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Adjuvant Treatment of HR Positive HER2 Negative EBC

CE / CME

Integrating the Evidence on Adjuvant Therapy for High-risk HR-Positive/HER2-Negative Early Breast Cancer

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurses: 0.50 Nursing contact hour

Pharmacists: 0.50 contact hour (0.05 CEUs)

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Released: February 05, 2025

Expiration: February 04, 2026

Aditya Bardia
Aditya Bardia, MD, MPH, FASCO
CME/CE Information

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Personal Perspective on Optimal Sequencing of CDK4/6 Inhibitors and Olaparib for HR-Positive/HER2-Negative EBC

For my patients with high-risk, HR-positive/HER2-negative, ALN-positive EBC receiving chemotherapy, I tend to use a CDK4/6 inhibitor as adjuvant therapy. If the patient has a gBRCA mutation and meets the criteria for olaparib, I would use adjuvant olaparib postchemotherapy. Of note, a CDK4/6 inhibitor cannot be administered together with olaparib. So, if the patient’s disease harbors a gBRCA mutation, I would start with adjuvant olaparib for 1 year. After the completion of olaparib, a CDK4/6 inhibitor (either abemaciclib or ribociclib) may be considered, although this is a data-free zone with the need to consider cumulative toxicity associated with sequential therapies. The NCCN guidelines as well as the ASCO guidelines are very helpful in terms of selecting which therapy to use and whether to use abemaciclib or ribociclib. In general, any patient who is a candidate for abemaciclib is potentially also a candidate for ribociclib. However, certain conditions can steer me to favor one over the other.

Expert’s Treatment Algorithm for Adjuvant Therapy in HR-Positive/HER2-Negative EBC 

For a patient with HR-positive/HER2-negative EBC and ≥4 positive nodes, the treatment choice depends on the presence or absence of a gBRCA mutation. If the disease harbors wild-type BRCA, adjuvant chemotherapy followed by ET plus a CDK4/6 inhibitor would produce optimal results. In this setting, some would favor abemaciclib because the eligibility criteria for the monarchE trial specifically included patients with ≥4 positive ALNs and the monarchE trial has more mature results; however, it is important to note that ribociclib is also an option to consider in this setting. Often, the decision is based on a thoughtful discussion with the patient about the current evidence, duration of therapy with each CDK4/6 inhibitor and the differential AE profile of each agent. As stated earlier, if the patient’s disease harbors a gBRCA mutation, adjuvant chemotherapy followed by ET plus olaparib for 1 year should be considered. Thereafter, a CDK4/6 inhibitor–based therapy may be recommended.

For a patient with 1-3 positive lymph nodes, the first parameter to consider is the menopausal status of the patient. If the menopausal status of the patient is unknown, determination of the AMH level can be helpful. If the patient is postmenopausal, I would recommend profiling using the Oncotype DX RS assay, MammaPrint, Ki-67 score determination, EndoPredict, or the Breast Cancer Index assay to determine the patient’s risk of recurrence. If the score/risk of recurrence is low, adjuvant ET alone without chemotherapy may be considered initially. However, if the score/risk of recurrence is high, adjuvant chemotherapy followed by ET is recommended.

For premenopausal patients, the current recommendation is to administer adjuvant chemotherapy followed by ET. For any patient without grade 3 disease but with 1-3 positive ALNs, I would consider ribociclib, especially if the tumor is ≤5 cm in size and/or if the patient has a bowel comorbidity. If the premenopausal patient has 1-3 positive ALNs with additional risk factors such as grade 3 disease and a tumor size of >5 cm, the options include abemaciclib vs ribociclib. For a patient with preexisting QT interval prolongation, I would favor abemaciclib over ribociclib.

Regardless of whether the patient has 1-3 vs ≥4 ALNs or whether the patient is premenopausal vs postmenopausal, if the patient’s disease harbors a gBRCA mutation, I would consider olaparib as initial adjuvant therapy based on the results of the OlympiA study.

CCO Interactive Decision Support Tool for HER2-Negative EBC 

CCO has an Interactive Decision Support Tool that can help to make treatment decisions for patients with HER2-negative EBC. Once the specific patient characteristics are entered, treatment recommendations from 5 different experts are provided. It is important to note that the tool was developed prior to the FDA approval of ribociclib based on the NATALEE trial results. The tool is freely available here.

CCO Patient Communication Checklist: EBC 

CCO also has a patient–healthcare professional (HCP) communication checklist that includes important information about HR-positive/HER2-negative, high-risk EBC that can help facilitate discussions with patients and their families. This checklist includes questions for patients to ask their HCPs and current strategies that can be used by HCPs to encourage patients’ adherence to oral therapies.

Adherence to treatment with oral agents is critical in order to achieve the desired treatment outcomes. Reduced adherence is linked to increased morbidity and mortality. So, regular assessments of adherence, identifying barriers, and developing solutions to overcome barriers are critical to successfully using oral therapies. The key is to educate patients about the importance of taking their medicine, the anticipated AEs, and to proactively have a plan in place for managing the AEs if they do develop. This way, there are no surprises to the patient.

Overall Conclusions  

In summary, CDK4/6 inhibitors and olaparib, a PARP inhibitor, have changed the way in which patients with high-risk, HR-positive/HER2-negative EBC are treated. For all my patients with high-risk, HR-positive/HER2-negative EBC harboring a gBRCA mutation, I would recommend adjuvant chemotherapy followed by ET plus olaparib for 1 year.

Abemaciclib and ribociclib are the 2 FDA-approved CDK4/6 inhibitors in this disease setting. If a patient is a candidate for either of these agents, I would use a patient-centered discussion to make treatment decisions. Typically, I would discuss the maturity of the datasets with the patient, noting that we have longer follow-up data for abemaciclib than for ribociclib. Next, I would compare the AE profiles of these agents, noting that the duration and frequency of treatment is different for these agents. Whereas ribociclib is taken once daily on a 3-week-on/1-week-off schedule for 3 years, abemaciclib is taken twice daily for 2 years. After putting all these factors into consideration, I would use an individualized approach to make an optimal treatment recommendation for the patient. Finally, to ensure that optimal outcomes are achieved, treatment adherence is of great importance. Besides routine follow-up every 6-12 months, it is important to regularly educate patients about the importance of adherence and monitor therapeutic compliance.

A 58-year-old woman who is postmenopausal presents with a 5-cm right breast mass with a suspicious node. Initial breast biopsy reveals invasive ductal carcinoma (IDC), grade 3, with the following biomarkers: estrogen receptor (ER) 80%; progesterone receptor 30%; HER2 negative by immunohistochemistry. Fine-needle aspiration of a palpable right axillary lymph node (ALN) reveals adenocarcinoma of the breast and germline BRCA (gBRCA) testing is negative.


The patient receives neoadjuvant doxorubicin, cyclophosphamide, and paclitaxel and then undergoes bilateral mastectomy. Right mastectomy specimen reveals a 4-cm IDC with minimal chemotherapy effect and 4/15 positive nodes. She returns to the clinic now to discuss adjuvant treatment options.

Based on the patient’s tumor characteristics and predictive biomarkers, which of the following would you recommend as the most appropriate systemic adjuvant therapy for this patient?

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