CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
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Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Pharmacists: 1.00 contact hour (0.1 CEUs)
Released: March 22, 2024
Expiration: March 21, 2025
Defining High-Risk HR-Positive/HER2-Negative EBC
I am happy to be able to share my thoughts on how outcomes are improving for patients with high‑risk HR‑positive/HER2‑negative breast cancer.
I would like to start by defining what we consider to be high-risk EBC and then discussing how we can individualize adjuvant therapy for HR‑positive/HER2‑negative disease.
We often define high-risk EBC based on tumor size, with T3 or T4 being particularly high risk; positive nodal status, with ≥4 lymph nodes being positive; and grade 3 disease.1 A higher Ki‑67 score, which correlates with a higher cancer cell proliferation rate, and lower ER levels also can elevate the risk of disease recurrence.
High-risk features can substantially increase the risk for disease recurrence and can improve the prognostic accuracy of the standard 21‑gene recurrence score and a 70‑gene genomic signatures score.
Another indication of high‑risk disease and an accurate predictor for poor outcomes is the failure of preoperative ET to suppress Ki‑67 to <10% on what is termed the definitive surgical specimen.
High‑risk subtypes of HR‑positive/HER2‑negative EBC include luminal B, HER2 enriched, and basal‑like. The various subtypes can be ascertained with use of BluePrint or Prediction Analysis of Microarray 50 (or PAM50) tests.
What underlies all of these high‑risk features is ET resistance. In patients who recur within the first 5 years or who are at risk of recurring within the first 5 years, it is because of either a degree of or very high levels of ET resistance.
Risk Assessment Criteria to Guide Adjuvant Therapy Selection in HR-Positive/HER2-Negative EBC
How do we decide on adjuvant chemotherapy?
This slide summarizes the various features we think about as we make the decision to recommend chemotherapy vs ET for individual patients.1 In addition to node‑positive status (1-3 positive axillary lymph nodes) and tumor size, we also think about local control, the type of surgery previously received, any consideration for re-excision or radiation therapy.
We often use data from genomic signatures to determine chemotherapy eligibility and potential for recurrence (21‑gene recurrence score or 70-gene signature).1
Another aspect to consider is whether we would need to recommend to premenopausal patients ovarian suppression or ablation. In essence, for a patient with node‑negative disease and a 21‑gene recurrence score of ≥16, we often recommend the addition of a luteinizing hormone‒releasing hormone (LHRH) agonist to tamoxifen. For other patients with a higher number of positive nodes and/or node negative disease with a higher 21-gene panel recurrence score, I would recommend the LHRH agonist plus an AI.
For most node-positive premenopausal patients and those who are node negative and have an elevated 21‑gene recurrence score of 16‑25, I recommend adjuvant chemotherapy.
In general, if patients have a high enough risk to require chemotherapy, I typically also add an LHRH agonist to an oral ET and would usually recommend an AI to them.
Expert’s Risk Assessment Algorithm to Inform Systemic Adjuvant Therapy Selection in HR-positive/HER2-negative EBC
To help summarize current guidelines1 and expert recommendations for recommending therapy to patients with EBC, this algorithm addresses what to do with some high-risk scenarios.
When considering neoadjuvant or adjuvant chemotherapy, hormonal therapy, and other combinations, we look at some of the latest clinical data for guidance. If the patient’s disease remains high risk following (neo)adjuvant chemotherapy, we may consider abemaciclib together with ET based on data from the monarchE trial evaluating adjuvant abemaciclib plus ET in patients with high-risk, node-positive, HR-positive/HER2-negative EBC.2
We also want to know whether patients have a germline BRCA1/2 alteration, because if they do, they may qualify for ET plus PARP inhibitor therapy based on data from the phase III OlympiA trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 high-risk EBC.3
We have numerous patients with substantial comorbidities who are frail but also carry a high risk of recurrence. In those patients, I may recommend single‑agent AI therapy because they are not good candidates for chemotherapy or a CDK4/6 inhibitor because of safety concerns.1
Summary of CDK4/6 Inhibitor Trials in EBC
The slide summarizes 4 of the key adjuvant CDK4/6 inhibitor trials that have been done to date in EBC for which we have efficacy and safety data.2,4-6
In the first column of the table, we can see summary data for the phase III monarchE trial, with 4‑year invasive disease‒free survival (iDFS) of 85.8% vs 79.4% and distant recurrence‒free survival (DRFS) of 88.4% vs 82.5% favoring the abemaciclib plus ET arm vs ET alone.2
In the PALLAS trial, patients received 2 years of adjuvant palbociclib plus ET vs placebo plus ET, and this did not result in improved 4‑year iDFS (84.2% vs 84.5%) or DRFS (88.4% vs 82.5%).4 Similarly, in the PENELOPE‑B trial in patients who had residual disease after preoperative chemotherapy in the breast and/or lymph nodes, 1 year of treatment with palbociclib did not yield improved 4‑year iDFS (73.0% vs 72.4%) or DRFS (76.3% vs 71.2%).5
The last column is for the phase III NATALEE trial evaluating adjuvant ribociclib plus ET vs ET in pre/postmenopausal women and men with HR-positive/HER2-negative EBC.6 We do have 3‑year data from the San Antonio Breast Cancer Symposium (SABCS), so I will update you on that in a moment, but we do not yet have 4‑year data to compare it with the other trials shown here.
monarchE: Adjuvant Abemaciclib + ET in High-Risk, Node-Positive, HR-Positive/HER2-Negative EBC
Let’s take a closer look at the updated 5‑year mature follow-up data from the phase III monarchE trial of adjuvant abemaciclib plus ET in high-risk, node-positive, HR-positive/HER2-negative EBC.2,7 Cohort 1, which is the cohort of patients for whom abemaciclib received FDA approval and that is endorsed by National Comprehensive Cancer Network (NCCN) guidelines, enrolled patients with ≥4 positive axillary lymph nodes or 1-3 positive axillary lymph nodes, histologic grade 3, and/or tumor size ≥5 cm; all had HR-positive/HER2‑negative EBC. Cohort 2 included patients with HR-positive/HER2‑negative EBC with 1-3 positive axillary lymph nodes, Ki-67 ≥20% per central testing, not grade 3, tumor size <5 cm. At the time of this report, there were not enough events for IDFS analysis in cohort 2 because it was a smaller group of patients (n = 500).
Patients could have had preoperative chemotherapy, and their eligibility for monarchE was based on assessment of their tumor grade, tumor size, and clinical node positivity status before they started their preoperative chemotherapy; 95% of patients on monarchE received preoperative or adjuvant chemotherapy. Patients were randomized to receive ET per standard of care of physician’s choice for 5‑10 years with or without 2 years of abemaciclib 150 mg orally twice daily. The primary endpoint of the study was iDFS.
monarchE: 5-Year iDFS in ITT Population (Interim Analysis 3)
The figure shows the mature 5‑year data from the monarchE trial. The 5‑year iDFS rate in the abemaciclib plus ET arm was improved compared with ET alone at 83.6% vs 76.0% (hazard ratio: 0.680; nominal P <.001). It is always good to see here that if we go from 3, 4, and up to 5+ years, we see the absolute improvement in iDFS year by year. At the time of this presentation, there was no hint that after patients stopped 2 years of adjuvant abemaciclib, that these curves were going to do anything but continue to pull apart. I look forward to longer follow-up data at 7-10 years out to see the absolute benefit from abemaciclib.
monarchE: Sustained DRFS Benefit in ITT
When looking at the DRFS data, here we also see an improvement with abemaciclib plus ET vs ET alone at 5 years (86.0% vs 79.2%; hazard ratio: 0.675; P <.001). The absolute improvement in DRFS continued to increase from Year 4 through Year 5. After 5 years, 6.7% fewer women will have developed a distant metastatic event because of 2 years of adjuvant abemaciclib plus ET.
At the time of the presentation, the survival data remain immature. However, numerically, there are fewer deaths with abemaciclib plus ET vs ET alone (hazard ratio: 0.903; P = .284), but of course further follow-up is needed.
monarchE: Efficacy Outcomes by Ki-67 Status (Cohort 1)
The table shows monarchE efficacy in Ki-67‒high (≥20%) and Ki‑67‒low (<20%) disease. Looking at 5‑year iDFS and DRFS in Ki‑67‒high disease, rates with abemaciclib plus ET vs ET alone were 81.0% vs 72.0% and 83.4% vs 75.2%, respectively. Patients with Ki-67‒high disease have a higher number of events, which makes sense because of the higher risk for recurrence in the first 5-8 years in this population.
Looking at 5‑year iDFS and DRFS in Ki‑67‒low disease, rates with abemaciclib plus ET vs ET alone were 86.3% vs 80.2% and 88.6% vs 83.5%, respectively. Patients with Ki‑67‒low disease are at generally a greater risk of recurrence after the first 5 years of adjuvant ET.
We can see in this table that regardless of Ki‑67 status, patients benefited from abemaciclib plus ET. For this reason, the FDA has removed the requirement in the abemaciclib prescribing information for patients to have high Ki‑67 to be candidates for adjuvant abemaciclib.
monarchE: Safety Summary
The safety profile of abemaciclib is shown on the right. The most frequent grade ≥3 AEs experienced by patients receiving abemaciclib plus ET vs ET alone included neutropenia (19.7% vs 0.9%), leukopenia (11.4% vs 0.4%), and diarrhea (7.8% vs 0.2%). Of note, diarrhea requires close monitoring and prompt supportive care in patients receiving abemaciclib. Patients also can experience low‑grade nausea, decreased appetite, and weight loss―which may occur on the first few months after starting abemaciclib. HCPs may recommend that patients take loperamide as needed for frequent loose stool or after each loose stool. It has been my experience that diarrhea gets considerably better 6-8 weeks after starting abemaciclib.
Approvals and Recommendations: Adjuvant Abemaciclib + ET
The 5-year survival data from monarchE provide support for the FDA approval of abemaciclib in patients with node-positive, HR-positive/HER2-negative EBC at high risk of disease recurrence,8 which is similar to the recommendations from the American Society of Clinical Oncology and NCCN.1,9
Phase III of Adjuvant Ribociclib + ET vs ET in HR-Positive/HER2-Negative EBC (NATALEE)
Next, I would like to discuss updated data for the phase III NATALEE trial presented at SABCS 2023.10 NATALEE is an international, randomized, open-label trial evaluating adjuvant ribociclib plus ET vs ET alone in patients with HR-positive/HER2-negative EBC.
Patients eligible for this trial were pre/postmenopausal women and men with stage IIA (either N0 with grade 2 and Ki-67 ≥20%, Oncotype DX recurrence score ≥26, or high risk via genomic risk profiling; N0 with grade 3; or N1), stage IIB (N0 or N1), or stage III disease. Prior ET up to 12 months and prior (neo)adjuvant chemotherapy were allowed. In all, this trial had both high‑risk and intermediate‑risk patients. Patients were to receive an NSAI for 5 years or longer with or without 3 years of ribociclib 400 mg daily, 3 weeks on and 1 week off. The primary endpoint of the study was iDFS.
NATALEE: iDFS (Final Analysis)
The slide shows the protocol-specified final analysis after 500 iDFS events in support of data submission to regulatory authorities. Here we can see a statistically significant 3.1% improvement in iDFS (90.7% vs 87.6%; hazard ratio: 0.749; P = .0006) with ribociclib plus NSAI vs NSAI alone.
We also see a benefit starting from year 2, where the improvement in iDFS was 1.5% (93.5% with ribociclib plus NSAI vs 92.0% with NSAI alone). At the time of this report, 25.1% of patients on NATALEE had experienced a reduction in the risk of invasive disease recurrence with ribociclib plus NSAI vs NSAI alone.
NATALEE: Distant Disease‒Free Survival (Final Analayis)
Looking at distant disease‒free survival, this also was significantly positive, with a hazard ratio of 0.749 (P = .0010) and a 2.5% absolute benefit with regard to reducing the risk of a distant recurrence with 3 years of adjuvant ribociclib.
NATALEE: iDFS in Key Patient Subgroups
If we look at 3-year iDFS by anatomic stage, in stage II disease, the hazard ratio for reducing the risk of recurrence was 0.7 when comparing ribociclib plus NSAI with NSAI alone. Similarly, for stage III disease, the hazard ratio was 0.755.
In looking at iDFS by nodal status of N0, here we see that the 3-year iDFS hazard ratio was 0.723. Moreover, looking at those with nodal status of N1 to N3, we see a 3-year iDFS hazard ratio of 0.759. Overall, we can say that there is absolute improvement in iDFS regardless of nodal status or stage with ribociclib plus NSAI vs NSAI alone.
NATALEE: Safety
In regard to safety, when you reduce the dose of ribociclib from 600 mg to 400 mg—as was done in NATALEE—there is a lower incidence of grade ≥3 neutropenia (44.3%), almost no febrile neutropenia (0.3%), and a low incidence of grade 3 QT interval prolongation (0.3%).
Liver function abnormalities signifying hepatic toxicity were the most frequent reason for discontinuation of adjuvant ribociclib. Approximately 26% of patients had any-grade liver-related AEs, and 9% had ≥3 liver-related AEs.
Dose reduction for higher-grade hepatic toxicity is a consideration. However, hepatic toxicity could be experienced again despite a dose reduction, so HCPs should use their best judgment as to whether to stop and dose reduce or completely stop adjuvant ribociclib. This treatment represents an important option in the treatment of high-risk HR-positive/HER2-negative EBC. We hope this treatment will receive regulatory approval soon and that it will become an option for our patients.
Adjuvant Olaparib vs Placebo in BRCAmut, HER2-Negative High-Risk EBC (OlympiA): iDFS (Primary Endpoint) and OS
Based on data from the OlympiA trial, one year of adjuvant olaparib is another option that we want to consider in patients with HR-positive/HER2-negative breast cancer with germline BRCA1/2 mutation status.11
The Kaplan-Meyer curves on the right show improvement in both 4-year iDFS (82.7% vs 75.4%; hazard ratio: 0.63) and 4-year OS (89.8% vs 86.4%; hazard ratio: 0.68; P = .009) in patients who received adjuvant olaparib vs placebo. It is important to note that these curves are continuing to pull apart over time, and we look forward to additional follow-up.
Additional Considerations of Adjuvant Therapy in Special Patients With High-Risk EBC
What other considerations do we want to think about with regard to adjuvant therapy recommendations for patients with high‑risk HR-positive/HER2-negative EBC?
First, the decision about using chemotherapy has different considerations than does the question of who will be treated with an adjuvant CDK4/6 inhibitor or a PARP inhibitor. In both the NATALEE trial and the monarchE trial, patients were not required to have had previous neoadjuvant or adjuvant chemotherapy, although the majority did.
When considering the use of chemotherapy, we often use genomic assays, prognostic and predictive scores, provided by the 21‑gene and 70‑gene signature scores, per the data in the TAILORx, RxPONDER, and MINDACT clinical trials.12-14
When considering targeted adjuvant therapy for high-risk patients, we do not have a head‑to‑head comparison of the PARP inhibitor olaparib vs a CDK4/6 inhibitor (eg, abemaciclib, palbociclib, or rucaparib). We also lack data on giving patients 1 year of olaparib first and then sequentially recommending a CDK4/6 inhibitor.
Based on the OlympiA survival results for patients with high-risk HR-positive/HER2-negative EBC with germline BRCA1/2 mutation status, I prioritize olaparib over an adjuvant CDK4/6 inhibitor for these patients.
Interactive Decision Support Tool for HER2-Negative EBC
I wanted to bring to your attention a helpful interactive decision support tool developed by Clinical Care Options with assistance from 5 breast oncology experts. This tool is available online; you also can find it using the link on the slide, the QR code, or the AliCEA app, which can be found in your app store.
To use the tool, enter key patient characteristics by answering a few questions, such as HR status, triple-negative status, and HER2 status, as well as germline BRCA1/2 status. The tool asks you to select the therapy you are planning or considering for your patient and then shows you the recommendations from the 5 experts, including caveats and commentary for context on their treatment of choice. I find these tools to be very interesting and helpful, and HCPs should explore them to see if there is something that might help them.
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