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Overview of Risk Assessment and Biomarker Testing to Inform Treatment in HER2-Negative Early Breast Cancer
  • CME
  • CE

Yara Abdou, MD
Released: April 6, 2022

Biomarker Testing for Risk Assessment and Treatment Benefit in Early HER2-Negative Breast Cancer

Guideline-Recommended Biomarker Testing for Breast Cancer

Breast cancer receptor status should be determined as part of the diagnostic workup for patients with newly diagnosed or recurrent breast cancer, including HER2 status by immunohistochemistry with or without fluorescence in situ hybridization, if needed, and HR status, including ER and PR.1-3 Several gene expression assays are available that can help predict risk of recurrence and response to systemic therapy. More recently, germline mutation testing has been incorporated into management of EBC, specifically looking for BRCA mutations to guide adjuvant therapy selection for patients with HER2-negative breast cancer.2 Lastly, measurement of the Ki-67 antigen can be helpful when considering specific targeted therapies such as abemaciclib.

Genomic Assays for Early-Stage Breast Cancer

Genomic assays are used for risk assessment and guiding choice of systemic therapy. These assays can be either predictive or prognostic, or both. The 21-gene assay is an example of a test that is both predictive and prognostic, meaning it predicts whether the patient is likely to benefit from chemotherapy and the risk of disease recurrence.

Predictive/Prognostic Genomic Assays

Several commercially available gene-based assays are useful in determining prognosis in patients with EBC by predicting likelihood of recurrence or survival.4-8 Of these, the 21-gene reverse transcription polymerase chain reaction assay is the only assay that has been clinically validated for predicting the likely benefit of adding adjuvant chemotherapy to further reduce the risk of recurrence in patients with HR-positive/HER2-negative EBC.4,9 Results of different assays may not be concordant with one another, and these assays have not been compared in prospective head-to-head trials. Therefore, healthcare professionals should order only 1 assay for a specific patient or tumor.

21-Gene Assay in Node-Positive, ER+ Breast Cancer

The 21-gene assay is one of the most validated multigene assays in use for EBC. The 21-gene assay has been shown to predict locoregional and distant recurrence in women with HR-positive/HER2-negative, node-negative tumors.4,10 This assay also has been validated to predict the benefit from adding adjuvant chemotherapy to adjuvant endocrine therapy for this patient population in the phase III SWOG-8814 trial.11 This study found that recurrence score was predictive of the likely benefit from chemotherapy in extending disease-free survival, overall survival (OS), and breast cancer–specific survival during the first 5 years. The higher the recurrence score, the more likely patients will gain an absolute benefit from adjuvant chemotherapy, with those with low scores unlikely to benefit.

RxPONDER: Adjuvant ET ± CT in HR+/HER2- EBC With 1-3 Positive Lymph Nodes and RS ≤25

The 21-gene assay also was studied in patients with HR-positive/HER2-negative EBC with limited lymph node involvement and a recurrence score ≤25 in the RxPONDER trial.12 This prospective, randomized phase III study assigned 5083 women with 1-3 positive axillary lymph nodes to standard endocrine therapy with or without adjuvant chemotherapy. The primary endpoint was iDFS.

RxPONDER: iDFS by Menopausal Status

At the third planned interim analysis, the impact of chemotherapy on iDFS differed by menopausal status.12 In postmenopausal women with recurrence score ≤25, the addition of chemotherapy to endocrine therapy had no significant impact on 5-year iDFS. However, in premenopausal women, a significant improvement in iDFS was seen with use of chemotherapy (hazard ratio: 0.60; 95% CI: 0.43-0.83; P = .002).

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

RSClin is another important prognostic and predictive tool for use in management of patients with HR-positive/HER2-negative EBC. This tool integrates the 21-gene recurrence score with clinical and pathologic features including the patient’s age, tumor grade, and tumor size to deliver a 10-year estimate of disease recurrence rate and chemotherapy benefit.13 The tool was developed from a meta-analysis of 10,004 women with HR-positive/HER2-negative, node-negative breast cancer receiving endocrine therapy with or without chemotherapy in the NASBP B-14 and TAILORx trials and subsequently was validated in 1098 women in the Clalit registry cohort. Results show that using RSClin provides greater prognostic information than either recurrence score or the clinical–pathology information alone.

70-Gene Signature Test: Survival Without Distant Metastasis

The 70-gene assay is a genetic test that measures the activity of 70 genes to determine the 5- to 10-year risk of relapse for women diagnosed with EBC. This test was approved for use by the FDA in 2007 and is an alternative platform to the 21-gene assay. The 70-gene assay has demonstrated the ability to identify patients with a low genomic risk despite having a high clinical risk, in whom chemotherapy may be omitted without a detrimental effect.14

OlympiA: Phase III Trial of Adjuvant Olaparib in Patients With gBRCA1/2-Mutated HER2- BC

Several recent studies of targeted therapy have impacted the management of HER2-negative EBC.

The double-blind phase III OlympiA trial included 1836 patients with high-risk EBC that was HER2 negative and BRCA1/2 mutation positive, including triple-negative breast cancer (TNBC) and HR-positive subtypes.15 Patients were randomly assigned to 1 year of the PARP inhibitor olaparib or placebo, each given orally, following completion of local treatment and neoadjuvant or adjuvant chemotherapy. The primary endpoint was iDFS. At 3 years, the iDFS rate was 85.9% with olaparib vs 77.1% with placebo, an absolute difference of 8.8% favoring olaparib (hazard ratio: 0.58; 95% CI: 0.41-0.82; P <.001). OS data are still immature.

monarchE: Phase III Trial of Adjuvant Abemaciclib + ET in High-Risk, Node-Positive, HR+/HER2- EBC

Similarly, monarchE was an open-label phase III trial that included 5637 patients with HR-positive/HER2-node-positive, high-risk EBC and prior surgery and radiotherapy as indicated and/or adjuvant or neoadjuvant chemotherapy.16 Patients were randomized to receive adjuvant endocrine therapy for 5-10 years, as clinically indicated, with or without adjuvant abemaciclib, a CDK4/6 inhibitor, for 2 years. The primary endpoint was iDFS. After a median follow-up of 19.1 months, treatment with abemaciclib plus endocrine therapy reduced the risk of an iDFS event by 28.7% (hazard ratio: 0.71; 95% CI: 0.58-0.87; P = .01).17 The benefit was even greater in patients with a high Ki-67 index.

Definitions of “High Risk” in EBC

There is no definitive definition of high-risk, so how was it defined in these trials? In OlympiA, risk assessment was different based on HR status and whether patients received neoadjuvant or adjuvant therapy.15 For patients who received neoadjuvant chemotherapy, high-risk HR-positive/HER2-negative tumors were defined as not having a pathologic complete response and a CPS plus EG score of ≥3. The CPS plus EG scoring system estimates relapse probability on the basis of clinical and pathologic stage, ER status, and histologic grade.18 In patients with TNBC who received neoadjuvant therapy, any residual disease was defined as high risk. Patients who received adjuvant chemotherapy for HR-positive/HER2-negative breast cancer were required to have ≥4 pathologically confirmed positive lymph nodes to be defined as high risk. Patients with TNBC who received adjuvant chemotherapy were required to have any lymph node–positive disease or an invasive primary tumor that measured ≥2 cm.

In the monarchE study, risk was defined by a compilation of clinical and pathologic features including nodal status, tumor size, histologic grade, and Ki-67 level.16 High risk was defined as having ≥4 positive lymph nodes or 1-3 positive nodes with either tumor size ≥5 cm, histologic grade 3, or Ki-67 score ≥20.

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

In summary, there are several factors to consider when assessing risk and making treatment decisions in patients with HER2-negative EBC. These include clinical and pathologic features such as patient age and menopausal status, HR/HER2 status, tumor size and grade, lymph node involvement, and response to neoadjuvant therapy. Gene expression assays such as the 21-gene assay or the 70-gene assay can help predict risk of disease recurrence and response to chemotherapy, and the RSClin tool integrates recurrence score with clinical–pathologic features to provide a risk estimate. More recent developments in biomarker screening include germline BRCA testing for patients who meet relevant criteria or when considering targeted therapy with adjuvant olaparib. Lastly, Ki-67 score can be helpful when considering adjuvant treatment with abemaciclib.

Additional Information

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

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