Miharu Kano

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.

Background: Boron neutron capture therapy (BNCT) is a type of targeted radiotherapy with considerable therapeutic potential that may be combined with immune checkpoint inhibitors (ICIs) to enhance systemic antitumor immunity. Its efficacy relies on the efficient and safe delivery of boron to cancer cells. This study evaluated the acute toxicity of a self-assembling peptide-based boron carrier composed of A6K and sodium borocaptate (BSH) at a 1:10 molar ratio (A6K/BSH boron drug), which had previously shown excellent tumor-selective accumulation and prolonged intracellular retention. Methods: A single-dose intraperitoneal toxicity study was performed in 6-week-old BALB/c mice (n = 6 per group; 3 males and 3 females). Animals received BSH-equivalent doses of 0, 30, 100, 300, or 600 mg/kg and were observed for 14 days. Mortality, clinical signs, body weight, gross necropsy findings, and histopathological characteristics of major organs were then assessed. Results: No mortality or treatment-related clinical signs were observed. Body weight changes were comparable between the control and treated groups. Gross necropsy revealed no treatment-related abnormalities. Histopathology showed mild hepatocellular hypertrophy and granular degeneration without dose dependency. No other organ toxicities or sex-related differences were detected. Conclusions: A single intraperitoneal administration of the A6K/BSH boron drug up to 600 mg/kg (BSH-equivalent) produced no evident acute systemic toxicity, suggesting that the approximate lethal dose exceeds 600 mg/kg for both sexes. This initial safety assessment supports the further development of the A6K/BSH boron drug as a boron delivery agent for BNCT. Further studies are needed to confirm its safety under clinically relevant conditions.

Background: Human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugates have been developed and a new treatment option for breast cancer patients, including those with HER2-low-expressing breast cancer. Previous reports have shown that HER2 crosstalk with the estrogen receptor, and that there is a high expression group of genes involved in androgen/estrogen metabolism in the molecular classification of triple negative breast cancer (TNBC). We have been performed to assess basal-like TNBC in clinical practice to immunohistochemical staining of EGFR, CK5/6 and androgen receptor (AR) since 2014. In this study, we evaluated the clinicopathological features of the differences between HER2-negative and HER2-low TNBC and hypothesized that HER2-negative TNBC would have more basal-like features and HER2-low TNBC would have more non-basal-like features. Methods: From April 2014 to May 2023, 195 patients diagnosed with triple-negative breast cancer (TNBC) through needle biopsy and immunohistochemical staining for EGFR, CK5/6, and AR were investigated. BRCA mutations, which are considered common in basal-like types, were also assessed. BRCA mutations were evaluated in germline-derived samples. PD-L1 and tumor-infiltrating lymphocytes (TILs) were evaluated for immunogenicity assessment. TILs were assessed by averaging the area occupied by lymphocytes and plasma cells (not hotspots) in the interstitial area within the invasive cancer area, as proposed by the International TILs Working Group. They were classified into four levels: 0%, 1-9%, 10-49%, and ≥50%. PD-L1 was assessed using the SP142 antibody, and positive cells were defined as those with 1% or more positive tumor-infiltrating immune cells. PD-L1 was evaluated at 0%, 1-9%, and ≥10%. Results: Among the TNBC biopsies, 74 cases (38%) were HER2-low (ITC 1+ or ITC 2+ and FISH negative or not performed), and 121 cases (62%) were HER2-negative. Significant differences were observed between HER2-low and HER2-negative for histological classification (P=0.011), BRCA mutation (P=0.032), and PD-L1 (P=0.008).Invasive ductal carcinoma (IDC) was found in 65% (48/74) of HER2-low and 79% (95/121) of HER2-negative (P=0.011). Apocrine carcinoma was found in 32% (24/74) of HER2-low and 15% (18/121) of HER2-negative. There was a correlation between apocrine carcinoma and AR expression (P<0.001). AR expression was 50% (37/74) positive and 50% (37/74) negative in HER2-low, while it was 20% (25/121) positive and 80% (96/121) negative in HER2-negative (P<0.001). BRCA mutations were found in 15% (5/34) of HER2-low and 55% (21/58) of HER2-negative. PD-L1 was positive in 43% (43/89) of HER2-low and 63% (54/86) of HER2-negative. There was a correlation between PD-L1 and TILs (P<0.001).There was no difference in Ki-67 (P=0.100), EGFR (P=0.363), CK5/6 (P=0.452), nuclear grade (P=0.490), neoajuvantchemotherapy treatment response (P=0.468) and TILs (P=0.546) between HER2-low and HER2-negative. Conclusion: AR is higher in HER2-low-expressing breast cancers and apocrine carcinoma is significantly more frequently classified. BRCA mutation and PD-L1 positivity are higher in HER2-negative TNBC. Our study revealed that HER2-negative breast cancer has more basal-like clinicopathologic features, while HER2 Low TNBC has non-basal features. Citation Format: Michiko Kato, Hiroko Masuda, Jun Ohara, Miharu Kano, Karen Suyama, Reika Yoshida, Asako Tsuruga, Sayuka Nakayama, Naoki Hayashi, Toshiko Yamochi. Clinicopathological characterized by HER2-low-expressing breast cancer in triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-11-17.