Pathobiology of preoperative chemotherapy

• Published in: Cancer 2002-08, Vol.95 (4), p.681-695
• Main Authors: Fisher, Edwin R., Wang, Jiping, Bryant, John, Fisher, Bernard, Mamounas, Eletherios, Wolmark, Norman
• Format: Article
• Language: English
• Subjects: breast carcinoma; cyclophosphamide; doxorubicin; National Surgical Adjuvant Breast Project (NSABP) protocol B‐18; neoadjuvant chemotherapy; pathobiology
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.10741

BACKGROUND Examination was performed on pathologic material from patients enrolled in the National Surgical Adjuvant Breast Project (NSABP) protocol B‐18, in which the clinical effects of preoperative (preop) and postoperative (postop) doxorubicin and cyclophosphamide (AC) were compared. METHODS Of the total number of 1523 patients, 1234 patients (81%) were in the pathologically evaluable cohort. Six hundred twenty‐six patients had been randomized prospectively to receive AC postop and 608 had been randomized to receive AC preop. Preentry diagnosis was made by fine‐needle aspiration (FNA) and/or Tru‐cut biopsy (TC). AC‐induced and other pathologic changes were identified, and their relation to pathologic response and overall survival (OS) and disease‐free survival (DFS) was determined. Frequencies of the number of lymph node metastases, their size, stromal reaction, and extracapsular extension (ECE) were compared in the two treatment groups, as was their correlation with OS and DFS. Survival estimates were based on 9 years of follow‐up. RESULTS Approximately 13% of primary breast carcinoma cases exhibited both a clinical complete response (cCR) and a pathologic complete response (absence of invasive tumor [pCR]) to preop AC. An additional 7% of patients exhibited a pCR in the absence of a cCR. A pCR occurred in 38% of those patients determined to have achieved a cCR. Poor nuclear grade of the tumor cells in the pre‐entry FNA and/or TC specimens significantly predicted a pCR. Patients with the latter exhibited a better OS and DFS compared with those with a pathologic partial response (presence of sparse invasive tumor [pPR]) or no pathologic response (pNR). Epithelial alterations considered to be induced in tumors by preop AC were comprised of types 1 and 2 giant cells with meganuclei, apocrine metaplasia, and cytoplasmic vacuolation. They had a high degree of specificity (range, 86–99%) but a low sensitivity (range, 7–38%). All were predictive of a pPR and were found to be related adversely to OS and DFS. A fibrous stromal reaction noted in tumors or their putative sites in the preop group was found to have only modest degrees of specificity (63%) and sensitivity (74%). Moderate/marked sclerosis of basement membranes of the ductal and ductular elements of the terminal ductolobular unit (TDLU) was significantly more frequent in nontumor‐bearing areas of breasts from patients in the preop treatment group compared with those in the postop treatment group (67%