MammaPrint predicts chemotherapy benefit in HR+HER2- early breast cancer: FLEX Registry real-world data

Abstract

Background: Gene expression assays help personalize adjuvant chemotherapy decisions for hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC). The 70-gene risk of distant-recurrence signature, MammaPrint, demonstrated clinical utility in guiding chemotherapy de-escalation in genomically low risk patients in the MINDACT trial. This study evaluates MammaPrint as a continuous predictor of chemotherapy benefit in HR+HER2- EBC using real-world data (RWD) from the FLEX Registry.

Methods: The study evaluated 1002 patients treated with endocrine therapy (ET) only or ET with chemotherapy (ET+CT) enrolled in FLEX (NCT03053193) with 5-year median follow-up. Propensity-score matching balanced treatment groups by menopausal status, T-stage, and nodal status. The primary endpoint was distant recurrence-free interval (DRFI). Regression and Cox proportional hazards models assessed chemotherapy benefit across MammaPrint Index (MPI) risk.

Results: Most patients were postmenopausal (70.1%), node-negative (70.0%), and had grade 2 tumors (51.2%). The regression models showed that MPI strongly predicted 5-year DRFI in ET only (R2 = 0.99, P < .001) and ET + CT (R2 = 0.90, P < .001) groups, corresponding to an average absolute chemotherapy benefit of 5.6% in High 1 and 10.9% in High 2. Minimal improvement in DRFI with chemotherapy was observed for Low (1.7%) and UltraLow (<1.0%) risk groups. A multivariate Cox model with an MPI-by-treatment interaction term demonstrated that increasing MPI risk was associated with greater chemotherapy benefit on DRFI (HR = 0.15, P = .047). Chemotherapy benefit was significantly associated with premenopausal status, but not age, T-stage, nodal status, or grade.

Conclusions: These RWD from the FLEX Registry demonstrate that MPI is predictive of both DRFI prognosis and chemotherapy benefit in HR+HER2- EBC. (NCT03053193).

Figure 1.

χ² comparison of distribution of patients’ clinical characteristics across MammaPrint Index. Frequency of A) pre/peri- and postmenopausal status, B) tumor grade, C) lymph node status, and D) tumor stage across MammaPrint Index. Abbreviation: LN = lymph node.

Figure 2.

The MammaPrint Index and prediction of risk of distant recurrence as a continuous variable for HR+HER2- breast cancer patients. Likelihood of distant recurrence free interval (DRFI) event risk as a continuous function of the MammaPrint Index for ET only and ET+CT treated patients. The dashed curves indicate 95% CI for the respective treatment groups. The MammaPrint Index and Risk categories are denoted on the x-axis. Percent average and percent range of risk for each treatment and MammaPrint Risk groups are defined within the shaded box. Abbreviations: ET = endocrine therapy; CT = chemotherapy; CI = confidence interval.

Figure 3.

Likelihood ratio tests of the interaction of chemotherapy treatment with MammaPrint Index (MPI) and clinical variables. This figure shows the same data presented in Table 2, but on a natural logarithmic scale. Data represented as HR (95% CI, P-value). P < .05 indicates significant risk factor. A significant interaction term suggests that the effect of chemotherapy on DRFI varies according to the status of the indicated variable. In this table, the association between chemotherapy use and DRFI is influenced by MPI. The HR of 0.15 for MPI indicates that for each 1-unit change toward higher MPI Risk, patients derive significantly greater benefit from chemotherapy, with an 85% reduction in the risk of a DRFI event. Abbreviations: HR = hazard ratio; CI = confidence interval.