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Treatment of HER2-Negative EBC

CE / CME

Expert Review of Treatment for HER2-Negative Early Breast Cancer

Pharmacists: 1.00 contact hour (0.1 CEUs)

Nurses: 1.00 Nursing contact hour

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 31, 2023

Expiration: August 30, 2024

Kevin Kalinsky
Kevin Kalinsky, MD, MS
CME/CE Information

Activity

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Course Completed

Guideline-Recommended Biomarker Testing for Breast Cancer

We start by discussing how subsets of patients are defined in EBC in today’s era of precision medicine, considering risk assessments and biomarker testing.

Immunohistochemistry has long been used to test for estrogen receptor and progesterone receptor in patients with breast cancer.1 In addition, HER2 testing is performed by immunohistochemistry, with or without in situ hybridization. We have guidelines to define each of these tests from ASCO and the College of American Pathologists.2,3 Other gene expression assays are available to help guide decisions on adjuvant CT if patients have estrogen-driven HER2-negative breast cancer with 0-3 lymph nodes involved. There are also indications for BRCA testing based on genetic or familial high-risk assessment, for example, for any patient (at any age) with TNBC, any patient with male breast cancer or family history of male breast cancer, those who meet criteria with personal or family history, and when considering olaparib in the adjuvant setting for HER2-negative EBC.4

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Genomic Assays for EBC

Genomic assays with predictive and/or prognostic capabilities are used for patients with HR-positive/HER2-negative EBC.5 We commonly use the recurrence score based on the 21-gene assay, which looks at 16 cancer-related genes and 5 reference genes.6 This assay gives prognostic information but, of more importance, helps us to determine who may benefit from the addition of CT to endocrine therapy (ET).

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

In 2022, the ASCO guidelines were updated in terms of biomarkers for adjuvant ET and CT in patients with HR-positive/HER2-negative EBC.7 The data supported use of the 21-gene (Oncotype DX) or 70-gene (MammaPrint) recurrence score assays in patients who are postmenopausal with node-negative disease or those with 1-3 nodes involved. For patients who have N2 disease (≥4 lymph nodes involved), there are currently no prospective data in a randomized setting to establish the utility of these assays. 

For premenopausal women with node-positive disease, there was insufficient evidence to recommend a biomarker for use, although some healthcare professionals use the 70-gene or 21-gene recurrence score for prognostic purposes.

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RSClin in Patients With HR+/HER2-, N0 EBC

A new tool, RSClin, was developed to more precisely guide adjuvant CT use in patients with HR-positive/HER2-negative, node-negative EBC, incorporating clinical and pathologic factors with the 21-gene recurrence score.8 The online tool (https://online.genomichealth.com/) further helps to individualize the risk that a patient may have, considering tumor size and grade along with the patient age and recurrence score. This tool is currently available for patients with node-negative disease, although we hope to use it for patients with node-positive (1-3 nodes involved) disease as well in the future.

RSClin was developed using meta-analysis data from 10,004 patients, with data from the NASBP B-14 and TAILORx trials used to establish prognostic factors and data from NASBP B-20 and TAILORx to establish predictive factors. The prognostic factors were also externally validated using real-world data from 1098 patients enrolled in the Israeli Clalit registry.

Which of the following assays has an available online tool known as RSClin that incorporates clinical and pathologic features to help individualize risk in node-negative HR-positive/HER2-negative EBC?

2023 NCCN Guidelines in Use of Biomarkers to Guide Adjuvant Decision-Making in EBC

Looking at the NCCN guidelines for use of biomarkers in patients with node-negative disease, there is level 1 evidence for the 21-gene recurrence score, which is the preferred assay.1 For patients with 1-3 nodes involved, the 21-gene recurrence score has level 1 evidence for postmenopausal patients and level 2A evidence for premenopausal patients. The guidelines also suggest level 1 evidence for the 70-gene assay and level 2A evidence for other assays including the PAM50 risk of recurrence score, Breast Cancer Index, and EndoPredict, in different patient populations.

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RxPONDER: Study Design

Let’s take a closer look at the data that led to the utility of the 21-gene assay for patients who have 1-3 nodes involved. The randomized phase III RxPONDER study compared CT followed by ET vs ET alone in 5083 patients with node-positive (1-3 nodes involved), HR-positive/HER2-negative EBC.9  Eligible patients had a recurrence score ≤25 and were candidates to receive taxane and/or anthracycline-based CT. The primary endpoint was invasive disease-free survival (iDFS) and whether the effect was influenced by recurrence score, with secondary endpoints including OS, distant DFS (DDFS), local disease-free interval, safety, and quality of life.

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RxPONDER: iDFS by Menopausal Status

In the postmenopausal population (n = 3328), there was no difference in 5-year iDFS for patients receiving CT in addition to ET (91.3% vs 91.9%; hazard ratio: 1.02; 95% CI: 0.82-1.26; P = .89) compared with ET alone.9 However, for premenopausal women, there was a 4.9% absolute difference in 5-year iDFS (93.9% vs 89.0%; hazard ratio: 0.60; 95% CI: 0.43-0.83; P = .002) in favor of those who received CT in addition to ET, compared with ET alone.

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Factors to Consider for Risk Assessment and Treatment Guidance in HER2-Negative EBC

In summary: What factors do we think about when considering risk assessment and treatment guidance in EBC? We think about features like age, HR and HER2 status, the tumor size and grade, whether or not there are lymph nodes involved, and response to prior neoadjuvant therapy (if any). For example, if patients had TNBC and they have residual disease, they are at a higher risk of an event compared with those who had a pCR.

The gene expression assays and RSClin prognostic tool that we discussed in this section add more information to help in decision-making, and in the next section, we will introduce the additional consideration of germline BRCA testing.

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