What are the definitions of low, intermediate, and high risk of relapse in Hormone Receptor positive (HR+) and Human Epidermal growth factor Receptor 2 negative (HER2-) early breast cancer?

Risk Stratification Definitions for HR+ HER2- Early Breast Cancer

Risk stratification in HR+ HER2- early breast cancer is primarily defined by integrating anatomic factors (tumor size, nodal status), tumor biology (grade, Ki-67, hormone receptor expression levels), and validated genomic assays, with no universally standardized numerical thresholds but rather a continuum of risk that guides treatment decisions. 1, 2

Clinical-Pathological Risk Categories

Low Risk Features

• Tumor size ≤2 cm (particularly T1a/T1b) with node-negative disease 1, 2
• Grade 1 (low histologic grade) indicating well-differentiated tumors 1, 2
• High ER/PR expression (strongly positive hormone receptors) 2, 3
• Low Ki-67 proliferation index (<15-20%) suggesting lower proliferative activity 2
• Absence of lymphovascular invasion (LVI) 2
• Special histological subtypes such as tubular, cribriform, or mucinous carcinomas 1

Intermediate Risk Features

• Tumor size >2 cm but ≤5 cm with limited nodal involvement (1-3 positive nodes) 1, 2
• Grade 2 tumors with mixed clinical-pathological features 2
• Moderate Ki-67 levels (15-30%) 2
• Clinical-genomic discordance where clinical and genomic risk assessments diverge 1

High Risk Features

• Four or more positive lymph nodes regardless of other factors 1, 3
• Grade 3 (high histologic grade) indicating poorly differentiated tumors 2
• Large tumor size (T3 or higher) 1
• High Ki-67 (>30%) suggesting aggressive biology 2
• Presence of lymphovascular invasion 2
• Young age (<40 years) associated with more aggressive disease 2

Genomic Risk Stratification

21-Gene Recurrence Score (Oncotype DX)

The ESMO 2024 guidelines and European Commission recommendations support using the 21-RS particularly in node-negative disease 1:

• Low genomic risk: Generally RS <26 (though exact thresholds vary by nodal status and menopausal status)
• Intermediate genomic risk: RS 26-30 in some classifications
• High genomic risk: RS >30, indicating potential chemotherapy benefit 1, 4

Important caveat: The 21-RS is suggested for lymph node-negative women with conditional recommendation due to very low certainty of evidence, with benefits likely larger in those with high clinical risk 1

70-Gene Signature (MammaPrint)

The European Commission guidelines provide specific recommendations 1:

• Low genomic risk: Patients classified as low by 70-GS
• High genomic risk: Patients classified as high by 70-GS

Critical distinction: The 70-GS should be used only in women at high clinical risk (conditional recommendation, low certainty), and is strongly recommended against in women at low clinical risk 1

Integrated Risk Assessment Algorithm

Step 1: Establish Anatomic-Pathologic Baseline

• Confirm tumor size, nodal status, grade, and LVI status 2
• Assess mandatory biomarkers: ER/PR status, HER2 status, Ki-67 2

Step 2: Apply Clinical Risk Categories

• Very low risk: T1a-b, Grade 1, node-negative, high ER, low Ki-67 → Consider endocrine therapy alone 1, 2
• Low-intermediate risk: Uncertainty exists → Consider genomic testing to guide chemotherapy decisions 1, 2
• High risk: ≥4 positive nodes, Grade 3, large tumors → Chemotherapy typically required 1

Step 3: Genomic Testing When Indicated

Genomic tests are NOT recommended for 1:

• Clinicopathological low-risk tumors (pT1a, pT1b, G1, ER high, pN0)
• Patients with comorbidities precluding chemotherapy
• Special low-risk histological types

Genomic testing should be considered when 1:

• Clinical-pathological factors leave treatment decisions uncertain
• Node-negative disease with intermediate clinical features
• 1-3 positive nodes with otherwise favorable features (for 21-RS)

Step 4: Treatment Decision Framework

The NCCN framework stratifies as follows 2:

• Very low risk: Endocrine therapy alone may be sufficient
• Low-intermediate risk: Genomic testing guides chemotherapy decision
• High risk: Systemic chemotherapy typically required

Critical Nuances and Pitfalls

No single threshold defines risk categories universally 5. The 2024 ESMO guidelines emphasize that absolute benefit of chemotherapy depends on individual recurrence risk, requiring informed decision-making incorporating side effects 1.

Clinical-genomic discordance requires careful interpretation 1. In the MINDACT trial, women with high clinical risk but low genomic risk (by 70-GS) showed potential benefit from avoiding chemotherapy (HR 0.64 for DFS), while low clinical/high genomic risk showed uncertain effects 1.

Luminal A-like versus Luminal B-like distinction 1:

• Luminal A-like: Endocrine therapy alone in majority; consider chemotherapy only if high tumor burden (≥4 nodes, T3+)
• Luminal B-like (HER2-negative): Chemotherapy followed by endocrine therapy for majority

The persistent risk of late relapse (>5-8 years) in HR+ disease means risk assessment must account for both early and late recurrence patterns 2, 6.