Avoidance and Period-Shortening of Neoadjuvant Chemotherapy Against Triple-Negative Breast Cancer in Stages I and II: Importance of Ki-67 Labeling Index and the Recognition of Apocrine-Type Lesions

Abstract

Background: Triple-negative breast cancer encompasses heterogeneous subtypes. Neoadjuvant chemotherapy is ineffective against some triple-negative breast cancers, while others show a favorable prognosis despite chemoresistance.

Methods: A total of 51 cases with stages I and II triple-negative breast cancer were analyzed; 34 triple-negative breast cancers treated with neoadjuvant chemotherapy were divided into "good responders" (n = 22), showing therapeutic effect G2b or G3 in surgical specimens, and "poor responders" with therapeutic effect G0, G1a, G1b, and G2a (n = 12). Neoadjuvant chemotherapy was spared in 17 cases (non-neoadjuvant chemotherapy group). Apocrine-type triple-negative breast cancer was defined as triple-negative breast cancer immunoreactive for both androgen receptor and forkhead-box protein A1. Triple-negative breast cancer other than apocrine-type (n = 16) and special types (myoepithelial, medullary, adenoid cystic, and spindle cell carcinomas, n = 6) was categorized as basal-like subtype (n = 29). Prognosis was evaluated in each category.

Results: Neoadjuvant chemotherapy provoked significant effects against basal-like triple-negative breast cancer with high Ki-67 labeling (≧50%), and tumor-infiltrating lymphocytes predicted high chemosensitivity. Neoadjuvant chemotherapy was avoidable in triple-negative breast cancer of apocrine- and special types showing low (<50%) Ki-67 labeling. Ten (59%) lesions in the non-neoadjuvant chemotherapy group belonged to the apocrine-type. When clinical complete remission shown by contrast-enhanced magnetic resonance imaging was reached in the course of neoadjuvant chemotherapy against basal-like triple-negative breast cancer, the neoadjuvant chemotherapy period was shortened in 14 (64%) of 22 good responders. Disease-free and overall survival rates were excellent in all groups.

Conclusions: The following 2 hypothetical proposals should be proven by large-scale clinical trials. Immunohistochemical recognition of apocrine-type triple-negative breast cancer with low Ki-67 labeling is important for avoiding ineffective/unnecessary neoadjuvant chemotherapy. By employing appropriate clinical imaging, period-shortening is achievable in basal-like triple-negative breast cancer with high Ki-67 labeling.

Keywords: FOXA1; androgen receptor; apocrine-type; avoidance of chemotherapy; basal-like subtype; period-shortening of chemotherapy; triple-negative breast cancer.

Figure 1.

Flow diagram of patients included in the present retrospective study. DCIS indicates ductal carcinoma in situ.

Figure 2.

Schematic illustration of the relationship between the chemotherapeutic effect of NAC and Ki-67 labeling indices in TNBC (n = 34), including 22 good responders and 12 poor responders. TNBCs with high Ki-67 labeling (50% or more) showed a good response to NAC, while those of low Ki-67 labeling (<50%) were frequently included in the poor responder. Statistical significance (P < .01) was proven. NAC indicates neoadjuvant chemotherapy; TNBC, triple-negative breast cancer.

Figure 3.

Immunohistochemical features of TNBC of basal-like subtype (a representative lesion in the good responder; A, H&E; B, ER; C, AR; D, FOXA1; E, p53; F, EGFR; G, CK5/6; H, GCDFP15). Highly atypical quadruple-negative cancer cells (histological grade 3) accompany the lymphoid stroma. ER, AR, FOXA1, and GCDFP15 are not expressed, while p53, EGFR, and CK5/6 are positive in the nuclei, on the plasma membrane, and in the cytoplasm of the cancer cells, respectively. AR indicates androgen receptor; CK5/6, cytokeratin 5/6; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FOXA1, forkhead-box protein A1; GCDFP15, gross cystic disease fluid protein-15; H&E, hematoxylin and eosin; TNBC, triple-negative breast cancer.

Figure 4.

Immunohistochemical features of TNBC of apocrine-type (a representative lesion in the good responder. A, H&E; B, ER; C, AR; D, FOXA1; E, p53; F, EGFR; G, CK5/6; H, GCDFP15). Highly atypical ER-negative cancer cells (histological grade 3) express AR, CK5/6, and GCDFP15 focally and FOXA1, p53, and EGFR diffusely. AR indicates androgen receptor; CK5/6, cytokeratin 5/6; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FOXA1, forkhead-box protein A1; GCDFP15, gross cystic disease fluid protein-15; H&E, hematoxylin and eosin; TNBC, triple-negative breast cancer.

Figure 5.

Histopathological appearance and Ki-67 immunostaining of TNBC of basal-like subtype and apocrine-type (upper panels: H&E, lower panels: Ki-67; A and E, a basal-like lesion in the good responder; B and F, another basal-like lesion in the good responder: C and G, an apocrine-type lesion in the good responder; D and H, another apocrine-type lesion in the non-NAC group). Triple-negative breast cancer of the basal-like subtype commonly reveals high histological grade (G3) and high Ki-67 labeling. Dense lymphoid stroma is evident in panel A. Triple-negative breast cancer of the apocrine type often reveals lower histological grade (G2 in panel C and G1 in panel D) and lower Ki-67 labeling. Typical apocrine appearance is seen in panel D. H&E indicates hematoxylin and eosin; NAC, neoadjuvant chemotherapy; TNBC, triple-negative breast cancer.

Figure 6.

Disease-free survival of cases with TNBC in stages I and II: comparison among the good responder (n = 22), the poor responder (n = 12), and the non-NAC group (n = 17). No statistical significance was observed among the groups (P = .321). G = good responder (black line), P = poor responder (red line), N = the non-NAC group (green line). NAC indicates neoadjuvant chemotherapy; TNBC, triple-negative breast cancer.

Figure 7.

The number of cycles of NAC and therapeutic effect against TNBC in stages I and II (n = 34). A, anthracycline-based regimen; T, taxane-based regimen. The number next to A and T means the repeated cycle number of the regimen. The areas on the thick red line (shadowed boxes) indicate standardized therapy zone of NAC. The areas indicated by the thick red arrow demonstrate cases with shortened NAC periods. Good responders are shown in red. In some poor responders, NAC was not completed because of poor responsiveness. NAC indicates neoadjuvant chemotherapy; TNBC, triple-negative breast cancer.