Publication: ESMO 2026

Authors: Michael Gnant, Mehran Habibi, Adam Brufsky, Laila Samiian, Sasha Davis, Eduardo Dias, Virginia Borges, Kent Hoskins, VK Gadi, Cynthia Osborne, Rakhshanda Layeequr-Rahman, Alfredo Santillan, Harshini Ramaswamy, Raquel Weber, Andrea Menicucci, William Audeh and Joyce O’Shaughnessy.

Title: 70-Gene Signature Provides Prognostic Value Beyond Ki67 in HR+HER2– Early Breast Cancer (EBC)

Abstract

Background: Ki67 is used as a biomarker to help inform chemotherapy decisions in HR+HER2– EBC. However, its utility is limited by variability and lack of consensus on cutoffs. Genomic assays such as the 70-gene MammaPrint® (MP) provide prognostic risk stratification and are used to guide therapy decisions. Using real-world data, we evaluated MP prognostic performance among tumors with Ki67 ≥20%.

Methods: A total of 4,261 patients with HR+HER2– EBC enrolled in the prospective FLEX study (NCT03053193) with MP results and follow-up were included. Distant recurrence-free survival (DRFS) was evaluated (STEEP 2.0) among tumors with Ki67 ≥20% stratified by MP UltraLow + Low Risk (UL+LR), High Risk 1 (H1), or High Risk 2 (H2). Survival analyses were performed (3.2 yrs median follow up). Cox proportional hazards models assessed associations between MP, clinical features, and DRFS.

Results: Among tumors with Ki67 ≥20% (n=1,887), 34% were classified as UL or LR.  Within the Ki67 ≥20% cohort, 3‑yr DRFS was 98.3% for UL+LR compared with 92.9% for H2 (absolute diff. 5.4%, p=0.011). In the overall cohort, univariable analysis demonstrated prognostic value for both MP High Risk and Ki67 ≥20%, but only MP remained significant in the multivariable (H2 compared to UL+LR; HR 2.46, p=0.005). Among Ki67 ≥20% tumors, H2 was associated with decreased DRFS vs. UL+LR (HR 2.31, p=0.003), along with other clinical factors in the univariate analysis. In the multivariable, H2 remained prognostic (>2-fold increased risk) compared to UL+LR (HR 2.33, p=0.026; Table 1).

Conclusions:  In HR+/HER2– early breast cancer with Ki67 ≥20%, MammaPrint identifies a distinct low‑risk subgroup with favorable survival outcomes despite high proliferative activity. Patients classified as MammaPrint Low risk show excellent DRFS, albeit short follow up, demonstrating that genomic risk stratification provides greater prognostic value than Ki67 alone and can identify patients who may safely avoid chemotherapy.