New results from the international, randomized, phase III OPTIMA trial indicate that select patients with clinically high-risk, estrogen receptor–positive, HER2-negative early breast cancer who have a low risk of recurrence based on tumor gene expression testing may be able to safely avoid chemotherapy.1 Patients whose treatment was guided by their risk-of-recurrence (ROR) score on the Prosigna assay (PAM50-based gene expression assay) had invasive breast cancer–free survival comparable to that of patients who received standard chemoendocrine therapy, according to Robert Stein, PhD, FRCP, of University College London Hospitals, who presented the findings at the 2026 ASCO Annual Meeting. “OPTIMA demonstrates that the 50-gene Prosigna test identifies a group of about two-thirds of patients with estrogen receptor–positive HER2-negative early breast cancer who are unlikely to derive meaningful benefit from adjuvant chemotherapy,” he said. “At most, two recurrences will be prevented for every 100 patients treated with chemotherapy.”
A subgroup analysis confirmed that these findings also applied to premenopausal women aged 40 years or older who received ovarian function suppression, patients with four to nine positive lymph nodes, and those with stage IIIa tumors. “These findings are new,” he noted.
Rationale and Design for OPTIMA
Tumor gene expression assays are widely used to guide chemotherapy decisions for postmenopausal patients with early breast cancer and up to three positive lymph nodes, but evidence supporting their use in premenopausal patients has been mixed. In addition, no prospective evidence has supported their use in patients with more extensive lymph node involvement. According to Dr. Stein, “The OPTIMA hypothesis was that the number of involved nodes does not affect chemotherapy response for low test-score tumors.”
KEY FINDINGS
- The phase III OPTIMA trial found that select patients with clinically high-risk, estrogen receptor–positive, HER2-negative early breast cancer who have a low risk of recurrence based on Prosigna gene expression testing may be able to safely avoid chemotherapy.
- Patients whose treatment was guided by their risk-of-recurrence score had invasive breast cancer–free survival comparable to that of patients who received standard chemo-endocrine therapy.
- The findings also applied to premenopausal women aged 40 years or older who received ovarian function suppression, patients with four to nine positive lymph nodes, and those with stage IIIa tumors.
OPTIMA enrolled 4,429 individuals aged ≥ 40 years with up to nine positive lymph nodes; node-negative patients were required to have tumors larger than 3 cm. Patients were randomly assigned to either a control arm that received chemotherapy plus endocrine therapy, or a test-directed arm in which treatment was guided by the ROR score on the Prosigna assay. Those with an ROR score greater than 60, indicating high risk, received chemotherapy plus endocrine therapy, whereas those with an ROR score of 60 or lower receivedendocrine therapy alone. Premenopausal women aged 40 years or older without chemotherapy-induced ovarian insufficiency also received ovarian function suppression as part of their endocrine therapy.
Key Findings
After a median follow-up of 4.0 years, the 5-year invasive breast cancer–free survival rate in the complete per-protocol population was 91.8% in the standard chemo-endocrine therapy arm and 90.3% in the test-directed arm (hazard ratio [HR] = 1.03; noninferiority P = .006). Among patients with low ROR scores, the corresponding 5-year rates were 94.8% and 93.6%, respectively (HR = 1.06; noninferiority P = .003). Both hazard ratios met the trial’s prespecified noninferiority margin. Outcomes were consistent across subgroups, including by menopausal status and nodal involvement.
Subgroup analyses of patients with low ROR score tumors showed the following invasive breast cancer–free survival rates in the control vs the test-directed arm at 5 years:
- Premenopausal status: 95.5% vs 94.2% (HR = 1.04, 95% confidence interval [CI] = 0.60–1.80)
- Postmenopausal status: 94.5% vs 93.2% (HR = 1.14, 95% CI = 0.76–1.71)
- One to three positive lymph nodes: 95.2% vs 93.6% (HR = 1.11, 95% CI = 0.76–1.64)
- Four to nine positive lymph nodes: 93.1% vs 91.5% (HR = 1.19, 95% CI = 0.62–2.29)
In the complete per-protocol population, the 5-year distant recurrence–free survival rate was 94.1% in the control arm and 93.3% in the test-directed arm (HR = 1.04, 90% CI = 0.83–1.30). Among patients with low ROR scores, the corresponding rates were 97.0% and 96.0%, respectively (HR = 1.17, 90% CI = 0.82–1.66).
DISCLOSURE: Dr. Stein had personal financial disclosures for GlaxoSmithKline and Veracyte.
REFERENCE
1. Stein RC, Makris A, Macpherson IR, et al: First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer. 2026 ASCO Annual Meeting. Abstract 500. Presented May 30, 2026.
EXPERT POINT OF VIEW
Jame Abraham, MD, Enterprise Chair of the Department of Hematology and Medical Oncology and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine, shared his thoughts on OPTIMA1 with The ASCO Post, where he serves as Senior Deputy Editor.
Jame Abraham, MD
“The updated OPTIMA results are a valuable addition to the growing body of literature surrounding test-determined approaches to treatment decision–making for chemotherapy in this patient population. From MINDACT, RxPONDER, TAILORx, and now OPTIMA—involving 18,000 patients in four prospective trials—we know that ovarian suppression plus endocrine therapy is not inferior to endocrine therapy plus chemotherapy in the presence of a favorable multigene expression assay. In spite of different genomic predictors, endpoints, and even patient populations, the results are remarkably consistent,” he pointed out.
“But I will add a few caveats here. The follow-up in OPTIMA is only 4 years, which some would argue is too short to judge outcomes in an estrogen receptor–positive population. Longer follow-up will be very informative. Secondly, the NCCN Guidelines recommend Oncotype DX rather than Prosigna for genomic assays in early-stage breast cancer; therefore, many clinicians are not familiar with this test. How Prosigna’s ROR score squares with Oncotype DX and its more familiar recurrence score, which is our usual way of gauging risk, has not been worked out,” he cautioned.
“But the bottom line is this,” Dr. Abraham, a breast cancer specialist, concluded. “Treatment with ovarian suppression plus endocrine therapy in patients with favorable genomic signatures is not inferior to chemotherapy, despite the higher clinical features of these patients, and this means that many of them can safely avoid chemotherapy. As always, of course, it is a shared decision-making process with the patients.”
Dr. Stein remarked that although the follow-up duration is short, analyses across multiple trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) show that most of the chemotherapy effect on recurrence is seen during the first 5 years. Time-dependent changes have not been seen in any of the three related trials.
DISCLOSURE: Dr. Abraham has served on an advisory board for ThinkBio.Ai.
REFERENCE
1. Stein RC, Makris A, Macpherson IR, et al: First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer. 2026 ASCO Annual Meeting. Abstract 500. Presented May 30, 2026.
