NCCN Guidelines Now Recognize MammaPrint Testing to Guide Anthracycline Use in HR+/HER2- Breast Cancer
核心洞察
Updated NCCN (搜索) clinical practice guidelines now recognize the 70-gene expression profile MammaPrint (搜索), combined with the 80-gene BluePrint (搜索) assay, as tools to identify HR+/HER2 (搜索)- early-stage breast cancer patients who benefit most from anthracycline-based chemotherapy.
Real-world evidence from the FLEX study of 1,261 patients showed that those with High Risk 2 molecular subtypes achieved 100% three-year invasive disease-free survival with anthracycline therapy versus 89.3% with non-anthracycline regimens.
The guideline update represents a shift toward precision oncology, allowing clinicians to optimize specific drug classes based on tumor biology rather than making binary chemotherapy decisions.
Updated NCCN (搜索) clinical practice guidelines now recognize the 70-gene expression profile MammaPrint (搜索) as a tool to assist clinicians in identifying a specific subset of patients with hormone receptor-positive (HR+), HER2 (搜索)-negative (HER2-) early-stage breast cancer who may derive the greatest benefit from anthracycline-based chemotherapy regimens.
The update reflects a shift toward more granular precision oncology, moving beyond the binary decision of whether to administer chemotherapy and toward the optimization of specific drug classes based on tumor biology. According to the updated NCCN (搜索) guidelines, the 70-gene expression profile, in conjunction with the 80-gene molecular subtyping assay BluePrint (搜索), provides evidence to guide the use of anthracyclines, such as doxorubicin, in patients classified as having high-risk 2 (H2) luminal-type tumors.
Evidence From the FLEX Study
The guideline revision was primarily informed by real-world evidence from the ongoing observational FLEX study (NCT03053193), a large-scale, whole-transcriptome registry of patients with early-stage breast cancer. The three-year analysis included 1,261 patients with HR+/HER2 (搜索)- early-stage breast cancer who were followed for a median of 3.2 years.
Data from the FLEX trial, presented at the 2025 San Antonio Breast Cancer Symposium, demonstrated that tumors identified by the 80-gene assay as H2 molecular subtypes—characterized by specific genomic drivers of proliferation and inflammation—showed a significant clinical response to anthracycline-containing regimens compared with non-anthracycline-based chemotherapy.
The study compared two types of treatment: adjuvant taxane with cyclophosphamide (TC) and anthracycline and taxane-based chemotherapy (AC-T). For patients in the High Risk 2 and Luminal B group, those treated with TC had a significantly worse three-year invasive disease-free survival (IDFS) of 89.3%. In contrast, patients in this same category who received AC-T had a 100% three-year IDFS, representing an absolute benefit of 10.7% for the anthracycline-based regimen.
The data for patients with MammaPrint (搜索) High Risk 1 and BluePrint (搜索) Luminal B tumors showed different results. In this group, there was no significant difference in three-year IDFS between those who received AC-T (95.6%) and those who received TC (94.6%). This suggests that patients with High Risk 1 tumors do not derive a meaningful benefit from the addition of anthracyclines to their chemotherapy plan.
"I am delighted that oncologists finally have a way to identify HR+/HER2 (搜索)- early breast cancer patients who will benefit from anthracycline therapy," said Dr. Joyce A. O'Shaughnessy, principal investigator for the FLEX Study. "I think the biologic rationale and the data underpinning the observation that High Risk 2 Luminal breast cancer patients benefit from anthracycline therapy are quite strong."
Clinical Implications of Anthracycline Stewardship
Anthracyclines have long been a cornerstone of breast cancer treatment, but they are associated with significant long-term toxicities, most notably dose-dependent cardiotoxicity and a small but serious risk of treatment-related leukemia. Historically, the decision to include or omit an anthracycline has been based on clinical risk factors, such as nodal status or tumor size, rather than molecular characteristics.
By utilizing the 70-gene expression profile and 80-gene molecular subtyping assay, clinicians can now differentiate between high-risk 1 (H1) and H2 profiles. The FLEX data suggest that although both groups are considered genomically high risk, the H2 subset exhibits a unique sensitivity to anthracyclines. This allows for a more tailored approach: intensifying treatment for those with the H2 subtype while potentially sparing H1 patients the additional toxicity of anthracyclines if a nonanthracycline regimen is deemed appropriate.
Anthracycline-based chemotherapy regimens are among the most effective adjuvant treatments for early-stage breast cancer, capable of lowering the yearly risk of death by at least one third compared to not receiving chemotherapy. However, for some patients, the absolute benefit of this treatment may be small when compared to potential side effects.
Real-World Evidence Methodology
The FLEX study represents a shift in how clinical evidence is generated, utilizing an all-comers registry design that captures whole-transcriptome data from more than 14,000 patients. This methodology allows for the identification of smaller, biologically distinct subgroups that might be missed in traditional randomized controlled trials.
To ensure the data were reliable, researchers used propensity score matching to balance differences between the treatment groups. This process accounted for factors such as age, tumor size and nodal status for both the High Risk 1 and High Risk 2 groups separately.
"The NCCN (搜索) guideline update is based on the strongest real-world evidence to date that MammaPrint (搜索) can help identify which patients are most likely to benefit from anthracycline-based therapy," said Dr. William Audeh, chief medical officer at Agendia. He noted that the FLEX study reinforces the value of using precision genomics to tailor treatments to the underlying biology of a tumor.
The 70-gene expression profile remains the only genomic assay with FDA clearance for use in early-stage breast cancer and holds Category 1 recommendations in the NCCN (搜索) guidelines for both node-negative and node-positive (1 to 3 nodes) disease. This latest update further expands its utility from a prognostic risk-stratification tool to a predictive tool for therapeutic selection.