Molecular Characterization of HER2-Low Invasive Breast Carcinoma by Quantitative RT-PCR Using Oncotype DX Assay

Area of Science:

• Oncology
• Genomics
• Pathology

Background:

• HER2 immunohistochemistry (IHC) shows suboptimal reproducibility for HER-low breast cancer cases (IHC 1+ or 2+).
• Accurate HER2 status is crucial for guiding breast cancer treatment decisions, particularly regarding adjuvant chemotherapy and HER2-targeted therapies.

Purpose of the Study:

• To evaluate the concordance between HER2 immunohistochemistry (IHC) and HER2 mRNA levels using the Oncotype DX Recurrence Score (RS) in HER2-low breast cancer.
• To determine the clinical implications of HER2-low status in relation to Oncotype DX RS and potential chemotherapy benefit.

Main Methods:

• Analysis of two cohorts: Yale (214 early-stage ER+ breast cancers with IHC 0, 1+, 2+ and RS) and Exact Sciences (957,624 patients with Oncotype DX RS).
• Comparison of HER2 mRNA levels across different IHC categories (0, 1+, 2+).
• Assessment of Oncotype DX RS values in HER2-low (IHC 1+/2+) breast cancer patients.

Main Results:

• HER2 mRNA levels showed increasing medians across IHC 0, 1+, and 2+ categories.
• 22.4% of HER2-low cancers had an Oncotype DX RS > 25.
• Over 98% of HER2-low cancers were classified as HER2-negative by the Oncotype DX assay's HER2 mRNA criteria.

Conclusions:

• While some HER2-low cancers exhibit higher mRNA levels, the majority have low Oncotype DX RS, indicating minimal benefit from current adjuvant chemotherapies.
• The findings highlight the complexity of HER2 assessment in HER2-low breast cancer and its implications for treatment stratification.