Every woman who receives a diagnosis of breast cancer is unique and requires a personalized treatment plan. An essential part of this plan is to understand the chance that breast cancer may have spread beyond the breast and could come back if not treated appropriately. The “risk” of this happening is different for every individual, and there are many pieces of information used to estimate this “risk of recurrence”. Because the goal of a personalized treatment plan is to reduce an individual’s risk of breast cancer recurrence, all available information, both clinical and genomic, is gathered to allow the physicians to make the best decisions.
One term that may create confusion, and anxiety, is when a woman is told their early-stage breast cancer is “High Risk”. For hormone receptor-positive breast cancer, this means that hormone therapy alone may not sufficiently reduce the risk of recurrence. Chemotherapy may be recommended to help lower that risk more effectively. Typically, ‘high risk’ is based on clinicopathologic features, such as tumor size, lymph node involvement, grade, or other clinical features. However, when diagnosed with early-stage breast cancer, your physician will likely order a genomic test, like MammaPrint. Results may come back as MammaPrint UltraLow Risk, Low Risk, High Risk 1 or High Risk 2. Although both use the term ‘high risk’, they are based on different analyses of the cancer, with genomic information provider deeper insights into the tumor biology.
Clinical risk is based on characteristics doctors can evaluate through imaging, pathology, and other traditional clinical features. MammaPrint provides a genomic assessment of distant recurrence risk by analyzing the activity of 70 genes within the tumor itself.
While clinical features remain an important part of treatment planning, genomic testing adds another layer of information by directly evaluating tumor biology. MammaPrint was clinically validated through studies linking genomic profiles with actual patient outcomes. Together, clinical and genomic information provide a more complete picture of recurrence risk than either approach alone and can help physicians develop more personalized treatment plans.
For many patients with early-stage breast cancer, a MammaPrint High Risk result supports the use of chemotherapy as part of treatment planning. Research continues to improve our understanding of the biological diversity that exists within MammaPrint High Risk breast cancers. Additional genomic information from BluePrint molecular subtyping can provide a deeper understanding of the pathways driving tumor behavior and may help inform treatment selection beyond traditional clinicopathologic factors.
Key Takeaways
- Clinical High Risk and MammaPrint High Risk provide different but complementary information.
- MammaPrint High Risk tumors are more likely to benefit from chemotherapy than MammaPrint Low Risk tumors.³
- MammaPrint further classifies High Risk tumors as High Risk 1 (H1) and High Risk 2 (H2).⁴
- BluePrint molecular subtyping provides additional insight into tumor biology beyond traditional pathology.⁵⁻⁷
- Research suggests that different MammaPrint and BluePrint subgroups may experience different responses to chemotherapy.⁵⁻⁷
What Is the Difference Between Clinical High Risk and Genomic High Risk?
Historically, recurrence risk was estimated using clinicopathologic features such as tumor size, lymph node involvement, tumor grade, hormone receptor status, HER2 status, and patient age. These factors remain an important part of treatment planning and continue to guide treatment recommendations today.
However, patients with similar clinical characteristics do not always experience the same outcomes. Two tumors with similar size, grade, and lymph node involvement may have very different underlying biology and therefore different risks of recurrence.
Genomic testing was developed to provide additional insight into tumor behavior. Rather than focusing solely on what a tumor looks like under a microscope, genomic testing evaluates patterns of gene activity within the tumor itself. This information can help physicians better understand how a cancer may behave over time and how likely it is to recur after treatment.
The landmark MINDACT trial (NCT00433589) demonstrated that many patients with clinically high risk breast cancer but MammaPrint Low Risk result had excellent outcomes without chemotherapy, highlighting the importance of understanding both clinical risk and genomic risk when making treatment decisions.¹˒²
What Does a MammaPrint High Risk Result Mean?
MammaPrint evaluates the expression of 70 genes associated with breast cancer behavior and recurrence risk. Unlike traditional clinical factors alone, MammaPrint was clinically validated through studies linking genomic profiles with actual patient outcomes, allowing physicians to incorporate genomic information alongside standard pathology findings when discussing treatment options.¹˒²
A MammaPrint High Risk result indicates that a tumor has biologic characteristics associated with a higher likelihood of distant recurrence compared with a MammaPrint Low Risk tumor. This information can help identify patients who are more likely to benefit from chemotherapy as part of their treatment plan.¹˒²˒³
Evidence from the MINDACT trial established the clinical utility of MammaPrint by demonstrating that some patients with clinically high risk disease but MammaPrint Low Risk results could safely avoid chemotherapy without compromising outcomes.¹˒² More recently, the FLEX Study (NCT03053193), the world’s largest early breast cancer genomics trial, demonstrated that patients with MammaPrint High Risk tumors derived greater benefit from chemotherapy than patients with MammaPrint Low Risk tumors and that chemotherapy benefit generally increased as genomic risk increased across the MammaPrint Index.³
In addition, a recent JCO Precision Oncology 2026 publication from FLEX further refined treatment insights within the MammaPrint High Risk population, demonstrating that patients with MammaPrint High 2 tumors experienced clinically meaningful benefit from anthracycline-containing chemotherapy, whereas those with MammaPrint High 1 tumors did not derive additional benefit despite having overlapping high-risk clinical features.
These findings highlight the ability of MammaPrint to identify biologically distinct subgroups within genomic High Risk group and support more precise chemotherapy regimen selection based on tumor biology rather than clinicopathologic features alone.
Together, these findings support the use of genomic testing alongside traditional clinical factors when discussing treatment options.
Looking Beyond Risk with BluePrint Molecular Subtyping
While MammaPrint helps assess recurrence risk, the BluePrint 80-gene assay provides additional information about the biology driving tumor growth.
Traditional pathology classifies tumors according to hormone receptor and HER2 status assigned by conventional immunohistochemistry (IHC) testing. BluePrint evaluates gene-expression patterns within the tumor and classifies breast cancers into molecular subtypes, including Luminal-type, HER2-type, and Basal-type disease.
Importantly, all of these BluePrint molecular subtypes can be found among patients with MammaPrint High Risk result. Studies have shown that BluePrint classifications do not always align with classifications assigned by conventional IHC testing. In some cases, tumors that appear similar by traditional pathology exhibit different molecular characteristics when evaluated using genomic testing.⁵⁻⁷
Furthermore, a recent 2026 publication by Sonya Reid et al. in npj Breast Cancer demonstrated that biologically aggressive BluePrint Basal-type tumors are disproportionately represented among Black women with HR+/HER2− early breast cancer. Specifically, more than twice as many Black women had genomically Basal-type tumors compared with White women, highlighting the importance of molecular subtyping to identify aggressive tumor biology that may not be apparent from clinicopathologic features alone. The study further showed that outcomes were driven by genomic risk and molecular subtype rather than race, underscoring the value of MammaPrint and BluePrint in enabling more precise, biology-based treatment decisions.
For this reason, pathology findings and genomic test results should both be considered when discussing treatment options with a physician. Together they provide a more comprehensive understanding of tumor biology than either approach alone.⁵⁻⁷
MammaPrint and BluePrint Together Help Refine Treatment Response
One of the most important goals of modern breast cancer research is understanding why some tumors respond differently to treatment than others.
Research from studies including NBRST (Neoadjuvant Breast Registry Symphony Trial; NCT01479101) has demonstrated that treatment response can vary across both MammaPrint genomic risk groups and BluePrint molecular subtypes. Differences in pathologic complete response (pCR) rates have been observed among these groups, suggesting that both recurrence risk and tumor biology contribute to treatment sensitivity.⁵⁻⁷
These findings reinforce the concept that even tumors that appear similar using traditional clinical measures may respond differently to treatment because of underlying biologic differences.
As our understanding of tumor biology continues to evolve, MammaPrint and BluePrint are helping researchers and physicians in the FLEX Study better understand the factors associated with treatment response and patient outcomes.
Questions You Can Ask Your Oncologist
- What does my MammaPrint result mean for my treatment plan?
- How does my genomic risk compare with my clinical risk factors?
- Is my tumor classified as MammaPrint High Risk 1 or High Risk 2?
- Was BluePrint testing performed? If so, what molecular subtype was identified?
- What benefit is expected from chemotherapy with my particular breast cancer?
- How do my pathology findings and genomic results fit together?
- Are there additional treatment options I should discuss with my care team?
Key Takeaway
A MammaPrint High Risk result provides genomic information that complements traditional clinical risk assessment and can help guide treatment discussions. Clinical risk and genomic risk measure different aspects of breast cancer and are most informative when considered together.
Together, MammaPrint and BluePrint, help physicians develop a more comprehensive understanding of breast cancer biology and support personalized treatment planning.
Ongoing research from studies such as MINDACT, FLEX, ISPY-2 and NBRST continues to expand our understanding of how genomic testing can inform prognosis and treatment response. As new evidence emerges, MammaPrint and BluePrint continue to advance the precision of breast cancer care.
Important Information
This article is intended for educational purposes only and should not be considered medical advice. Treatment decisions should always be made in consultation with your oncology team. Individual recommendations depend on many factors, including clinical characteristics, pathology findings, genomic test results, medical history, and personal preferences. Discussion of MammaPrint, BluePrint, and published research is intended to provide information about scientific studies and should not be interpreted as a recommendation for any specific treatment.
References
- Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729.
- Piccart M, van’t Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: Updated results of the phase 3 randomized MINDACT trial. Lancet Oncol. 2021;22(4):476-488.
- Brufsky AM, Hoskins KF, Conter HJ, et al. MammaPrint predicts chemotherapy benefit in HR+/HER2− early breast cancer: FLEX Registry real-world data. JNCI Cancer Spectr. 2025.
- O’Shaughnessy J, Brufsky AM, Rahman RL, et al. Prediction of anthracycline benefit in hormone receptor-positive, HER2-negative early-stage breast cancer by the MammaPrint 70-gene signature. JCO Precis Oncol. 2026.
- Whitworth PW, Beitsch PD, Pellicane JV, et al. Distinct neoadjuvant chemotherapy response and 5-year outcome in patients with estrogen receptor-positive, HER2-negative breast tumors reclassified as Basal-type by the 80-gene signature. JCO Precis Oncol. 2022.
- Whitworth PW, Beitsch PD, Murray MK, et al. Genomic Classification of HER2-Positive Patients With 80-Gene and 70-Gene Signatures Identifies Diversity in Clinical Outcomes With HER2-Targeted Neoadjuvant Therapy. JCO Precis Oncol. 2022.
- Beitsch PD, Whitworth PW, Baron P, et al. Pertuzumab/trastuzumab/CT improves pathologic complete response in HER2-positive breast cancer using BluePrint molecular subtyping. Ann Surg Oncol. 2017;24(3):669-675.
