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Role of CDK4/6 Inhibitors in HR+/HER2- EBC

CE / CME

Risk Factors for Recurrence, Molecular Testing, and Treatment of Patients With HR-Positive/HER2-Negative EBC

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: January 24, 2025

Expiration: January 23, 2026

Sara M. Tolaney
Sara M. Tolaney, MD, MPH
CME/CE Information

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What Is “High Risk” in HR+/HER2- EBC? 

There are a number of factors that are taken into account when defining high-risk, HR-positive, HER2-negative EBC. These include tumor size, involvement of ALNs, higher-grade disease, and high proliferation scores using the Ki-67 index.1-3 Other factors that can influence treatment outcomes include the degree of ER expression, with lower ER levels being associated with an increased risk of recurrence. It is known that specific intrinsic subtypes of breast cancer such as luminal B, HER2-enriched and basal-like are associated with a higher risk of disease recurrence. Also, primary endocrine therapy (ET) resistance is a key feature of high-risk HR-positive/HER2-negative EBC that recurs within 2 years of diagnosis. There are some early data suggesting that response to preoperative ET can potentially predict prognosis, with the failure of preoperative ET to suppress Ki-67 predicting poor outcomes with adjuvant ET.1,3

Regarding the risk of first recurrence after primary treatment, patients who have higher clinical anatomic risk seem to experience disease recurrence earlier.2 For example, typically patients with stage III breast cancer experience recurrence earlier than those with stage I disease. For patients with ER-positive breast cancer, recurrence can be bimodal, with some patients experiencing early events, and some with disease recurrence years later, sometimes 5 to 15 years after diagnosis.

2022 ASCO Guidelines: Biomarkers for Adjuvant ET and CT for HR+/HER2- EBC

There are guidelines from the American Society of Clinical Oncology (ASCO) about looking for biomarkers to guide the choice of adjuvant ET and chemotherapy for patients with HR-positive/HER2-negative EBC.4 For premenopausal patients, the ASCO guidelines recommend the use of the Oncotype Dx Recurrence score (RS) assay for those with node-negative disease. For premenopausal patients with node-positive disease, however, there is insufficient evidence to routinely recommend the use of any particular biomarker test. In the postmenopausal setting, the ASCO guidelines include the use of genomic assays for patients with node-negative and node-positive disease, except for patients with 4 or more positive lymph nodes where there is insufficient evidence for biomarker utilization.

2024 NCCN Guidelines in Use of Biomarkers to Guide Adjuvant Decision-making in EBC

Similarly, the NCCN guidelines recommend the utilization of genomic assays to guide adjuvant treatment decision-making for patients with EBC.5 Of note, for premenopausal patients with 1 to 3 positive lymph nodes, the level of evidence for the use of the 21-gene RS assay is lower (category 2A) compared with postmenopausal patients (category 1). All genomic assays, however, have been found to be prognostic. It is more restricted in terms of the limitations of predictive benefit, where the 21-gene RS assay is more predictive of benefit from chemotherapy compared with the other genomic assays.

Factors That Play a Role in Treatment Decision-making

There are many areas of controversy when thinking about recurrence risk in ER-positive/HER2-negative EBC. An area of controversy is how strongly the patient’s age is factored into this. It is known that younger patients have more biologically aggressive disease. There seems to be a higher incidence of relapse within the younger patient population compared to older patients. We also have challenges with regard to the incorporation of menopausal status into treatment decision-making for patients with EBC, where, as noted earlier, within the population of premenopausal patients with 1 to 3 positive lymph nodes, the role of genomic assays is less clear, suggesting that pre- and postmenopausal patients are not necessarily being treated in the same manner especially with regard to the use of biomarkers in the high-risk EBC setting. 

For patients with EBC, we are currently using genomic assays to help with making therapeutic decisions about the need for chemotherapy. Of importance, there are other types of molecular assays that look at parameters such as measurable residual disease. To date, some questions remain unanswered regarding the use of biomarker tests: should a circulating tumor DNA (ctDNA) assay be incorporated into the EBC setting?  Should tests for intrinsic subtyping be incorporated into treatment decision-making? What should be done regarding tests for genomic alterations?

At the current point in time, ctDNA, and intrinsic subtyping have not yet made their way into the treatment decision-making process for patients with EBC. However, germline genetic testing is used in making treatment decisions and has therapeutic implications for patients with high-risk EBC. 

Which of the following is associated with high risk of recurrence and would help to inform optimal adjuvant therapy for newly diagnosed patients with HR-positive/HER2-negative EBC?

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