Clinical Summary: 

• Design/Population: The international, phase 3 OPTIMA trial enrolled patients over 40 with HR-positive, HER2-negative early breast cancer and 0-9 positive lymph nodes. Patients were randomized to standard chemoendocrine therapy or a Prosigna (PAM50)–guided treatment strategy, in which patients with low risk of recurrence (ROR ≤60) received endocrine therapy alone.
• Key Outcomes: The trial met its primary noninferiority end point, with 5-year invasive breast cancer–free survival rates of 90.4% in the Prosigna-guided arm and 91.5% in the standard-treatment arm. Among patients with low ROR scores, outcomes remained noninferior despite omission of chemotherapy, with no significant differences across menopausal status or nodal burden subgroups.
• Clinical Relevance: These findings demonstrate that approximately 68% of patients with HR-positive, HER2-negative early breast cancer can safely avoid chemotherapy, including premenopausal women receiving ovarian function suppression and patients with substantial nodal involvement.

Robert Stein, PhD, University College London, London, United Kingdom, discusses results from the phase 3 OPTIMA trial evaluating whether Prosigna (PAM50) genomic testing can guide chemotherapy decisions in patients with HR-positive, HER2-negative early breast cancer. The study enrolled more than 4,400 patients across 6 countries and represents one of the largest randomized evaluations of genomic assay–directed treatment selection.

The trial demonstrated that patients with low-risk Prosigna scores achieved outcomes comparable to those receiving routine chemoendocrine therapy despite omission of chemotherapy. Importantly, the benefit of a test-directed strategy was maintained across clinically important subgroups, including premenopausal women treated with ovarian function suppression and patients with 4 or more involved lymph nodes, supporting broader implementation of genomic-guided treatment de-escalation.

Dr Stein presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hello, I'm Rob Stein, I'm a professor of medical oncology at University College London in England. I'm talking about the OPTIMA trial.

This is a large randomized clinical trial in hormone receptor-positive, HER2-negative early breast cancer looking at ways of reducing unnecessary chemotherapy use in this population. We recruited 4,429 patients from six countries over the course of nine years. Patients were aged 40 years or older, and the oldest participant was 84 years old. Patients eligible for the trial had ER-positive, HER2-negative early breast cancer and had been recommended to receive chemotherapy. Most patients had node-positive disease, although node-negative patients with tumors larger than 30 mm were also eligible. 

Patients were randomized between two arms. The first arm was the control arm, in which everybody received standard treatment consisting of chemotherapy followed by endocrine therapy, or chemoendocrine therapy. In the test-directed arm, all patients underwent Prosigna, or PAM50, testing. Patients whose tumors had a high risk-of-recurrence, or ROR, score greater than 60 received the same chemoendocrine therapy as the control arm. Patients with low ROR score tumors, defined as 60 or below, received endocrine therapy alone. Premenopausal women treated without chemotherapy also received ovarian function suppression unless they developed chemotherapy-induced ovarian insufficiency. The study used a noninferiority design. What we wanted to show was that outcomes in the test-directed arm would not be meaningfully worse than outcomes in the control arm.

We now have a median follow-up of 3.9 years, and 280 invasive breast cancer–free survival events have occurred. The 5-year invasive breast cancer–free survival rate was 91.5% in the control arm and 90.4% in the test-directed arm. The hazard ratio was 0.99, and the study met its predefined noninferiority endpoint. So overall, we saw no meaningful difference in recurrence rates between the two treatment approaches. 

We also looked specifically at the subgroup of patients with low ROR score tumors, which represented about 68% of the study population. In the control arm, these patients still received chemoendocrine therapy because all patients in that arm received chemotherapy. In the test-directed arm, they received endocrine therapy alone. Effectively, this created a comparison between endocrine therapy alone and chemoendocrine therapy in patients with low-risk tumors. Again, we saw no meaningful difference. The 5-year invasive breast cancer–free survival rates were 94.9% and 93.7%, respectively, and this analysis also met the predefined noninferiority criteria. 

We then performed formal statistical analyses to estimate the potential benefit of chemotherapy in these patients. We cannot be certain that chemotherapy provided any benefit in the low-ROR population. However, if there was a benefit, our data suggest that at most about two patients out of every hundred treated with chemotherapy would have a recurrence prevented.

We also examined important subgroups. We looked at premenopausal women, all of whom received ovarian function suppression when treated without chemotherapy, and again we saw no difference in outcome. This is the first time this has been demonstrated in a randomized study.

We also looked at patients with more extensive nodal involvement, including those with four to nine positive lymph nodes, and again observed no significant difference in outcome. Importantly, there was no significant heterogeneity of treatment effect across subgroups, including menopausal status and nodal status. 

What OPTIMA has shown is that approximately two-thirds of patients with ER-positive, HER2-negative early breast cancer who have low ROR score tumors can safely avoid chemotherapy without compromising outcomes. The study provides evidence supporting test-directed chemotherapy decisions, including in premenopausal women receiving ovarian function suppression and in patients with higher levels of nodal involvement. We hope these findings will help change clinical practice and allow many patients to avoid unnecessary chemotherapy.

Source: 

Stein R, 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. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 500.