NCCN Update Supports MammaPrint to Guide Anthracycline Use in Breast Cancer

Updated NCCN clinical practice guidelines now recognize the 70-gene expression profile MammaPrint as a tool to assist clinicians in identifying a specific subset of patients with hormone receptor–positive (HR+), HER2-negative (HER2–) early-stage breast cancer who may derive the greatest benefit from anthracycline-based chemotherapy regimens.¹

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 guidelines,² the 70-gene expression profile, in conjunction with the 80-gene molecular subtyping assay BluePrint, provides evidence to guide the use of anthracyclines, such as doxorubicin, in patients classified as having high-risk 2 (H2) luminal-type tumors.¹

Evidence From the FLEX Study

The guideline revision was primarily informed by real-world evidence from the ongoing observational FLEX study (NCT03053193),³ a large-scale, whole-transcriptome registry of patients with early-stage breast cancer. 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 (Table).⁴

"I am delighted that oncologists finally have a way to identify [patients with] HR+/HER2– early breast cancer who will benefit from anthracycline therapy," Joyce O’Shaughnessy, MD, principal investigator for the FLEX study, said in a news release.¹ "I think the biologic rationale and the data underpinning the observation that [patients with H2] luminal breast cancer 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 (such as docetaxel and cyclophosphamide) is deemed appropriate.

The Role of Real-World Data

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.

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 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.

REFERENCES

1. Agendia announces NCCN guideline update recognizing MammaPrint to guide personalized anthracycline use in HR+/HER2- early‑stage breast cancer. News release. Agendia Inc. January 20, 2026. Accessed January 20, 2026. https://tinyurl.com/36s73xzn

2. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 1.2026. Accessed January 20, 2026. https://tinyurl.com/3v9vy9x4

3. MammaPrint, BluePrint, and full-genome data linked with clinical data to evaluate new gene EXpression profiles (FLEX). ClinicalTrials.gov. Updated August 20, 2025. Accessed January 20, 2026. https://clinicaltrials.gov/study/NCT03053193

4. O’Shaughnessy J, Brufsky A, Graham CL, et al. Differential benefit of anthracycline-based chemotherapy in MammaPrint High 1 and high 2 Luminal-type early-stage breast cancer: results from the FLEX registry. Poster presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Poster PS2-07-03.