PURPOSE: Lehmann et al have identified four molecular subtypes of triple-negative breast cancer (TNBC)—basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor—and an immunomodulatory (IM) gene expression signature modifier. Our group previously showed that the response of TNBC to neoadjuvant systemic chemotherapy (NST) differs by molecular subtype, but whether NST affects the subtype was unknown. Here, we tested the hypothesis that in patients without pathologic complete response, TNBC subtypes can change after NST. Moreover, in cases with the changed subtype, we determined whether epithelial-to-mesenchymal transition (EMT) had occurred. MATERIALS AND METHODS: From the Pan-Pacific TNBC Consortium data set containing TNBC patient samples from four countries, we examined 64 formalin-fixed, paraffin-embedded pairs of matched pre- and post-NST tumor samples. The TNBC subtype was determined using the TNBCtype-IM assay. We analyzed a partial EMT gene expression scoring metric using mRNA data. RESULTS: Of the 64 matched pairs, 36 (56%) showed a change in the TNBC subtype after NST. The most frequent change was from BL1 to M subtypes (38%). No tumors changed from M to BL1. The IM signature was positive in 14 (22%) patients before NST and eight (12.5%) patients after NST. The EMT score increased after NST in 28 (78%) of the 36 patients with the changed subtype ( v 39% of the 28 patients without change; P = .002254). CONCLUSION: We report, to our knowledge, for the first time that the TNBC molecular subtype and IM signature frequently change after NST. Our results also suggest that EMT is promoted by NST. Our findings may lead to innovative adjuvant therapy strategies in TNBC cases with residual tumor after NST.

Objectives: Tenascin-C (TNC) is an extracellular matrix protein associated with tissue remodeling, tumor progression, and poor prognosis in breast cancer. Although TNC has attracted interest as a potential stromal biomarker, its baseline histopathological distribution in untreated breast cancer has not been fully characterized. This exploratory pilot study aimed to characterize the immunohistochemical distribution of TNC in representative treatment-naïve breast cancer tissues. Methods: Immunohistochemical staining for TNC was performed in representative breast cancer tissue specimens obtained from 16 treatment-naïve patients encompassing major histological and molecular subtypes. Tumor and non-tumor areas were evaluated descriptively by two board-certified pathologists using consensus assessment. Results: Heterogeneous TNC expression was observed in the stroma surrounding invasive tumors in all cases. In most specimens, TNC staining was predominantly localized to the peritumoral stroma, whereas occasional staining was observed around non-invasive lesions. Non-tumor breast stroma was largely negative, although positive staining was observed in biopsy scars and sclerotic areas. No consistent subtype-specific pattern of TNC distribution or staining intensity was identified. Conclusions: TNC showed heterogeneous stromal expression in treatment-naïve breast cancer and was also detected in biopsy scars and areas of stromal remodeling. These findings provide baseline histopathological information regarding TNC localization in untreated breast cancer. Further studies are required to determine the potential clinical utility of TNC as a stromal biomarker, including its application in the post-neoadjuvant setting.