Jingna Wu, Yunuo Zhang, Qiuming Wang, Jinfeng Zhang, Bo Gao, Yan ChenDepartment of Breast Oncology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, Guangdong, People’s Republic of ChinaCorrespondence: Yan Chen, Department of Breast Oncology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, No. 63, Xinfeng Road, Meijiang District, Meizhou, Guangdong, People’s Republic of China, Email chenyan4@mzrmyy.comBackground: Breast cancer patients with dual primary malignancies (DPMs) exhibit distinct clinical features and survival outcomes. Although several relevant studies have been published, clinical evidence focusing on Hakka women is scarce. This study aimed to identify prognostic factors for overall survival (OS) among these patients.Methods: This single-center retrospective study included Hakka women with breast cancer-associated DPMs in Meizhou. Patients were divided into synchronous and metachronous groups based on a 6-month diagnostic interval. We analyzed clinical features of breast cancer and other primary malignancies, including tumor sites of the latter, as well as their intergroup differences. OS was evaluated using the Kaplan–Meier method and Log rank test. Univariable and multivariable Cox regression analyses identified independent prognostic factors.Results: A total of 155 patients were included, including 51 synchronous and 104 metachronous cases. Significant intergroup differences were observed in age, surgery and chemotherapy for breast cancer (all P < 0.05). Other primary malignancies were mainly located in the gynecological system, thyroid gland and lung. Multivariable analysis identified that longer interval time (HR 0.07, 95% CI 0.02– 0.22; P < 0.001) was associated with better survival, whereas advanced breast cancer TNM stage (HR 2.49, 95% CI 1.11– 5.60; P = 0.027) and advanced disease extent of other primary malignancies (HR 6.63, 95% CI 2.65– 16.58; P < 0.001) were associated with worse survival.Conclusion: The prognosis of Hakka women with breast cancer-associated DPMs is collectively influenced by interval time, breast cancer TNM stage, and disease extent of other primary malignancies. These findings provide real-world data for this patient group and highlight the importance of evaluating both primary malignancies in prognostic assessment. Given the retrospective single-center design and limited death events, these findings should be interpreted with caution.Keywords: dual primary malignancies, breast cancer, prognosis, overall survival, hakka population
Ying Chen, Bin Song, YuHui MaCancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, People’s Republic of ChinaCorrespondence: YuHui Ma, Email mayuhui@sxbqeh.com.cn Bin Song, Email songbin@sxbqeh.com.cnAbstract: Breast cancer metastasis remains the primary cause of mortality, driving the search for novel therapeutic vulnerabilities. The cathepsin family of lysosomal proteases has emerged as a pivotal signaling network that orchestrates tumor progression, therapy resistance, and organ-specific metastasis. This narrative review synthesizes current knowledge on key cathepsins (B, D, L, S, C, G, and V) in breast cancer, detailing their multifaceted roles in extracellular matrix remodeling, immune modulation, angiogenesis, and epigenetic regulation. We highlight their specialized functions: cathepsin B (CTSB) and cathepsin L (CTSL) as core executors of invasion; cathepsin S (CTSS), cathepsin C (CTSC), and cathepsin G (CTSG) as mediators of immune crosstalk and organotropic metastasis to brain, lung, and bone; and cathepsin D (CTSD)/cathepsin V (CTSV) as hormonally-linked regulators with nuclear roles. Critically, we evaluate the emerging preclinical strategies of cathepsins as diagnostic biomarkers and therapeutic targets, reviewing emerging strategies including small-molecule inhibitors, antibody-based therapies, activatable prodrugs, and imaging probes. Advancing the understanding of this context-dependent protease network and developing selective interventions hold significant promise for paving the way towards more effective and personalized treatment strategies.Keywords: cathepsins, breast cancer, tumor microenvironment, metastasis, therapeutic targets, triple-negative breast cancer
Hongxu Ren,1,* Wencheng Chi,2,* Xiao Han,2 Linfeng Guo,1 Junlin Li,1 Jiakang Jiang21First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junlin Li, First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, People’s Republic of China, Email m13098229190@163.com Jiakang Jiang, Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, People’s Republic of China, Email 576260989@qq.comAbstract: Central nervous system (CNS) metastasis is an increasingly important challenge in advanced breast cancer, yet brain parenchymal metastases (BM) and leptomeningeal metastases (LM) are often considered within a single framework despite occupying biologically distinct CNS compartments. In this narrative review, we synthesize breast cancer-specific mechanistic and clinical evidence to examine how these two forms of CNS disease differ in metastatic entry, local adaptation, molecular evolution, biomarker representation, and therapeutic vulnerability. Parenchymal BM primarily arise through haematogenous dissemination and subsequent adaptation to a neurovascular, neural, and immune-rich environment, where successful colonization requires more than blood–brain barrier traversal and is supported by reciprocal tumour–host interactions and metabolic plasticity. By contrast, LM develops within a fluid-dominated, CSF-facing compartment characterized by distinct meningeal and blood–CSF interfaces, constrained resource availability, and dynamic immune conditions. C3–C3aR-mediated barrier remodeling and LCN2–SLC22A17-dependent iron acquisition are supported mainly by experimental LM models and selected patient-derived observations, including mixed-cancer cohorts, and require broader breast cancer-specific clinical validation. Genomic and phenotypic studies further indicate that BM and LM can share metastatic ancestry while undergoing branched and compartment-associated evolution, although observed divergence may also reflect pre-existing heterogeneity, treatment selection, elapsed time, and sampling effects. Therapeutic efficacy therefore depends not only on CNS drug access but also on target expression, tumour state, niche support, disease geometry, and prior treatment. By integrating metastatic dissemination, niche adaptation, molecular evolution, biomarker representation, and therapeutic vulnerability within a single comparative framework, this review links compartment-associated biology to molecular sampling, experimental modeling, and clinical trial design. Clinically, this framework may inform compartment-specific molecular sampling and trial stratification by BM treatment status and LM presentation, although its utility for individual treatment selection requires prospective validation. Future studies combining paired multi-compartment sampling, lineage-resolved models, and serial CSF and plasma profiling will be needed to distinguish shared ancestry from niche-associated adaptation and treatment-driven evolution.Keywords: breast cancer, brain metastasis, leptomeningeal metastasis, CNS compartmentalization, tumour microenvironment, clonal evolution, cerebrospinal fluid
Background: Breast cancer remains a significant global health concern. The residual cancer burden (RCB) system quantifies response to neoadjuvant therapy. This study evaluates pathological response as a prognostic indicator in patients with residual invasive breast carcinoma through a retrospective single-center validation. Methods: In this retrospective cohort study, we analyzed 100 surgical specimens from patients who underwent neoadjuvant therapy and mastectomy at a Brazilian public hospital. The RCB was calculated according to MD Anderson guidelines and classified as RCB-0 (complete response), RCB-I (minimal), RCB-II (moderate), or RCB-III (extensive). Clinicopathological correlations and survival analysis were performed. Results: The cohort was predominantly female (98%) with a mean age of 58.7 years. Invasive carcinoma of no special type was most common (86%). Extensive residual burden (RCB-III) predominated (66%), followed by RCB-II (29%), RCB-0 (3%), and RCB-I (2%). Higher RCB class was significantly associated with higher tumor grade (p< 0.0001), larger tumor size (p< 0.0001), greater lymph node involvement (p< 0.0001), and distant metastasis (p= 0.039). Mortality correlated with increasing RCB (74.6% of deaths were RCB-III). Survival analysis showed a significant difference among RCB classes (p= 0.024), with the most pronounced difference between RCB-II and RCB-III (p= 0.007). The luminal A subtype was more common in RCB-0, while luminal B HER2+ and triple-negative subtypes were more frequent in RCB-III. Conclusion: Within this historical cohort, the RCB index provides valuable prognostic information, effectively stratifying institutional patients based on recurrence and metastasis risk. While its routine adoption in clinical practice is supported to complement risk stratification, conclusions regarding its universal independent value across all classes are bounded by the low number of RCB-0 and RCB-I cases.
