The OPTIMA trial presented at ASCO 2026 demonstrates that Prosigna-guided therapy is noninferior to standard chemotherapy plus endocrine therapy in high-risk ER-positive, HER2-negative early breast cancer. This landmark study provides robust evidence that genomic testing can safely guide treatment de-escalation, allowing clinicians to omit chemotherapy in appropriately selected patients without compromising invasive breast cancer–free survival outcomes.

Clinical Takeaway

The OPTIMA trial establishes Prosigna-guided therapy as a viable alternative to standard chemotherapy in high-risk ER-positive, HER2-negative early breast cancer. Patients with low-risk Prosigna scores (ROR ≤60) can safely receive endocrine therapy alone, avoiding chemotherapy without compromising invasive breast cancer–free survival outcomes.

Prosigna Test Profile

The Prosigna assay is a gene expression profiling test that analyzes 50 genes to classify breast tumors into intrinsic subtypes and provide a risk of recurrence score. The test utilizes NanoString nCounter technology to measure RNA expression from formalin-fixed, paraffin-embedded tissue samples.

  • Technology: RNA-based gene expression profiling using NanoString platform
  • Sample requirement: Formalin-fixed, paraffin-embedded tumor tissue
  • Output: Risk of recurrence score (0-100) and intrinsic subtype classification
  • Risk stratification: Low, intermediate, or high risk based on score thresholds

Target Population

The OPTIMA trial enrolled patients with high-risk ER-positive, HER2-negative early breast cancer who would typically be candidates for adjuvant chemotherapy based on traditional clinicopathologic factors.

  • Eligibility criteria:
    • ER-positive, HER2-negative early breast cancer
    • Age >40 years
    • 0–9 involved axillary lymph nodes
    • Tumors >30 mm if node-negative
    • Recommended to receive adjuvant chemotherapy based on clinical risk factors

Study Design

OPTIMA is a randomized, open-label, phase 3 noninferiority trial comparing Prosigna-guided therapy with standard chemotherapy plus endocrine therapy in high-risk early breast cancer.

  • Design: Randomized 1:1, multicenter, open-label noninferiority trial
  • Treatment arms:
    • Control arm: Standard chemotherapy + endocrine therapy
    • Experimental arm: Prosigna-guided therapy (endocrine alone if low risk, chemo + endocrine if high risk)
  • Enrollment: 4,429 randomized patients
  • Follow-up: Median 3.9 years (IQR 2.0–5.9)
  • Noninferiority margin: 3% absolute margin for 5-year invasive breast cancer–free survival in the per-protocol population

Primary and Secondary Endpoints

  • Primary endpoint:
    • Invasive breast cancer–free survival (IBCFS)
  • Secondary endpoints:
    • Additional analyses included outcomes within the low-ROR population and subgroup analyses by menopausal and nodal status.

Efficacy Outcomes

The OPTIMA trial met its primary noninferiority endpoint, demonstrating that a Prosigna-guided therapy strategy was noninferior to standard chemotherapy plus endocrine therapy for invasive breast cancer–free survival.

  • 5-year IBCFS: 91.5% in the control arm versus 90.4% in the test-directed arm
  • Hazard ratio: 0.99 (90% CI, 0.81–1.20), meeting the predefined noninferiority criterion
  • 280 IBCFS events occurred, with 66% representing distant recurrences
  • Approximately 68% of patients had low ROR score tumors (≤60)

Among patients with low-ROR tumors, 5-year IBCFS rates were 94.9% in the control arm and 93.7% in the test-directed arm (HR 1.06; 90% CI, 0.78–1.46), again demonstrating noninferiority.

Key Clinical Implications

✔ Prosigna testing can safely guide chemotherapy decisions in high-risk ER-positive, HER2-negative early breast cancer, with noninferior invasive breast cancer–free survival outcomes

✔ Approximately 68% of high-risk patients can avoid chemotherapy without compromising efficacy, reducing treatment burden and toxicity

✔ Genomic testing integration into clinical practice can personalize treatment decisions beyond traditional clinicopathologic factors

Bottom Line

The OPTIMA trial demonstrated that a Prosigna-guided therapy strategy was noninferior to standard chemotherapy plus endocrine therapy in patients with high-risk ER-positive, HER2-negative early breast cancer. Approximately 68% of patients had low ROR score tumors and could safely avoid chemotherapy without compromising invasive breast cancer–free survival outcomes. The findings support the use of genomic risk assessment to guide adjuvant treatment decisions, including in premenopausal women receiving ovarian function suppression and patients with substantial nodal involvement.

Sources:

  • 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. J Clin Oncol. 2026;44(suppl 16):500. Presented at: American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL.
  • Veracyte Inc. Landmark OPTIMA trial delivers practice-changing evidence that Veracyte’s Prosigna test identifies patients with high-risk breast cancer who can safely avoid chemotherapy. News release. May 29, 2026. Accessed June 11, 2026.