3 approved CDK4/6 inhibitors for use in the setting of metastatic breast cancer: palbociclib, ribociclib, and abemaciclib.12 Several trials have examined whether these drugs improve the efficacy of ET in early-stage HR+ breast cancer. They include PALLAS (NCT02513394), PENELOPE-B (NCT01864746), monarchE (NCT03155997), and NATALEE (NCT03701334).

Reported CDK4/6 Inhibitor Adjuvant Trials

Mixed results have emerged from clinical trials that tested CDK4/6 inhibitors with ET for adjuvant treatment of high-risk HR+/HER2- EBC. PALLAS and PENELOPE-B examined adjuvant palbociclib plus ET in high-risk EBC; however, neither trial met its primary endpoint.13,14 The monarchE trial looked at abemaciclib plus ET and reported significant improvement in invasive DFS (iDFS) in this patient population.8,15

NATALEE: Adjuvant Ribociclib Plus ET in HR+/HER2- EBC

The ongoing phase III NATALEE trial is a randomized, open-label trial of ET with or without ribociclib in HR+/HER2- stage II or III EBC. The trial has completed accrual (N = 5101). The primary endpoint is iDFS, and secondary endpoints include recurrence-free survival, distant DFS, overall survival, safety, and tolerability.16

monarchE: Adjuvant Abemaciclib plus ET in High-Risk, Node-Positive, HR+/HER2- EBC

The open-label, phase III monarchE trial randomly assigned node-positive, HR+/HER2-, high-risk EBC patients to receive adjuvant therapy with ET alone (n = 2829) or with ET plus abemaciclib (n = 2808). Abemaciclib was administered for 2 years. Patients in cohort 1 had ≥4 positive axillary lymph nodes (ALN), or 1-3 positive ALNs plus a tumor with histologic grade 3 and/or a tumor ≥5 cm. Patients in cohort 2 had 1-3 positive ALNs and a centrally established Ki-67 score ≥20% with no tumor ≥5 cm or grade 3.8 The primary endpoint was iDFS.

Definition of High Risk in monarchE Trial

There is no uniformly accepted definition of high risk in EBC. In the monarchE trial, high risk was defined as having ≥4 positive ALNs or 1-3 ALNs with one of the following additional characteristics: tumor size ≥5 cm, tumor of histologic grade 3, or a centrally assessed Ki-67 score of ≥20%.8

monarchE: Baseline Patient Characteristics

Baseline characteristics and demographics in monarchE were similar between the 2 study arms.8

monarchE: Continued iDFS Benefit With Additional Follow-up in Intention-to-Treat Population

At an interim analysis, the trial met its primary endpoint of improved iDFS.8 In the most recent analysis, abemaciclib plus ET reduced the risk of iDFS by 30.4% (hazard ratio: 0.696; 95% CI: 0.5888-0.823; nominal P = .0001). The absolute difference in the 3-year iDFS rate is 5.4% favoring abemaciclib (88.8% vs 83.4%), an improvement in iDFS benefit from the earlier analysis.15,17

monarchE: Continued Distant Relapse-Free Survival Benefit With Additional Follow-up in Intention-to-Treat Population

Longer follow-up also showed that treatment with abemaciclib plus ET reduced the risk of developing a distant relapse event by 31.3% (hazard ratio: 0.687; 95% CI: 0.571-0.826; nominal P = .0001). The absolute difference in distant relapse-free survival rate between the arms was 4.2% favoring abemaciclib (90.3% vs 86.1%).15,17

monarchE (Cohort 1): Ki-67 as Prognostic Marker of iDFS

An analysis of iDFS by Ki-67 expression level in cohort 1 found that high Ki-67 expression was prognostic for poorer outcomes. The benefit with abemaciclib was consistent regardless of the Ki-67 index; thus, Ki-67 levels were not predictive for abemaciclib benefit.15,18

monarchE: Preliminary Overall Survival Results

Overall survival was a secondary endpoint in monarchE. At the time of the most recent analysis, the data are immature, but death rates were similar for patients who received abemaciclib plus ET or ET alone (3.4% vs 3.2%).19

monarchE: Safety

The combination of abemaciclib plus ET had a tolerable and manageable safety profile, which is particularly important in the adjuvant setting.8,15,17,20 Grade 3/4 adverse events (AEs) were experienced by approximately 50% of patients in the abemaciclib arm vs 16% in the ET arm.20 Treatment was discontinued by 18.5% of patients receiving abemaciclib due to AEs, and 6.5% discontinued both abemaciclib and ET vs 1.1% discontinuation in the ET alone arm.

monarchE: Treatment-Emergent AEs of Special Interest

Furthermore, serious AEs were reported by 15% vs 9% in the 2 arms, respectively.

Treatment-emergent AEs of special interest include elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), alopecia, venous thromboembolism (VTE), and interstitial lung disease—all of which were reported more often in the abemaciclib arm.20

Of the patients who received abemaciclib, 15 died due to AEs, and 2 deaths—diarrhea and pneumonitis— were deemed related to study treatment. Out of the patients who received ET only, 10 died due to AEs.

monarchE: VTE Characterization and Management

The number of patients with VTE was higher in the abemaciclib arm vs the ET alone arm (any grade, 2.4% vs 0.6%; grade ≥3, 1.3% vs 0.3%, respectively). Tamoxifen treatment was associated with higher incidence of VTE compared with aromatase inhibitors. Most patients continued abemaciclib after a VTE, and VTEs were well managed with anticoagulants.21

Adjuvant Abemaciclib for High-Risk HR+/HER2- EBC: Approved by FDA

On October 12, 2021, the FDA approved abemaciclib with ET for adjuvant treatment of adult patients with HR+/HER2-, node-positive EBC and who have a high risk of recurrence and a Ki-67 score ≥20% as determined by an FDA-approved test.22 Several guidelines recommend adjuvant abemaciclib for patients who meet high-risk criteria as defined in the monarchE trial.2,23

Dose Modifications for Abemaciclib

The recommended starting dose for abemaciclib (taken with an aromatase inhibitor, tamoxifen, or fulvestrant) is 150 mg twice daily. If dose modifications are required, the first dose reduction is to 100 mg BID, and the second dose reduction is to 50 mg BID. If further dose reductions are needed, the drug should be discontinued.24

Management of Abemaciclib-Induced Diarrhea

Diarrhea was the most frequently reported AE for patients in the abemaciclib arm of the monarchE trial.8,20 Supportive care (ie, antidiarrheal medication and increased fluid intake) should be started and maintained at the first sign of loose stools. Abemaciclib should be held for grade ≥2 diarrhea. Once diarrhea has resolved to grade <1, abemaciclib can be resumed at the same dose after grade 2 diarrhea or at a lower dose after grade ≥3 diarrhea.

Practical Management Strategies: Hepatobiliary Toxicity With Abemaciclib and Ribociclib

Elevated levels of AST and ALT were reported with abemaciclib in monarchE. Levels of AST, ALT, and serum bilirubin should be measured prior to initiating therapy and monitored every 2 weeks for the first 2 months of therapy, and then monthly for the subsequent 2 months. Persistent or higher-grade hepatotoxicity may require dose reduction or drug discontinuation based on the level of toxicity as described in the prescribing information.24

Engaging the Patient in the Discussion

Healthcare professionals should help their patients understand the nature of their disease and the roles that their receptor status and lymph node involvement play in their short-term and long-term outcomes. The potential benefit of initiating and adhering to adjuvant abemaciclib therapy with ET may become more compelling to well informed patients.

Healthcare professionals also should educate patients about AEs, including mild to moderate gastrointestinal symptoms to help manage expectations for patients. Potentially serious AEs also should be discussed so patients can recognize them early and contact their providers. Healthcare professionals should offer strategies to improve and maintain adherence to the regimen. Understanding the needs and preferences of patients can enhance trust, communication, and cooperation between the healthcare team and their patients.

Additional Information

Additional modules in this program will delve more deeply into clinical trial data that affect the management of patients with HER2- EBC. Please check the program page for additional activities.

Provided by Clinical Care Options, LLC

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Produced in collaboration with
Supported by educational grants from
Merck Sharp & Dohme Corp.

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