Hidetaka Kawabata

Background: Chemotherapy-induced alopecia (CIA) significantly impacts patient quality of life (QoL). Scalp cooling therapy (SCT) is effective, but its success in clinical settings remains variable. Objective: To evaluate the association between a refined multidisciplinary team-based approach, integrating appearance care professionals, and SCT efficacy in breast cancer patients. Methods: This retrospective before–after single-institution study compared SCT outcomes before (Group A, n = 66) and after (Group B, n = 79) implementing a refined care model among patients who completed their full planned chemotherapy courses. The baseline characteristics were comparable except for a significantly higher proportion of patients starting a weekly regimen in Group B (54.4% vs. 30.3%, p = 0.004). The model featured enhanced staff training, a specialized hair/scalp charting system, and task-sharing between nurses and integrated certified hairdressers. The primary endpoint was the number of cycles with Grade 2 or higher alopecia (CTCAE v5.0). Results: The refined approach was associated with improved scalp cooling outcomes. The percentage of patients with Grade 2+ alopecia at treatment completion decreased from 53.0% in Group A to 32.9% in Group B (p = 0.015). The overall proportion of time spent with Grade 2+ alopecia fell from 17.3% to 6.5% (p < 0.001). In the ddAC f/b wPTX regimen, the median number of Grade 2+ cycles reduced from 10.0 to 4.0 (p = 0.033). While the wPTX f/b ddAC regimen showed a numerical reduction (1.0 vs. 0.0 cycles), it did not reach statistical significance (p = 0.326). Conclusions: The refined multidisciplinary approach, including the integration of appearance care professionals, was associated with improved scalp cooling outcomes and lower median cycle numbers across regimens. Although these findings may be partly influenced by the baseline imbalance in chemotherapy regimens, this comprehensive team-based care model offers a feasible strategy for enhancing patient support in oncology settings.

To investigate long-term outcomes for triple‑negative breast cancer (TNBC) patients enrolled in JBCRG-22. TNBC (cT1c-T3, cN0-1, M0) patients were stratified by homologous recombination deficiency (HRD) and germline BRCA mutation (gBRCAm) status. Group A patients (aged < 65 years with HRD-positive tumors, or those with gBRCAm, if available) were randomized to receive 4 cycles of weekly paclitaxel (group A1) or eribulin (group A2), both with carboplatin, followed by 4 cycles of anthracycline. Group B patients (aged < 65 years with HRD-negative tumors or aged ≥ 65 years) were randomized to receive 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2). Five-year invasive disease-free survival (IDFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed. Additionally, data were analyzed by biomarker levels including lymphocyte count (LC) and neutrophil-to-lymphocyte ratio (NLR). Ninety-nine patients were followed for a median of 5.6 years. In patients who received eribulin-based therapy (groups A2 + B1 + B2), 5-year IDFS and OS rates, respectively, were 95% and 100% in patients who achieved pCR after neoadjuvant therapy (n = 20) and 71.4% and 80.2% in those who did not (n = 56), showing significantly better prognosis in the pCR cohort (p < 0.05). OS tended to be better in patients with baseline LC ≥ 1500/mm³ and NLR < 3, particularly in eribulin-treated patients, although differences were non-significant. These findings will help guide the development of eribulin-based neoadjuvant chemotherapy for selected TNBC patients. Our exploratory analysis of LC and NLR results may help inform clinical prediction models for eribulin-treated patients. The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( https://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Background Chemotherapy is crucial for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and its survival benefit may outweigh adverse events. Oncotype DX (ODX) assesses this balance; however, it is expensive. Using nomograms to identify cases requiring ODX may be economically beneficial. We aimed to identify clinicopathological variables that correlated with the recurrence score (RS) and develop a nomogram that predicted the RS. Methods We included 457 patients with estrogen receptor-positive, HER2-negative breast cancer with metastases in less than four axillary lymph nodes who underwent surgery and ODX at our hospital between 2007 and 2023. We developed nomograms and internally validated them in 310 patients who underwent surgery between 2007 and 2021 and validated the model’s performance in 147 patients who underwent surgery between 2022 and 2023. Results Logistic regression analysis revealed that progesterone receptor (PgR) level, histological grade (HG), and Ki67 index independently predicted the RS. A nomogram was developed using these variables to predict the RS (area under the curve [AUC], 0.870; 95% confidence interval [CI], 0.82–0.92). The nomogram was applied to the model validation group (AUC, 0.877; 95% CI, 0.80–0.95). When the sensitivity of the nomogram was 90%, the model was able to identify 52.3% low-RS and 41.2% high-RS cases not requiring ODX. Conclusions This was the first nomogram model developed based on data from a cohort of Japanese women. It may help determine the indications for ODX and the use of nomogram to identify cases requiring ODX may be economically beneficial.

Background The Chemotherapy-induced Alopecia Distress Scale (CADS) is a patient-reported outcome measure for assessing distress associated with Chemotherapy-induced alopecia (CIA). This study aimed to confirm the psychometric validity of the Japanese version of the CADS (CADS-J). Methods A total of 132 patients with breast cancer who developed CIA were asked to complete the CADS-J twice at 2 week intervals to confirm test–retest reliability. The body image domain of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) breast cancer-specific module, the self-esteem scale from the Rosenberg Self-Esteem Scale, and the emotional domain of the EORTC QLQ Core 30 were used to confirm the convergent validity of the CADS-J. The overall quality of life and physical domains of the EORTC QLQ Core 30 were used to confirm the discriminant validity of the CADS-J. Results In total, 125 participants provided valid responses. The mean age was 52.2 years. The overall Cronbach’s alpha for the CADS-J was 0.903. The intraclass correlation coefficients of the first and second responses were r = 0.874, r = 0.952, r = 0.911, and r = 0.959 for the physical domain, emotional domain, activity domain, and relationship domain, respectively. In terms of convergent validity, the total CADS-J score was moderately correlated with body image (r = − 0.63), self-esteem (r = − 0.48), and the emotional domain (r = − 0.61). Regarding discriminant validity, the total CADS-J score was weakly correlated with the overall quality of life (r = − 0.34) and physical domain (r = − 0.24). Conclusions The CADS-J is psychometrically reliable and valid for evaluating the distress caused by CIA. It is expected to be used in daily practice and as an endpoint in various studies.

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.Significance:This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.

This file contains Supplementary Figure S1. High PSF expression is positively associated with poor prognosis of breast cancer patients.; Supplementary Figure S2. ESR1 expression is elevated in endocrine resistance model hydroxytamoxifen-resistant OHTR cells and ESR1 knockdown represses OHTR cell proliferation.; Supplementary Figure S3. PSF knockdown represses the proliferation and cell cycle progression of ER-positive T47D breast cancer cells.; Supplementary Figure S4. PSF correlates with estrogen signaling pathway and regulates the expression of estrogen target genes without altering its own mRNA expression.; Supplementary Figure S5. PSF regulates ESR1 expression at the posttranscriptional level.; Supplementary Figure S6. PSF overexpression enhances ESR1 expression and overcomes OHT-dependent cell proliferation inhibition.; Supplementary Figure S7. Mapping of PSF-immunoprecipitated RNAs in the vicinity of known PSF-associated genes or PSF-nonassociated gene and identification of PSF-binding RNAs with RIP-seq.; Supplementary Figure S8. PSF regulates SCFD2, TRA2B and ASPM expression at posttranscriptional level in ER-positive breast cancer cells.; Supplementary Figure S9. PSF knockdown promotes nuclear accumulation of SCFD2 and TRA2B but not ASPM in ER-positive breast cancer cells, whereas high expression of TRA2B and ASPM is significantly associated with shorter survivals of breast cancer patients.; Supplementary Figure S10. High expression of PSF-targeted SCFD2 is associated with shorter relapse-free survival of ER-positive breast cancer patients and SCFD2 knockdown represses T47D cell proliferation.; Supplementary Figure S11. PSF siRNA injection downregulates ER+ expression in xenograft tumors inoculated with tamoxifen-resistant cancer cells without altering mouse body weight and pre-mRNA expression of ESR1 and SCFD2.; Supplementary Table S1. Primers used in this study.; Supplementary Table S2. Association between PSF status and clinicopathological parameters in Shikoku Cancer Center cohort including 73 cases of human ER-positive breast cancers.; Supplementary Table S3. Clinicopathological parameters associated with distant disease-free or overall survival in univariate and multivariate analyses in Shikoku Cancer Center cohort (n = 73).; Supplementary Table S4. Association between PSF status and clinicopathological parameters in Toranomon Hospital cohort including 114 breast cancer cases.; Supplementary Table S5. Clinicopathological parameters associated with overall survival in univariate and multivariate analyses in Toranomon Hospital cohort (n = 114).; and Supplementary Experimental Procedures.

This file contains Supplementary Figure S1. High PSF expression is positively associated with poor prognosis of breast cancer patients.; Supplementary Figure S2. ESR1 expression is elevated in endocrine resistance model hydroxytamoxifen-resistant OHTR cells and ESR1 knockdown represses OHTR cell proliferation.; Supplementary Figure S3. PSF knockdown represses the proliferation and cell cycle progression of ER-positive T47D breast cancer cells.; Supplementary Figure S4. PSF correlates with estrogen signaling pathway and regulates the expression of estrogen target genes without altering its own mRNA expression.; Supplementary Figure S5. PSF regulates ESR1 expression at the posttranscriptional level.; Supplementary Figure S6. PSF overexpression enhances ESR1 expression and overcomes OHT-dependent cell proliferation inhibition.; Supplementary Figure S7. Mapping of PSF-immunoprecipitated RNAs in the vicinity of known PSF-associated genes or PSF-nonassociated gene and identification of PSF-binding RNAs with RIP-seq.; Supplementary Figure S8. PSF regulates SCFD2, TRA2B and ASPM expression at posttranscriptional level in ER-positive breast cancer cells.; Supplementary Figure S9. PSF knockdown promotes nuclear accumulation of SCFD2 and TRA2B but not ASPM in ER-positive breast cancer cells, whereas high expression of TRA2B and ASPM is significantly associated with shorter survivals of breast cancer patients.; Supplementary Figure S10. High expression of PSF-targeted SCFD2 is associated with shorter relapse-free survival of ER-positive breast cancer patients and SCFD2 knockdown represses T47D cell proliferation.; Supplementary Figure S11. PSF siRNA injection downregulates ER+ expression in xenograft tumors inoculated with tamoxifen-resistant cancer cells without altering mouse body weight and pre-mRNA expression of ESR1 and SCFD2.; Supplementary Table S1. Primers used in this study.; Supplementary Table S2. Association between PSF status and clinicopathological parameters in Shikoku Cancer Center cohort including 73 cases of human ER-positive breast cancers.; Supplementary Table S3. Clinicopathological parameters associated with distant disease-free or overall survival in univariate and multivariate analyses in Shikoku Cancer Center cohort (n = 73).; Supplementary Table S4. Association between PSF status and clinicopathological parameters in Toranomon Hospital cohort including 114 breast cancer cases.; Supplementary Table S5. Clinicopathological parameters associated with overall survival in univariate and multivariate analyses in Toranomon Hospital cohort (n = 114).; and Supplementary Experimental Procedures.

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.Significance:This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.

Background: Solitary fibrous tumors (SFT) are uncommon mesenchymal neoplasms which can arise in any anatomical location. Pleural SFTs have been most frequently documented; however, breast SFT is an exceedingly rare entity and seldom present in male breast, with only 8 previously reported cases. Recently, STAT6 immunostaining was considered to be a definitive marker of SFT, however, no case of the male breast SFT showing STAT6 positivity preoperatively has been reported. Methods and Results: We describe a case of breast SFT in a 73-year-old male patient with a 12-month history of a palpable breast mass. The only associated clinical symptom was bilateral gynecomastia. An ultrasound scan examination revealed an oval, well-circumscribed and hypoechoic mass with hypervascularity. A core-needle biopsy was performed, and microscopic examination with immunohistochemistry confirmed the diagnosis of SFT. He underwent a complete surgical resection with clear margins, and there were no signs of high cellularity, remarkable mitotic activity, pleomorphism, hemorrhage or necrosis. Conclusion: A perioperative immunohistochemical evaluation for diffuse and intense nuclear expression of STAT6 was helpful to distinguish SFT from myofibroblastoma. We, herein, describe the first case of SFT in a male breast, confirmed by STAT6 immunostaining positivity. We also conducted a literature review of all previous cases of breast SFTs.

Recent advances in RNA studies have revealed that functional long noncoding RNAs (lncRNAs) contribute to the biology of cancers. In breast cancer, estrogen receptor α (ERα) is an essential transcription factor that primarily promotes the growth of luminal-type cancer, although only a small number of lncRNAs are identified as direct ERα targets and modulators for ERα signaling. In this study, we performed RNA-sequencing for ER-positive breast cancer cells and identified a novel estrogen-inducible antisense RNA in the COL18A1 promoter region, named breast cancer natural antisense transcript 1 (BNAT1). In clinicopathological study, BNAT1 may have clinical relevance as a potential diagnostic factor for prognoses of ER-positive breast cancer patients based on an in situ hybridization study for breast cancer specimens. siRNA-mediated BNAT1 silencing significantly inhibited the in vitro and in vivo growth of tamoxifen-resistant ER-positive breast cancer cells. Notably, BNAT1 silencing repressed cell cycle progression whereas it promoted apoptosis. Microarray analysis revealed that BNAT1 silencing in estrogen-sensitive breast cancer cells repressed estrogen signaling. We showed that BNAT1 knockdown decreased ERα expression and repressed ERα transactivation. RNA immunoprecipitation showed that BNAT1 physically binds to ERα protein. In summary, BNAT1 would play a critical role in the biology of ER-positive breast cancer by modulating ERα-dependent transcription regulation. We consider that BNAT1 could be a potential molecular target for diagnostic and therapeutic options targeting luminal-type and endocrine-resistant breast cancer.