Some of the more commonly used gene expression assays, such as the 21-gene Oncotype DX Breast Recurrence Score test (Exact Sciences Corporation), do not have a role in early-stage HER2+ disease, as their use is largely restricted to estrogen receptor–positive (ER+)/HER2- breast cancer. The clinical usefulness of the 21-gene recurrence score was established in a series of prospective studies that were performed in retrospectively derived cohorts and, subsequently, were prospectively validated in the randomized TAILORx trial. In this study, we showed that a multigene prognostic assay can increase precision in estimating the absolute risk of recurrence among women with select disease features and molecular findings, thereby helping to identify low-risk patients with ER+/HER2- breast cancer who do not need adjuvant chemotherapy.

While the vast majority of patients with early-stage HER2+ disease are cured with current approaches, substantial heterogeneity also exists in HER2+ breast cancer with regard to tumor biology and prognosis. Opportunities to either escalate or de-escalate systemic therapy in this setting continue to be explored. Toward that end, efforts to integrate genetic and molecular information with the standard prognostic features of HER2+ breast cancer (eg, nodal status, tumor size, and grade) to further delineate distinct risk groups are underway.

A useful new test for patients with early-stage HER2+ breast cancer called HER2DX integrates classical clinicopathological breast cancer features with gene expression profiling. The combined prognostic score model was based on 17 clinicopathological and genomic variables and was developed using tumor samples from the phase 3 Short-HER trial. The following 4 variables had previously been shown to provide independent prognostic information in that trial: (1) tumor size, (2) nodal status, (3) tumor-infiltrating lymphocytes, and (4) PAM50 subtype. The final model incorporated tumor size, nodal status, number of tumor-infiltrating lymphocytes, subtype (eg, HER2-enriched and basal-like), and 13 genes. Thus, the model tracks immune infiltration, tumor cell proliferation, luminal differentiation, and the expression of an HER2 amplicon.

The HER2DX prognostic score has been analytically and clinically validated, and it is prognostic for a recurrence in HER2+ breast cancer after standard adjuvant chemotherapy plus anti-HER2 therapy or a pathologic response to neoadjuvant chemotherapy plus anti-HER2 therapy. What remains to be determined are the clinical utility of this test and how it should be used to help inform treatment decisions. Fully understanding these unknowns will require additional studies that are specifically designed to address them.