Akimitsu Yamada

Background: Aurora kinase A ( AURKA ) is a serine/threonine kinase that regulates mitotic entry, spindle assembly, and chromosomal segregation. AURKA overexpression has been linked to multiple malignancies. The biological and clinical significance of AURKA expression within estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2−) breast cancer has yet to be fully elucidated. Methods: A total of 8896 patients were analyzed across bulk transcriptomic datasets. Single-cell RNA sequencing datasets were also analyzed. ER+/HER2− tumors were divided into AURKA -high or -low groups according to the median AURKA expression within each cohort. Results: AURKA expression was associated with Nottingham histological grade and Ki-67 expression ( p < 0.001) and enrichment of cell cycle-related pathways across The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium, and Sweden Cancerome Analysis Network-Breast datasets (all false discovery rate 2). AURKA expression was associated with genomic instability, increased mutational burden and enhanced DNA repair-related genes (all p < 0.001) and with increased infiltration of type 1 and 2 T-helper cells, M1-like macrophages, and total macrophages (all p < 0.001). Conversely, AURKA -low tumors were enriched for epithelial mesenchymal transition, myogenesis, coagulation, angiogenesis, and transforming growth factor-β signaling pathways (most false discovery rate p < 0.001). Clinically, higher AURKA expression was associated with pathological complete response after neoadjuvant chemotherapy in three of nine ER+/HER2− cohorts and with worse survival outcomes. AURKA expression also decreased after neoadjuvant chemotherapy in all three paired cohorts analyzed, regardless of subtype. Conclusion: High AURKA expression was associated with a highly proliferative, immune-engaged tumor phenotype and with worse survival despite better therapeutic response in ER+/HER2− breast cancer.

Background: Refractory malignant pleural effusion impairs activities of daily living in patients with advanced cancer, and pleurodesis is used to palliate dyspnea. However, factors associated with pleural effusion reaccumulation after pleurodesis in breast cancer remain insufficiently defined. We explored clinicopathological factors and selected local pleural immune responses associated with pleural fluid control after pleurodesis. Methods: We retrospectively included 34 patients with advanced or recurrent breast cancer who underwent pleurodesis for malignant pleural effusion during 2015-2025. Patients were classified according to the presence or absence of documented pleural effusion reaccumulation after pleurodesis, irrespective of whether repeat drainage was subsequently performed. Associations between clinicopathological factors and reaccumulation were evaluated. Immunohistochemistry for MPO, a neutrophil marker, and CD206, an M2-like macrophage marker, was performed on available pleural effusion cell blocks. Results: Of the 34 patients, 23 (68%) had no documented reaccumulation and 11 (32%) had reaccumulation. Hormone receptor positivity was more frequent in the non-reaccumulation group ( P = .045), which also showed trends towards longer disease-free interval and time to malignant pleural effusion. No clear differences were observed in systemic inflammatory markers. Immunohistochemistry showed trends towards more MPO-positive cells and fewer CD206-positive cells in the non-reaccumulation group, although neither difference was statistically significant. Conclusions: Pleural fluid control after pleurodesis may be related to the clinical disease course of breast cancer. Opposite directional trends in MPO- and CD206-positive cells raise a hypothesis regarding the potential role of local inflammatory and immunoregulatory processes. These exploratory findings warrant further investigation.

Background and Purpose: Postoperative radiotherapy (RT) after breast-conserving surgery (BCS) is standard of care, but its benefit in older patients remains debated, particularly in societies with high life expectancy. We evaluated the age-stratified effect of RT on local recurrence and overall survival in a large real-world Japanese cohort.Materials and Methods: This retrospective, multicenter cohort study included women who underwent BCS for stage 0-III breast cancer across 23 Japanese institutions. Propensity score matching (PSM) balanced baseline characteristics between patients who received RT and those who did not. Local recurrence was analyzed with Fine-Gray competing risk regression; overall survival was analyzed with Cox proportional hazards models incorporating age interactions.Results: Among 8,851 eligible patients, PSM yielded 925 RT-treated and 925 untreated patients. RT reduced 10-year local recurrence from 10.82% to 2.36% (subdistribution hazard ratio, 0.20; 95% CI, 0.11-0.38), consistently across all age groups, including patients aged 75 years and older (hazard ratio, 0.14). RT also improved overall survival (hazard ratio, 0.30; 95% CI, 0.18-0.48), with a significant RT-by-age interaction (P = .042): the survival benefit was most pronounced at 50-74 years but attenuated, though still statistically significant, in patients 75 years and older (hazard ratio, 0.52).Conclusions: RT after BCS provides consistent local control benefit and a retained, albeit attenuated, survival benefit in patients 75 years and older. Chronological age alone is an insufficient criterion for RT-omission decisions; treatment should be individualized based on overall health and competing mortality risk.

Purpose: Tumor-associated nerves have recently emerged as an understudied key regulator of cancer biology. However, its quantification using histological or transcriptomic approaches is challenging because their small diameters hinder reliable detection and their cell bodies that hold most mRNA reside outside the tumor. This study evaluated a Schwann cell (SC)-related transcriptomic score as a surrogate for tumor-associated nerves in tumors from triple-negative breast cancer (TNBC) patients. Methods: Transcriptomic and clinical data from three independent TNBC cohorts, TCGA ( n = 170), METABRIC ( n = 335), and SCAN-B ( n = 174) were analyzed. An SC score was calculated from SC-related gene signatures, and spatial transcriptomics was used to validate SC localization. In addition, seven independent neoadjuvant chemotherapy (NAC) cohorts were analyzed to evaluate the association between SC score and treatment response. Associations between the SC score and clinical features, genomic features, proliferation, treatment response, and the tumor microenvironment (TME) were evaluated. Results: SC signature genes spatially localized to intratumoral nerve regions, confirming that the SC score reflects their presence within tumors. SC-high tumors were associated with lower mutation burden and with less cell proliferation in the TCGA, METABRIC, and SCAN-B cohorts. SC-high tumors were also associated with low immune activity and fewer infiltrating immune cells, along with enrichment of epithelial–mesenchymal transition (EMT), TGF-beta signaling and stromal remodeling pathways. Conclusions: The SC score-high TNBC is associated with lower cell proliferation, enhanced stromal remodeling and EMT and suppressed immune activity, suggesting a role of neural-associated TME features in shaping TNBC biology.

Background: Metastatic breast cancer (MBC) presents heterogeneous clinical behavior depending on the metastatic site and molecular subtype. However, only a few studies have directly compared prognostic outcomes by the organ of initial distant recurrence. This multi-institutional retrospective study aimed to clarify the clinical and biological characteristics of MBC based on cases with single-organ metastasis at the time of initial MBC diagnosis, using real-world data from Japanese patients. Methods: We retrospectively analyzed 309 Japanese women treated for early-stage breast cancer at six institutions between 2007 and 2021, who developed distant recurrence confined to a single organ (brain, lungs, liver, or bones) as the first site of metastasis. Patients with multi-organ metastases at initial recurrence were excluded. Results: The median distant metastasis-free survival and post-relapse survival (PRS) were 29.4 and 39.7 months, respectively. PRS was longest in patients with bone recurrence, followed by those with lung and liver recurrence, and shortest in those with brain recurrence (P < 0.001). Bone and lung metastases were more frequently associated with hormone receptor-positive tumors, whereas liver and brain metastases were enriched for human epidermal growth factor receptor 2 (HER2)-negative and triple-negative tumors. The multivariable Cox model identified older age, triple-negative subtype, and symptomatic recurrence as independent poor prognostic factors, while liver and brain metastases were also independently associated with shorter PRS. Site-specific analyses revealed that triple-negative subtype and symptomatic presentation were consistent markers of poor prognosis across most metastatic sites. Conclusions: Based on a single-organ metastasis cohort, this study identified distinctive clinicopathological features and survival outcomes according to the site of initial distant recurrence. Brain metastases were associated with the poorest outcomes, highlighting the need for improved risk stratification and treatment strategies.

Background: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are preventive options for women with hereditary breast and ovarian cancer (HBOC). The Japanese national medical insurance began covering RRM and RRSO for patients with HBOC in April 2020. Methods: We retrospectively analyzed 59 individuals with pathogenic germline variants (PGVs) from 55 families diagnosed with HBOC between 2010 and 2024 to assess the prevalence of RRM and RRSO after April 2020. Results: The median age at diagnosis was 50 years. Ten individuals (16.9%) were diagnosed before April 2020, whereas 49 (83.1%) were diagnosed afterward. PGVs included BRCA1 (28 individuals) and BRCA2 (31 individuals). The most common cancer was breast cancer (74.6%), followed by ovarian (13.6%), and pancreatic cancer (3.3%); 15.3% had no cancer history. RRM was performed in 19 of 41 individuals (46.3%), with the highest rate observed among BRCA1 PGV individuals (55.0%). RRSO was conducted in 30 of 41 individuals (73.1%), with higher rates among BRCA1 and BRCA2 PGV individuals. None of the individuals without a history of breast and/or ovarian cancer underwent these procedures. The median age was 50 for RRM and 49 for RRSO. Most surgeries (64.7% for RRM and 76.0% for RRSO) occurred within a year of genetic testing. Multivariate analysis showed that breast cancer history was strongly associated with RRM. Conclusions: National insurance coverage has enhanced access to genetic testing and preventive surgeries, with 46.3% and 73.1% undergoing RRM and RRSO, respectively. However, individuals without a cancer history remain underrepresented.

Postmastectomy radiation Therapy (PMRT) reduces locoregional recurrence (LRR) and breast cancer mortality in patients with ≥4 positive lymph nodes. However, evidence supporting PMRT in patients with 1–3 positive nodes remains limited. While the 2014 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis demonstrated benefit in this population, the constituent trials preceded current standard practices including sentinel lymph node biopsy, contemporary systemic therapies, and modern radiation therapy techniques. This analysis examines the applicability of EBCTCG findings to current clinical practice. Historical trials reported elevated LRR rates, potentially attributable to inadequate axillary staging and suboptimal systemic therapy regimens such as cyclophosphamide, methotrexate, and fluorouracil. Contemporary studies demonstrate substantially lower LRR rates in comparable patients managed without PMRT, particularly those with favorable tumor characteristics. Current adjuvant therapies—including anthracyclines, taxanes, trastuzumab, endocrine agents, and targeted therapies such as abemaciclib and olaparib—have markedly reduced recurrence risk. Retrospective analyses yield conflicting results regarding PMRT efficacy, while randomized trials (SUPREMO, TAILOR RT) seek to refine treatment indications. Contemporary practice should not universally recommend PMRT for intermediate-risk patients (1–3 nodes); instead, individualized risk assessment is warranted. The role of PMRT remains undefined in patients without axillary lymph node dissection or those achieving pathologic complete response following neoadjuvant therapy. Clinical decision-making must consider treatment benefits relative to potential late toxicities and reconstructive complications. Personalized, evidence-based approaches informed by emerging trial data represent the optimal strategy for patient management.