After a diagnosis of early-stage hormone receptor–positive (HR+) and HER2-negative (HER2–) breast cancer, conversations with your oncology team about treatment options may include whether chemotherapy should be part of your care.

One of the most important things to understand is that there are two separate decisions involved:

1. Can chemotherapy help me?
2. If chemotherapy is recommended, what type of chemotherapy is best for me? (There are different kinds of chemotherapy that may be more or less effective for a particular type of tumor.)

Current advances in genomic testing have helped clarify the first decision — identifying patients with early-stage breast cancer who can safely avoid chemotherapy and those who will likely benefit from it.^1,2

Emerging data show how genomic tests like MammaPrint + BluePrint can help refine the second decision: The type of chemotherapy you may need, such as the inclusion of anthracycline — a powerful chemotherapy agent that can offer additional benefit in some cancers when added to the more commonly used taxane-based regimens for HR+/HER2− breast cancer.

Data presented at the 2025 San Antonio Breast Cancer Symposium (SABCS),³ and now referenced in the most recent NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 2.2026, suggests that patients with MammaPrint High Risk 2, early-stage HR+/HER2− breast cancer may benefit from the addition of anthracyclines to taxane-based chemotherapy.

Key Takeaways

• Not all patients with early-stage HR+/HER2− breast cancer require chemotherapy.
• Among patients who do require chemotherapy, not all need anthracycline-containing regimens.
• Anthracyclines are powerful and effective drugs but carry the risk for additional side effects, so should be used only when necessary.
• Clinical features alone (tumor size, lymph nodes, grade) do not reliably predict who benefits most from anthracyclines.
• Emerging evidence suggests genomic risk classification may help refine chemotherapy selection.
• This evolving evidence is now referenced in the NCCN Guidelines (Version 2.2026).

How to Determine Whether Chemotherapy Is Needed and How Risk is Traditionally Assessed by Oncologists

For patients with early-stage HR+/HER2− breast cancer, the first question is whether chemotherapy is necessary in addition to surgery and endocrine therapy.

Historically, doctors assessed recurrence risk using:

• Tumor size
• Lymph node involvement
• Tumor grade
• Patient age
• Presence of lymphovascular invasion

Patients with larger tumors or positive lymph nodes were often classified as “high risk” and recommended chemotherapy.

However, clinical features do not always reflect true  tumor biology (risk of recurrance and pathways driving tumor growth) and how it might respond to therapy. For example, two patients with similar tumor size and nodal status can have different underlying tumor biology and could be considered for different types of treatments.

The Role of Genomic Testing

Genomic tests analyze gene activity inside the tumor and provide biological insight into what is driving a tumor’s growth and how likely the tumors will metastasize in the future.

The MINDACT trial¹ showed that patients with early-stage breast cancer who had high clinical risk, but low genomic risk by MammaPrint, had excellent long-term outcomes without chemotherapy, suggesting MammaPrint was a better predictor of tumor biology than clinical risk alone. This trial helped establish that some patients with clinically high risk HR+/HER2− breast cancer can safely avoid chemotherapy altogether.

For patients whose tumors are classified as genomically high risk, data demonstrate that they are more likely to benefit from chemotherapy.²

This leads to the second decision.

If Chemotherapy Is Needed, When and What Type?

Once chemotherapy is recommended, patients with early-stage HR+/HER2− breast cancer often face multiple treatment decisions with their physicians. This includes whether to receive neoadjuvant chemotherapy (given before surgery) and a choice between two general regimens: anthracycline-containing regimens with a taxane and cyclophosphamide or non-anthracycline regimens with a taxane and cyclophosphamide.

Anthracycline-Containing Regimens (e.g., AC-T or TAC)

These regimens include:

• An anthracycline (such as doxorubicin: [Adriamycin® or Doxil®])
• A taxane (such as paclitaxel [Adriamycin® or Doxil®] or docetaxel [Taxotere®])
• Cyclophosphamide (Cytoxan®)

Non-Anthracycline Regimens (e.g., TC)

These regimens typically include:

• A taxane
• Cyclophosphamide

Large international analyses involving tens of thousands of patients with early-stage breast cancer have shown that anthracycline- and taxane-based chemotherapy regimens reduce the risk of recurrence and breast cancer–related death compared with older chemotherapy approaches.⁴

However, the addition of anthracyclines also carry potential risks:

• Dose-related cardiotoxicity (effects on heart function)^5,6
• Rare risk of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)⁷

Because of these risks, doctors aim to use anthracyclines when the added benefit justifies exposure.

Several major clinical trials comparing anthracycline–taxane regimens with taxane-based regimens alone have shown similar outcomes in many patients with early-stage HR+/HER2− breast cancer — even in patients with high-risk clinical features.

This raised an important question:

If treatment outcomes are often similar, how do we determine which patients truly benefit from the addition of anthracyclines?

Why Determining Clinical Risk Alone Is Not Enough

In observational and randomized studies, traditional factors such as:

• Lymph node positivity
• Larger tumor size
• Higher tumor grade

have not consistently predicted additional benefit from anthracycline-containing therapy among patients with early-stage HR+/HER2− breast cancer.^8–11

In fact, some patients with small tumors and no lymph node involvement may have biologically aggressive disease, while others with larger tumors may not.

Clinical features provide part of the picture, but tumor biology offers a deeper layer of insight. Understanding tumor biology is similar to opening the hood of a car. From the outside, two cars may look the same, but what is happening under the hood can be very different. Genomic tests help doctors look “under the hood” of a tumor to better understand how it behaves and whether certain treatments are more likely to help.

Emerging Evidence: Biology May Influence Anthracycline Benefit

At SABCS 2025, researchers presented real-world registry data examining outcomes in patients with early-stage HR+/HER2− breast cancer whose tumors were classified as genomically high risk by MammaPrint and Luminal B-Type by BluePrint genomic testing.³

Within this group, two biologic subtypes were evaluated:

• MammaPrint High Risk 1 (H1)
• MammaPrint High Risk 2 (H2)

The findings suggested:

• Patients with H1 tumors had similar outcomes whether treated with anthracycline-containing chemotherapy or taxane-based therapy without anthracycline.
• Patients with H2 tumors appeared more likely to benefit from anthracycline-containing therapy, with fewer early recurrences observed when anthracycline was included.

Although these findings were derived from observational data rather than a randomized trial, they were considered clinically meaningful and are now referenced in the 2026 update of the NCCN Clinical Practice Guidelines in Oncology (Version 2.2026).

This signals that the oncology community recognizes that genomic stratification by MammaPrint + BluePrint can help inform the type of adjuvant chemotherapy patients may need.

Why Might Some Tumors Respond Differently?

Research suggests that tumors classified as High Risk 2 may exhibit¹²:

• Higher rates of tumor cell division
• More immune-related gene expression
• Lower estrogen-associated cellular activity
• Molecular features that overlap with more aggressive cancers

These biologic characteristics may contribute to increased sensitivity to anthracycline-containing regimens. In the registry data presented, early recurrences appeared more common among patients with High Risk 2 tumors when anthracycline was omitted.

In contrast, tumors classified as High Risk 1 may not demonstrate the same biologic features associated with anthracycline responsiveness.

What NCCN Recognition Means

The NCCN Guidelines are widely used across oncology practices both within the United States and outside the United States.

When emerging evidence is referenced in the NCCN Guidelines, it indicates that expert panels consider the data clinically relevant.

The NCCN Guidelines (Version 1.2026) acknowledge emerging evidence suggesting genomic risk classification may help inform chemotherapy regimen selection in patients with early-stage HR+/HER2− breast cancer.

Although this does not mandate treatment decisions, it does support individualized and shared treatment decision making with patients and physicians.

Safety and Monitoring with Anthracycline Treatments

Cardiac Risk

Anthracyclines can affect heart function, particularly at higher cumulative doses. To address these concerns, physicians typically:¹³

• Assess baseline cardiac function
• Monitor periodically during therapy
• Adjust treatment if needed

With modern monitoring strategies, most patients complete treatment safely.

Secondary Malignancy Risk

Therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is rare but recognized. While the absolute risk is low, this potential complication is part of informed consent discussions.⁷

Practical Decision Pathway

Breast cancer treatment is evolving from broad risk categories to biologic precision.

For patients with early-stage HR+/HER2− breast cancer, genomic testing can play an important role in shaping your treatment plan. Here’s how that decision-making process may look like:

1. Confirm stage and hormone receptor/HER2 status.
2. Assess clinical risk.
3. Determine genomic risk classification.
4. Estimate chemotherapy benefit.
5. Evaluate whether tumor biology suggests additional benefit from anthracycline.
6. Engage in shared decision-making.

Frequently Asked Questions

Do all patients with early-stage HR+/HER2− breast cancer need anthracyclines?

No. Many patients do well with non-anthracycline regimens, particularly when biological features suggest limited incremental benefit.^4,8–11

Why not give anthracycline to everyone?

While effective, anthracyclines carry additional risks. Treatment decisions aim to balance benefit and long-term safety.^6,7

Can genomic testing help guide chemotherapy intensity?

Emerging evidence suggests genomic classification by MammaPrint + BluePrint may help refine not only whether chemotherapy is needed but also which regimen may be most appropriate.³

References

1. 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 with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476-488. doi:10.1016/S1470-2045(21)00007-3
2. 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;9(5). doi:10.1093/JNCICS/PKAF079
3. O’Shaughnessy J, Brufsky A, Graham CL, et al. Abstract PS2-07-03: Improved 3-year IDFS with anthracycline-based therapy for patients with 70-gene signature High 2, Luminal B, HR+HER2- early-stage breast cancer. Clinical Cancer Research. 2026;32(4_Supplement):PS2-07-03. doi:10.1158/1557-3265.SABCS25-PS2-07-03
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023;401(10384):1277-1292. doi:10.1016/S0140-6736(23)00285-4
5. Larsen CM, Garcia Arango M, Dasari H, et al. Association of Anthracycline With Heart Failure in Patients Treated for Breast Cancer or Lymphoma, 1985-2010. JAMA Netw Open. 2023;6(2):e2254669-e2254669. doi:10.1001/jamanetworkopen.2022.54669
6. Vo JB, Ramin C, Veiga LHS, et al. Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors. JNCI: Journal of the National Cancer Institute. 2024;116(8):1384-1394. doi:10.1093/jnci/djae107
7. Lee JW, Oh H, You JY, et al. Therapy-related myeloid neoplasm in early breast cancer patients treated with adjuvant chemotherapy. Eur J Cancer. 2023;191:112952. doi:10.1016/j.ejca.2023.112952
8. Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). Journal of Clinical Oncology. 2017;35(23):2647-2655. doi:10.1200/JCO.2016.71.4147,
9. Nitz U, Gluz O, Clemens M, et al. West German Study PlanB Trial: Adjuvant Four Cycles of Epirubicin and Cyclophosphamide Plus Docetaxel Versus Six Cycles of Docetaxel and Cyclophosphamide in HER2-Negative Early Breast Cancer. J Clin Oncol. 2019;37(10):799-808. doi:10.1200/JCO.18.00028
10. Yu K Da, Liu XY, Chen L, et al. Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial. Lancet Reg Health West Pac. 2021;11. doi:10.1016/j.lanwpc.2021.100158
11. Ejlertsen B, Tuxen MK, Jakobsen EH, et al. Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial. J Clin Oncol. 2017;35(23):2639-2646. doi:10.1200/JCO.2017.72.3494
12. Cobain EF, Pusztai L, Graham CL, et al. Elucidating the immune active state of HR+HER2- MammaPrint High 2 early breast cancer. Journal of Clinical Oncology. 2024;42(16_suppl):506-506. doi:10.1200/JCO.2024.42.16_SUPPL.506
13. Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American society of clinical oncology clinical practice guideline. Journal of Clinical Oncology. 2017;35(8):893-911. doi:10.1200/JCO.2016.70.5400