High-Risk Node-Negative HR+/HER2− Early Breast Cancer May Carry Recurrence Risk Similar to N1 Disease
For many years, nodal status has been one of the clearest clinical anchors in early breast cancer risk assessment. Node-positive disease has generally signaled a need for more intensive discussion around recurrence risk, while node-negative disease has often carried a more reassuring tone.
A new real-world analysis published in the Journal of the National Cancer Institute challenges that simplified view in hormone receptor-positive/HER2-negative early breast cancer.
The study analyzed 7,481 patients with stage I-III HR+/HER2− early breast cancer from the Flatiron Health US electronic health record database. All patients underwent surgery and received adjuvant endocrine therapy in a period largely before widespread use of adjuvant CDK4/6 inhibitors.
The central message is clinically important: high-risk node-negative disease may carry recurrence and mortality risks similar to N1 disease.
Why This Question Matters Now
The adjuvant treatment landscape for HR+/HER2− early breast cancer has changed substantially.
Endocrine therapy remains the foundation of treatment, but recurrence risk assessment now increasingly informs whether additional therapy should be considered. Chemotherapy, PARP inhibitors in selected germline BRCA-mutated disease, and CDK4/6 inhibitors have made risk stratification more consequential.
The relevance of this question has grown after two major adjuvant CDK4/6 inhibitor trials: monarchE, which evaluated abemaciclib plus endocrine therapy in high-risk node-positive disease, and NATALEE, which evaluated ribociclib plus endocrine therapy in a broader stage II/III population that included selected high-risk node-negative patients.
Because these trials used different eligibility criteria, real-world data can help clarify how many patients resemble each trial population and what their recurrence risk looks like outside the controlled environment of randomized clinical trials.
A Large Real-World Cohort Before Broad CDK4/6 Use
This retrospective study used Flatiron Health electronic health record data from 2011 to 2023.
Among 7,481 patients included in the analysis:
- 72.0% had N0 disease
- 21.7% had N1 disease
- 6.3% had N2-N3 disease
Within the N0 population, 604 patients, or 11.2%, were classified as high risk according to NATALEE-style criteria. These included patients with high-risk anatomic or biologic features such as larger tumors, grade 3 disease, or grade 2 disease with Ki-67 ≥20% or high genomic risk.
This distinction is essential. The study did not treat all node-negative disease as one group. Instead, it separated node-negative patients with higher-risk tumor features from those without these features.
That is where the most important signal emerged.
High-Risk N0 Disease Resembled N1 Disease
At 5 years, patients with high-risk N0 disease had recurrence and mortality estimates that were close to those observed in N1 disease.
For high-risk N0 disease, the 5-year outcomes were:
- Overall recurrence risk: 10.1%
- Distant recurrence risk: 8.8%
- All-cause mortality risk: 7.0%
For N1 disease, the corresponding outcomes were:
- Overall recurrence risk: 9.5%
- Distant recurrence risk: 7.2%
- All-cause mortality risk: 8.1%
The study’s Kaplan-Meier curves show that the high-risk N0 and N1 groups tracked closely over time, while N2-N3 disease had substantially higher recurrence and mortality risk and non-high-risk N0 disease remained clearly lower.
In Cox analyses, recurrence risk in the N0 high-risk group was statistically similar to the N1 group, significantly higher than the N0 non-high-risk group, and significantly lower than the N2-N3 group.
This finding is not just statistical. It is clinically intuitive: a node-negative tumor with large size, high grade, high proliferation, or high genomic risk may behave more aggressively than nodal status alone would suggest.
The Clinical Message: Nodal Status Is Necessary, but Not Sufficient
This study does not diminish the importance of lymph node involvement. Nodal status remains a powerful prognostic factor.
But it reinforces that nodal status should not be used in isolation.
In HR+/HER2− early breast cancer, recurrence risk is shaped by a broader set of variables, including tumor size, grade, Ki-67, genomic risk, anatomic stage, menopausal status, treatment history, and patient-level factors.
The finding that high-risk N0 disease can resemble N1 disease supports a more integrated approach to adjuvant decision-making. A patient should not be reassured solely because nodes are negative if other tumor features suggest meaningful recurrence risk.
NATALEE and monarchE Eligibility: A Real-World Difference
The study also compared how many patients in routine practice would have met eligibility criteria for NATALEE and monarchE.
Among the full cohort:
- 33.9% were NATALEE-eligible
- 15.5% were monarchE-eligible
This means that more than twice as many real-world patients met NATALEE eligibility criteria compared with monarchE eligibility criteria.
The difference reflects trial design. NATALEE included a broader stage II/III population, including selected high-risk node-negative patients. monarchE focused on high-risk node-positive disease.
In the study, no node-negative patients were eligible for monarchE, while high-risk N0 patients were included in the NATALEE-eligible group.
This matters because it highlights a group of patients who may have meaningful recurrence risk but would not be captured by node-positive-only escalation frameworks.
Distant Recurrence Remains the Key Unmet Need
For HR+/HER2− early breast cancer, distant recurrence is the event with the greatest long-term clinical consequence. Once disease becomes metastatic, treatment remains possible, but cure is generally no longer expected.
Even in patients treated with surgery and adjuvant endocrine therapy, the study found substantial recurrence risk in trial-eligible populations.
At 5 years:
- NATALEE-eligible DRFS: 83.1%
- monarchE-eligible DRFS: 74.6%
The lower DRFS in the monarchE-eligible population is expected, given the higher-risk node-positive criteria used in that trial. But the NATALEE-eligible population also showed meaningful distant recurrence risk, reflecting the broader population included in that framework.
The implication is not that every patient needs escalation. Rather, it is that risk discussions should be more precise, especially for patients who fall outside traditional high-risk definitions but still carry adverse clinicopathologic features.
What This Study Adds to the Field
This analysis adds value in three ways.
First, it provides real-world data from a large US cohort treated before adjuvant CDK4/6 inhibitors became common. That makes it useful for estimating baseline recurrence risk under endocrine therapy-based care.
Second, it directly compares nodal subgroups, including high-risk N0 disease, N1 disease, and N2-N3 disease.
Third, it connects recurrence risk with modern trial eligibility frameworks, helping clinicians understand how NATALEE- and monarchE-like populations appear in routine practice.
For OncoDaily Breast readers, the most relevant takeaway is that high-risk node-negative HR+/HER2− early breast cancer should not be treated conceptually as low-risk disease.
Important Cautions
This was a retrospective real-world analysis, not a randomized trial.
The study was based on a US electronic health record database, so applicability outside the US may vary. Ki-67 and genomic testing were not available for all patients, which may have led to underestimation or misclassification of some high-risk N0 cases.
Cause of death was not available, so the mortality endpoint was all-cause mortality rather than breast cancer-specific survival.
The study was also supported by Novartis, which is relevant when interpreting data connected to ribociclib eligibility. This does not invalidate the findings, but it should be transparently considered when reading the analysis.
Finally, HR-positive breast cancer is known for late recurrence. Longer follow-up may further refine the absolute risk estimates, especially beyond 5 to 7 years.
The Bottom Line
This real-world JNCI analysis supports a more mature conversation about recurrence risk in HR+/HER2− early breast cancer.
Node-negative disease is not always low risk.
Patients with high-risk N0 disease showed recurrence and mortality patterns similar to N1 disease, while remaining clearly different from lower-risk node-negative patients.
In modern adjuvant breast oncology, risk assessment should not stop at the lymph nodes. It should combine nodal status with tumor biology, clinicopathologic features, genomic risk when available, and trial-based criteria.
The study does not provide a one-size-fits-all treatment answer. It provides something equally important: a reminder that some patients with node-negative disease deserve a deeper, more individualized discussion about recurrence risk and evidence-based escalation strategies.
References
- Tarantino P, Curigliano G, Hamilton E, Kim J, Graff SL, Neven P, Schlam I, Harbeck N, Cardoso F, Akdere M, Santarsiero L, Ye F, Angehrn Z, Jhaveri K. Recurrence risk in HR-positive/HER2-negative early breast cancer: real-world US electronic health records study. Journal of the National Cancer Institute. 2026. doi:10.1093/jnci/djag201.
- Slamon DJ, Lipatov O, Nowecki Z, et al. Ribociclib plus endocrine therapy in early breast cancer. New England Journal of Medicine. 2024;390:1080-1091.
- Hortobagyi GN, Lacko A, Sohn J, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Annals of Oncology. 2025;36:149-157.
- Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR-positive, HER2-negative, node-positive, high-risk early breast cancer. Journal of Clinical Oncology. 2020;38:3987-3998.
- Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, high-risk early breast cancer: 5-year efficacy outcomes. Journal of Clinical Oncology. 2024;42:987-993.
