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About two thirds of patients with high-risk ER-positive, HER2-negative early breast cancer had similar outcomes whether or not they received chemotherapy alongside endocrine therapy, suggesting many may be able to safely avoid chemotherapy, according to findings from the phase 3 OPTIMA trial.

Patients with low-risk recurrence scores (≤ 60), identified using the 50-gene Prosigna test (Veracyte, Inc.), received endocrine therapy alone in the test-directed arm, whereas comparable patients in the control arm received chemotherapy followed by endocrine therapy. The corresponding 5-year invasive breast cancer-free survival rates were similar between the test and control arms: 93.6% vs 94.8%.

At most, adding chemotherapy would prevent about two invasive breast cancer events per 100 patients with low-risk recurrence scores. This represents a large population of patients aged 40 years or older with four to nine involved lymph nodes or stage IIIA tumors who would otherwise receive chemotherapy but would derive little, if any, benefit, lead investigator Robert Stein, MD, professor of breast oncology at the University College London, London, England, reported at the American Society of Clinical Oncology (ASCO) 2026.

Invited discussant Martine Piccart-Gebhart, MD, of Université Libre de Bruxelles, Brussels, Belgium, said the findings are practice-changing.

“I will now recommend a genomic assay for all post- and premenopausal women older than 40 years with any number of positive nodes,” Piccart-Gebhart said. “A low-risk genomic test result will now trigger shared decision-making based on trade-offs regarding the use of chemotherapy in the presence of endocrine therapy.”

Currently, tumor gene expression assays are widely used to assist chemotherapy decisions for postmenopausal women with early breast cancer who have up to three involved lymph nodes, but the evidence for their use in premenopausal patients and those with higher lymph node counts has been mixed or lacking.

In the OPTIMA trial, Stein and colleagues hypothesized that the number of involved nodes would not affect chemotherapy response in patients with low risk for recurrence scores.

Overall, the trial enrolled 4153 patients aged 40 years or older with ER-positive, HER2-negative early breast cancer and 0-9 positive axillary lymph nodes. Node-negative patients were eligible if their tumors met minimum size requirements.

Patients were randomized to standard chemotherapy followed by endocrine therapy or to treatment guided by Prosigna results, with chemotherapy omitted in those with recurrence scores of 60 or lower. Endocrine therapy in premenopausal women included ovarian function suppression in the absence of chemotherapy-induced ovarian insufficiency.

Patients were followed for a median of 4 years (interquartile range, 2-6 years). Patients in the two treatment groups were well balanced, Stein noted.

In the full population, the 5-year invasive breast cancer-free survival rate was 91.8% in patients randomized to standard treatment vs 90.3% in those randomized to the test-directed group (hazard ratio [HR], 1.03; 90% CI, 0.85-1.25), with the findings demonstrating the noninferiority of test-directed therapy (P 3% noninferiority = .006).

The corresponding 5-year invasive breast cancer-free survival rate among patients with low recurrence risk scores was 93.6% in the test-directed arm vs 94.8% in the control arm (HR, 1.06; 90% CI, 0.80-1.40), again demonstrating noninferiority (P noninferiority = .003).

Outcomes were generally consistent across menopausal status and nodal burden subgroups.

Stein noted, however, that the findings are limited by the exclusion of women younger than 40 years, the predominantly White patient population, and the follow-up of less than 5 years in most patients.

“We can’t say much about Prosigna in non-White populations and patients younger than 40,” he said.

Still, the findings indicate that the 50-gene test “can assist safe adjuvant chemotherapy decisions” for postmenopausal women and for premenopausal women aged 40 years or older who received ovarian function suppression, and those with four to nine involved lymph nodes or stage IIIA tumors, Stein explained.

The primary objectives of OPTIMA align with public health concerns surrounding overtreatment and cost-effectiveness, noted Piccart-Gebhart. In other words, can one forego adjuvant chemotherapy in patients considered at high clinical risk, but whose tumor multigene assay indicates low risk?

OPTIMA reinforces the evidence in postmenopausal women and provides encouraging findings in premenopausal patients, she said.

Two ongoing trials — OFSET in the US, and OPTIMA YOUNG in Europe — could provide independent confirmation in years to come, she noted, but the current findings can still have immediate practice-changing implications.

Piccart-Gebhart’s takeaway is that “gene expression signatures do allow safe tailoring of adjuvant chemotherapy in postmenopausal women and in premenopausal women older than 40 years receiving ovarian function suppression.”

Stein disclosed having relationships, including stock and other ownership interests, research funding, and or travel and accommodations expenses, with GlaxoSmithKline and Veracyte. Piccart-Gebhart disclosed having consulting or advisory roles, and/or receiving research funding to her institution, or other relationships with AstraZeneca, Frame Therapeutics, Immunomedics/Gilead Sciences, Gilead Sciences, Eli Lilly and Company, Menarini, MSD, NBE Therapeutics, Novartis, Oncolytics Biotech, Pfizer, Radius Health, Roche-Genentech, Seagen, Servier, and Synthon.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@medscape.net or on X: @SW_MedReporter.