Multigene genomic assays help to diagnose, prognosticate, and assist with treatment decisions in early-stage breast cancer (BC). In 2022, the American Society of Clinical Oncology issued a guideline update on the use of biomarkers to help guide treatment decisions involving adjuvant endocrine and chemotherapy in early-stage BC. However, these guidelines did not adequately address certain patient scenarios, such as those with early-stage BC with four or more positive lymph nodes and premenopausal patients with one to three positive lymph nodes.

A recent review has addressed the evolving role of genomic testing in early-stage BC and its implications for diagnosis, prognosis, and therapy. The purpose of this paper was threefold: to provide a comprehensive review and comparison of the clinically validated genomic assays in early-stage BC; to evaluate the supporting evidence for the use of these tests in various patient populations; and to assess the effect that genomic testing has on healthcare costs and its impact on clinical decision making.

The paper provides a comparison between the commercially available RNA-based genomic assays used to evaluate the patient with early-stage BC. Among these assays are Mammaprint, Oncotype Rx, Prosigna (PAM-50), Endopredict, and Breast Cancer Index (BCI). It reviews the number of genes, sample type (e.g., frozen specimen), profiling method (e.g., quantitative polymerase chain reaction [PCR] testing), risk stratification cut-offs, availability of testing (i.e., whether the assay can be analyzed in-house or needs to be sent to a central laboratory), and test status both in the United States and in Europe.

Among the first-generation genomic tests for early-stage BC are Oncotype DX and MammaPrint. They are utilized for their prognostic and predictive value and to help determine the need for neoadjuvant or adjuvant chemotherapy in early-stage BC patients who are at high risk of recurrence. Mammaprint tests for 70 genes, whereas Oncotype DX only tests for 21 genes, which include 16 genes of interest and five reference genes. Mammaprint has a Genomic Risk Score that ranges from 0.001 to 1,000 (indicates low risk) to 1,000 to 0 (represents high risk of recurrence).

Oncotype DX has three recurrence scores: <18 (low risk), 18-30 (intermediate risk), and >30 (high risk). A disadvantage of Oncotype Dx is that the intermediate-risk classification is less informative regarding the benefit of chemotherapy in this group. The utility of Oncotype DX has been enhanced by the development of RSClin, which is a new prognostic tool that integrates the 21-gene Recurrence Score with tumor grade and size and patient age for a more personalized risk assessment. MammaPrint is the first assay to be cleared at the 510(k) level by the FDA’s new in vitro diagnostic multivariate index assay classification, which indicates that it is safe and effective for its intended use.

Another first-generation genomic assessment test is the BCI. Unlike the other two first-generation tests, which have been given a Grade A recommendation by the European Society of Medical Oncology (ESMO), BCI has been given a Grade B rating. It analyzes seven genes to determine the risk of late distant recurrence (risk score), offering both prognostic and predictive value. It provides a yes or no prediction of benefit for the use of extended endocrine therapy beyond the usual 5 years of treatment.

Two second-generation genomic assays for early-stage BC include Prosigna and EndoPredict. Both have prognostic value and help clinicians decide on the use of adjuvant or neoadjuvant chemotherapy depending on the risk score achieved. These tests also have a Grade B rating by ESMO.

Prosigna (also referred to as PAM-50) can analyze 50 genes associated with early-stage BC, including eight reference genes, eight positive control genes, and eight negative control genes whereas Endopredict can evaluate 12 genes, which represent eight genes of interest, three reference genes, and one control gene. Prosigna provides a risk of recurrence of low (0-40), intermediate (41-60), and high (41-100) risk. Endopredict has only two risk categories based on the EndoPrint Score (<5 is low risk whereas >5 is high risk). Prosigna also has FDA-510(k) clearance. EndoPredict combines the 12-gene molecular score with patient-specific data, including tumor size and lymph node status, to provide more personalized results.

The paper also discusses ASCO guidelines for the appropriate use of these genomic tests. It divided their utility into two categories based on patient populations: premenopausal women aged <50 years and postmenopausal women or those aged >50 years. Unfortunately, there is a dearth of information about the use of these tests in premenopausal women. Only Oncotype DX has sufficient information to provide a recommendation for use in this younger age group, and this is only for those with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) node-negative early-stage BC. There are insufficient data to recommend use of these tests in premenopausal with positive lymph node(s).

For postmenopausal women or those aged older than 50 years with node-negative BC, Oncotype Dx has the strongest recommendations, followed by MammaPrint, EndoPredict, Prosigna, and BCI. These tests, with the exception of Prosigna, can also be used in older women with one to three positive nodes. No test has sufficient evidence available supporting their use for postmenopausal women or those aged older than 50 years with four or more positive nodes, however.

The article also describes the clinical validity and the utility of these genomic tests for early-stage BC. It identified both challenges and opportunities associated with the use of these tests. Among the topics addressed are whether the testing can be performed in-house or has to be outsourced; their cost-utility analysis based on the volume of test performed and the need for capital investment; and the role of these tests in meeting unmet clinical needs when their utility can be limited in specific populations and can involve issues with implementation of services and reimbursement.

This paper provides pharmacists with insight into the pros and cons of the various multigene prognostic genomic assays that are currently available for use in early-stage BC. The information provided can be used by pharmacists serving on interdisciplinary care teams to optimize therapeutic decisions and for educating patients so that they can make informed decisions about their care.

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