Dr Stein on the Background of the Phase 3 OPTIMA Trial in ER+, HER2– Early Breast Cancer

“There has been a long-term clinical belief that [patients] with the common ER-positive, HER2-negative subtype of breast cancer were being over treated with chemotherapy in the adjuvant setting. We were giving chemotherapy to a lot of women who were not benefiting.”

Robert Stein, MBBS, PhD, an honorary consultant oncologist at University College London (UCL) Hospitals and a professor of breast oncology at UCL Cancer Institute, discussed the background and design of the phase 3 OPTIMA trial (ISRCTN42400492), which evaluated test-directed chemotherapy in patients with high clinical risk estrogen receptor (ER)–positive HER2-negative early breast cancer. Data from this study were presented during the 2026 ASCO Annual Meeting.

For many years, a substantial proportion of patients with positive, HER2-negative breast cancer have received adjuvant chemotherapy despite deriving little or no benefit from the treatment, Stein began. Although chemotherapy has been a standard component of care for many patients, the lack of reliable biomarkers made it difficult to identify individuals who could safely forgo chemotherapy without compromising clinical outcomes, he continued. To address this unmet need, investigators designed a large international clinical trial, OPTIMA, evaluating the use of the Prosigna genomic assay to guide adjuvant treatment decisions, he explained.

The study enrolled 4429 patients from 6 countries over a 9-year period, Stein said. Participants were randomly assigned 1:1 to the investigational or control arm. Patients in the control arm received the conventional standard of care, consisting of adjuvant chemotherapy followed by endocrine therapy, Stein said. Patients in the experimental arm underwent genomic testing with the Prosigna assay, which measures a tumor’s Risk of Recurrence (ROR) score using tissue obtained during surgery, he said.

Treatment in the experimental arm was determined by the ROR score, Sein said. Patients with high-risk tumors, defined by an ROR score greater than 60, received the same chemoendocrine therapy administered in the control arm, he noted. In contrast, patients with low-risk tumors, defined by an ROR score below 60, received endocrine therapy alone, allowing chemotherapy to be omitted, he added.

In addition to evaluating outcomes in the overall study population, investigators conducted a focused analysis of patients with low-ROR tumors, Stein said. Because all low-risk patients in the control arm received chemotherapy plus endocrine therapy, while those in the test-directed arm received endocrine therapy alone, this subgroup effectively functioned as a randomized comparison between chemoendocrine therapy and endocrine therapy alone, Stein explained.

The OPTIMA trial was designed to determine whether genomic risk assessment could safely identify patients who could avoid chemotherapy without sacrificing treatment efficacy, Stein explained. By tailoring therapy according to tumor biology rather than relying solely on traditional clinicopathologic factors, the study sought to reduce overtreatment and spare patients the toxicities of chemotherapy while maintaining long-term outcomes, he concluded.