What is Pathologic Complete Response (pCR)?
Pathologic complete response (pCR) is defined as the complete absence of residual invasive carcinoma in both the breast and all sampled axillary lymph nodes following neoadjuvant therapy, and achieving pCR correlates with substantial improvements in both event-free survival and overall survival. 1
Core Definition and Standardization
The optimal definition of pCR requires no invasive cancer in both breast and axillary nodes (ypT0ypN0 or ypT0/isypN0). 2 This definition provides the strongest discrimination between patients with favorable versus unfavorable outcomes, with a hazard ratio of 0.446 for disease-free survival compared to patients without pCR. 3
The DCIS Controversy
There is ongoing debate about whether residual ductal carcinoma in situ (DCIS) should exclude a patient from being classified as having achieved pCR:
The FDA-supported pooled analysis of 12 neoadjuvant trials found similar event-free survival and overall survival in patients without residual invasive carcinoma regardless of presence or absence of residual DCIS. 2
However, German and Austrian Breast Group data demonstrated significantly worse event-free survival for patients with ypTisypN0 compared to ypT0ypN0, though overall survival was not significantly different. 2
The most stringent definition (ypT0ypN0—no invasive disease and no DCIS) provides the best prognostic discrimination. 3
Why Nodal Status Matters
There is general consensus that residual disease in axillary lymph nodes indicates worse prognosis even when there is pCR in the breast, which is why the definition must include absence of disease in both sites. 2
Prognostic Significance in T2N2 Breast Cancer
For patients presenting with T2N2 disease who achieve pCR after neoadjuvant therapy:
Five-year overall survival reaches 89-96% and disease-free survival 87-93% in patients achieving pCR, compared to 64% overall survival and 58% disease-free survival in those with residual disease. 4, 5
However, younger patients and those with clinical stage IIIB-C disease at diagnosis remain at increased risk of distant metastasis even after achieving pCR. 5
Subtype-Specific Implications
pCR is an independent predictor of favorable outcomes across all molecular subtypes, but the rate of achieving pCR and its prognostic impact varies substantially by subtype: 6
- Triple-negative and HER2-positive (non-luminal) tumors achieving pCR have excellent prognosis 3
- pCR rates: Triple-negative 31%, HER2-positive/non-luminal 36%, luminal B/HER2-positive 22%, luminal B/HER2-negative 15%, luminal A 7.5% 6
- pCR is a suitable surrogate endpoint for luminal B/HER2-negative, HER2-positive (non-luminal), and triple-negative disease but not for luminal A or luminal B/HER2-positive tumors 3
Critical Clinical Pitfalls
Assessment Challenges
The pCR rate can vary dramatically based on pathologist training and standardization—in the I-SPY 1 trial, pCR rates fell by almost 10% after pathologists were trained on standardized assessment methods. 2
Accurate documentation of pCR requires intelligent mapping and adequate sampling of the correct tumor bed area, not exhaustive sampling of the entire specimen. 2 Correlation of clinical imaging, tumor markers, and gross pathology is indispensable. 2
Treatment Implications Despite pCR
Radiation therapy indications and treatment fields must be based on pre-treatment tumor characteristics, not post-neoadjuvant pathology. 1, 7 For T2N2 disease at presentation, this typically means:
- Regional nodal radiation is indicated despite achieving pCR if the patient had clinical N2 disease before neoadjuvant therapy 1
- Breast-conserving surgery patients require whole breast radiation regardless of pCR status 1
Patients achieving pCR do not require additional cytotoxic chemotherapy beyond what was administered neoadjuvantly. 1
For HER2-positive disease, complete the full one-year course of trastuzumab even after achieving pCR. 1
For hormone receptor-positive disease, initiate or continue adjuvant endocrine therapy for 5-10 years based on the original diagnostic biopsy receptor status, regardless of pCR. 1