What is the classification and treatment of breast cancer based on the TNM (Tumor, Node, Metastasis) staging system?

TNM Staging and Treatment of Breast Cancer

Overview of TNM System

The AJCC 8th edition TNM staging system integrates anatomic extent of disease (tumor size, nodal involvement, metastases) with prognostic biomarkers (ER, PR, HER2, grade) to determine final prognostic stage groups, which directly guide treatment decisions. 1

Primary Tumor (T) Classification

The T stage quantifies tumor size and local extension:

• T1: ≤20 mm in greatest dimension 1
• T2: >20 mm but ≤50 mm 1
• T3: >50 mm 1, 2
• T4a: Extension to chest wall (not merely pectoralis muscle involvement) 1, 2
• T4b: Ulceration and/or ipsilateral satellite nodules and/or skin edema 1, 2
• T4c: Both T4a and T4b features present 1, 2
• T4d: Inflammatory carcinoma 1, 2

Regional Lymph Node (N) Classification

Pathologic Node Staging (pN)

Micrometastases are distinguished from isolated tumor cells based on size thresholds:

• pN0(i+): All metastatic lesions ≤0.2 mm detected by H&E or IHC 1
• pN0(i-): No detectable tumor cells 1
• pN1mi: Micrometastases >0.2 mm but ≤2.0 mm 1
• pN1: 1-3 axillary lymph nodes involved, OR internal mammary nodes detected by sentinel node procedure only 1
• pN2a: 4-9 axillary lymph nodes involved (at least one deposit >2.0 mm) 3
• pN2b: Clinically detected internal mammary nodes WITHOUT axillary involvement 3, 1
• pN3a: ≥10 axillary lymph nodes OR infraclavicular (level III) nodes 3
• pN3b: Clinically detected internal mammary nodes WITH axillary involvement, OR >3 axillary nodes plus internal mammary micrometastases/macrometastases by sentinel biopsy but not clinically detected 3
• pN3c: Ipsilateral supraclavicular lymph nodes 3, 1

Distant Metastasis (M) Classification

• M0: No clinical or radiographic evidence of distant metastases 3
• cM0(i+): No clinical/radiographic metastases, but molecularly/microscopically detected tumor cells ≤0.2 mm in blood, bone marrow, or non-regional nodes 3
• M1: Distant detectable metastases by clinical/radiographic means and/or histologically proven >0.2 mm 3

Stage Groupings

Early Stage Disease

• Stage 0: Pure noninvasive carcinomas 1
• Stage I-II: Operable local-regional invasive carcinoma 1

Locally Advanced Disease (Stage III)

• Stage IIIA: T3N1M0, T0-2N2M0, or T3N2M0 1, 2
• Stage IIIB: T4N0-2M0 (inoperable locally advanced disease) 1, 2
• Stage IIIC: Any T, N3, M0 1, 2

Mandatory Biomarker Assessment

All invasive breast cancers require determination of ER, PR, and HER2 status by immunohistochemistry, with ambiguous HER2 results (2+) requiring FISH or CISH confirmation. 1, 4

• ER/PR status: Determined using standardized IHC methodology (e.g., Allred or H-score) 3, 4
• HER2 status: Mandatory determination per ASCO-CAP guidelines 4
• Tumor grade: Using standardized grading systems (WHO classification) 3, 4
• Ki67 proliferation index: Provides supplemental information when standardized 3, 4
• Oncotype DX Recurrence Score: Incorporated into prognostic staging for ER+/HER2-/node-negative or 1-3 positive node disease 4

Required Staging Workup by Stage

Early-Stage (I-IIA)

• History, physical exam, CBC, liver function tests, alkaline phosphatase 4
• Bilateral diagnostic mammography with ultrasound 4
• No routine systemic staging unless signs/symptoms present 4

Locally Advanced (Stage III)

• All early-stage workup components PLUS: 4
• Chest CT 2, 4
• Abdominal/pelvic CT or MRI 2, 4
• Bone scan or sodium fluoride PET/CT 2, 4
• Optional FDG-PET/CT 4

Pre-Treatment Cardiac Assessment

• Cardiac ultrasound or MUGA scan before anthracycline and/or trastuzumab therapy 4

Treatment Algorithm by Stage

Operable Disease (Stage I-II, Operable IIIA)

• Breast-conserving surgery with radiation OR mastectomy 1
• Sentinel lymph node biopsy with clip placement for suspicious nodes before neoadjuvant therapy 4
• Systemic therapy decisions based on tumor biology (ER, PR, HER2 status) 1

Inoperable Locally Advanced Disease (Stage IIIB-IIIC)

• Neoadjuvant chemotherapy required before definitive surgery 2
• Dose-dense anthracycline and taxane-based regimens preferred 1

Triple-Negative Breast Cancer (Stage II-III)

• Neoadjuvant chemotherapy preferred 1

Critical Pitfalls to Avoid

• Do not perform comprehensive laboratory and radiological staging for early stage (N0) breast cancer, as these patients do not benefit from such workup 3
• Ensure accurate documentation of the number of involved lymph nodes, as this directly impacts N staging and treatment decisions 4
• Recognize that M1 designation persists throughout treatment, even if metastases respond to therapy 3
• Distinguish operable from inoperable locally advanced disease, as this fundamentally changes the treatment approach (upfront surgery vs. neoadjuvant chemotherapy) 2