MammaPrint Genomic Profiling Predicts Anthracycline Benefit in HR+HER2- Early Breast Cancer, Guiding NCCN Guideline Update
核心洞察
Real-world FLEX Study data show MammaPrint (搜索) High Risk 2 patients had significantly improved 3-year invasive disease-free survival with anthracycline (搜索)-containing regimens (100% vs 94.8%, p=0.023).
MammaPrint (搜索) High Risk 1 patients showed no additional benefit from anthracyclines, with identical 3-year IDFS rates of 95.9% for both chemotherapy regimens.
The NCCN Guidelines now recognize MammaPrint (搜索) as the only genomic test to personalize anthracycline (搜索) use in HR+HER2- early-stage breast cancer (搜索).
Agendia has announced that new data from the prospective, real-world FLEX Study demonstrate MammaPrint (搜索)'s ability to predict which patients with hormone receptor-positive, HER2-negative (HR+HER2-) early-stage breast cancer (EBC) are most likely to benefit from anthracycline (搜索)-based chemotherapy. The findings, published in JCO Precision Oncology, have already prompted an update to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines), which now recognize MammaPrint as the only genomic test to guide personalized anthracycline use in this patient population.
"Patients with HR+HER2-negative breast cancer who are candidates for adjuvant chemotherapy continue to face uncertainty around whether they will derive meaningful benefit from anthracycline (搜索)-containing regimens," said Joyce O'Shaughnessy, M.D., principal investigator for the FLEX Study. "This long-standing clinical dilemma underscores the need for predictive biomarkers that can identify which patients are most likely to benefit from anthracyclines and who may safely avoid unnecessary toxicity."
FLEX Study Demonstrates Predictive Value of MammaPrint (搜索)
The observational study included 1,259 patients with stages I to III, HR+HER2- EBC, classified as MammaPrint (搜索) High Risk 1 (H1) or High Risk 2 (H2) and BluePrint (搜索) Luminal B. Patients received adjuvant chemotherapy with either anthracycline (搜索) and taxane-based chemotherapy (AC-T) or adjuvant taxane with cyclophosphamide (TC), with a median follow-up of 3.2 years. Inverse probability of treatment weighting (IPTW) was performed to balance clinical characteristics between treatment groups.
The key findings revealed a clear divergence in outcomes based on MammaPrint (搜索) risk classification. Patients with H2 tumors demonstrated significantly improved 3-year invasive disease-free survival (IDFS) with AC-T versus TC, with IDFS rates of 100% versus 94.8%—an absolute benefit of 5.2% (p=0.023). In contrast, patients with H1 tumors showed no significant difference in 3-year IDFS, with identical rates of 95.9% for both regimens, despite overlapping high-risk clinical features.
A statistically significant treatment-by-MammaPrint (搜索) interaction demonstrated that AC-T benefit increased with higher genomic risk (p=0.036), confirming that MammaPrint H2 classification is predictive of anthracycline (搜索) benefit.
"This study answers a question that randomized clinical trials have been unable to resolve, illustrating the value of genomic profiling to predict benefit from a specific cancer therapy," said William Audeh, M.D., M.S., Chief Medical Officer of Agendia and co-author of the study.
Biological Rationale: HRD Links to Anthracycline (搜索) Sensitivity
Additional data to be presented at the 2026 ASCO Annual Meeting provide mechanistic insight into why MammaPrint (搜索) High Risk 2 tumors may be particularly sensitive to anthracyclines. A real-world analysis of 1,298 patients from the FLEX Study evaluated the association between MammaPrint and BluePrint (搜索) classifications and homologous recombination deficiency (搜索) (HRD). Using both a 228-gene HRD signature and a refined 26-gene panel, researchers found that MP High Risk 2 tumors demonstrated significantly higher HRD scores than High Risk 1 tumors (both p<0.001).
Among Luminal tumors, Luminal H2 tumors had significantly higher HRD scores than Luminal H1 tumors across both HRD signatures (both p<0.001). Basal tumors demonstrated higher HRD scores than Luminal tumors within both H1 and H2 groups (all p=0.002), with Basal H2 tumors showing the highest overall HRD levels.
"These findings provide a biological rationale for the anthracycline (搜索) chemotherapy benefit observed in patients with MammaPrint (搜索) High Risk 2 tumors," said Steven Isakoff, M.D., Ph.D., Medical Oncologist and Clinical Director, Breast Oncology Program, Mass General Brigham Cancer Institute. "Following the recent NCCN Guidelines update recognizing MammaPrint as the only genomic test to personalize the use of anthracycline-based regimens in HR+HER2- early-stage breast cancer (搜索), the data further validate the assay's ability to stratify risk and guide treatment selection."
Integrating Molecular Subtyping and Immune Profiling in HER2+ Disease
A second ASCO 2026 presentation will highlight the integration of BluePrint (搜索) molecular subtyping with the ImPrint (搜索) immune signature to predict pathologic complete response (pCR) in HER2-positive EBC. In a cohort of 252 patients treated with neoadjuvant chemotherapy plus trastuzumab and pertuzumab, researchers found that 52% of HR+HER2+ tumors were classified by BluePrint as non-HER2 subtypes—Luminal A (6%), Luminal B (44%), and Basal (2%)—underscoring the genomic diversity within clinically HER2+ disease.
The highest pCR rates were observed in tumors classified as BP-HER2/ImPrint (搜索)+, indicating that patients whose tumors were genomically HER2-type and immune-active derived the greatest benefit from neoadjuvant therapy. In multivariate analysis, BluePrint (搜索) subtype and ImPrint status independently predicted pCR in HR+HER2+ disease after controlling for nodal status and tumor size.
"These findings demonstrate how integrating molecular subtyping with immune profiling may improve our ability to predict response to neoadjuvant therapy in HER2-positive early-stage breast cancer and may be hypothesis-generating for chemotherapy de-escalation studies," said Dr. Audeh.
Clinical Implications and the Toxicity Question
While anthracyclines are highly effective antitumor agents, they carry potentially serious toxicities including cardiotoxicity and secondary leukemias. Multiple randomized controlled trials—including the ABC trials, Plan B trial, MASTER trial, and DBCG 07-READ trial—have attempted to determine whether anthracycline (搜索)-free regimens are non-inferior to anthracycline-containing regimens in clinically high-risk HER2-negative EBC, but found no significant difference among HR+HER2- patients overall. The FLEX Study data now suggest that this lack of difference may be driven by the inclusion of patients without the genomic profile predictive of anthracycline benefit.
"The FLEX Study highlights the power of a multi-modal real-world evidence database to produce robust, clinically relevant data which not only inform treatment decisions, but also change clinical practice guidelines," Dr. Audeh added.