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Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1 -related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression ( p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1 -targeted therapies could be used in combination regimens for breast cancer patients.

Objective: To compare the clinical and patient-reported outcomes of minimal access and conventional nipple-sparing mastectomy (C-NSM). The secondary outcomes investigated included medical costs and oncological safety., Background: Minimal-access NSM has been increasingly applied in the treatment of patients with breast cancer. However, prospective multicenter trials comparing robotic-assisted NSM (R-NSM) versus C-NSM or endoscopic-assisted NSM (E-NSM) are lacking., Methods: A prospectively designed 3-arm multicenter, nonrandomized trial (NCT04037852) was conducted from October 1, 2019 to December 31, 2021, to compare R-NSM with C-NSM or E-NSM., Results: A total of 73 R-NSM, 74 C-NSM, and 84 E-NSM procedures were enrolled. The median wound length and operation time of C-NSM was (9 cm, 175 minutes), (4 cm, and 195 minutes) in R-NSM, and (4 cm and 222 minutes) in E-NSM. Complications were comparable among the groups. Better wound healing was observed in the minimal-access NSM group. The R-NSM procedure was 4000 and 2600 United States Dollars more expensive than C-NSM and E-NSM, respectively. Wound/scar and postoperative acute pain evaluation favored the use of minimal access NSM over C-NSM. Quality of life in terms of chronic breast/chest pain, mobility, and range of motion of the upper extremity showed no significant differences. The preliminary oncologic results showed no differences among the 3 groups., Conclusions: R-NSM or E-NSM is a safe alternative if compared with C-NSM in terms of perioperative morbidities, especially with better wound healing. The advantage of minimal access groups was higher wound-related satisfaction. Higher costs remain one of the major limiting factors in the widespread adoption of R-NSM., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The study used clinical data to develop a prediction model for breast cancer survival. Breast cancer prognostic factors were explored using machine learning techniques. We conducted a retrospective study using data from the Taipei Medical University Clinical Research Database, which contains electronic medical records from three affiliated hospitals in Taiwan. The study included female patients aged over 20 years who were diagnosed with primary breast cancer and had medical records in hospitals between January 1, 2009 and December 31, 2020. The data were divided into training and external testing datasets. Nine different machine learning algorithms were applied to develop the models. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1-score. A total of 3914 patients were included in the study. The highest AUC of 0.95 was observed with the artificial neural network model (accuracy, 0.90; sensitivity, 0.71; specificity, 0.73; PPV, 0.28; NPV, 0.94; and F1-score, 0.37). Other models showed relatively high AUC, ranging from 0.75 to 0.83. According to the optimal model results, cancer stage, tumor size, diagnosis age, surgery, and body mass index were the most critical factors for predicting breast cancer survival. The study successfully established accurate 5-year survival predictive models for breast cancer. Furthermore, the study found key factors that could affect breast cancer survival in Taiwanese women. Its results might be used as a reference for the clinical practice of breast cancer treatment., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: This study aimed to compare the effectiveness and safety of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based combination therapy regimen as neoadjuvant therapy for early breast cancer., Methods: Patients with stage I-III breast cancer who underwent neoadjuvant therapy followed by surgery between January 2018 and December 2019 were retrospectively reviewed. The primary outcome was pathological complete response (pCR) rate. The secondary outcome was radiologic complete response (rCR) rate. Outcomes were compared between treatment groups PLD-cyclophosphamide followed by docetaxel (LC-T group) or epirubicin-cyclophosphamide followed by docetaxel (EC-T group), using both propensity-score matched (matched) and unmatched data., Results: Data were analyzed from patients who received neoadjuvant LC-T (n = 178) or EC-T (n = 181) treatment. The overall pCR rate and rCR rate were higher in the LC-T group compared with the EC-T group (unmatched pCR: 25.3% vs. 15.5%, p = 0.026; rCR: 14.7% vs. 6.7%, p = 0.016; matched pCR: 26.9% vs. 16.1%, p = 0.034; rCR: 15.5% vs. 7.4%, p = 0.044). Analysis by molecular subtype showed that compared with EC-T treatment, LC-T treatment achieved significantly greater pCR rate in triple-negative subtype and greater rCR rate in Her2 (+) subtype., Conclusions: Neoadjuvant PLD-based therapy may be a potential option for patients with early-stage breast cancer. The current results warrant further investigation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression., Methods: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells., Results: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy., Conclusions: Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer., (© 2022. The Author(s).)

Background: Endoscopy-assisted total mastectomy has been used for surgical intervention of breast cancer patients; however, large cohort studies with long-term follow-up data are lacking., Methods: Breast cancer patients who underwent endoscopy-assisted total mastectomy from May of 2009 to March of 2018 were collected prospectively from multiple centers. Clinical outcome, impact of different phases, oncologic results, and patient-reported aesthetic outcomes of endoscopy-assisted total mastectomy were reported., Results: A total of 436 endoscopy-assisted total mastectomy procedures were performed; 355 (81.4 percent) were nipple-sparing mastectomy, and 81 (18.6 percent) were skin-sparing mastectomy. Three hundred fourteen (75.4 percent) of the procedures were associated with immediate breast reconstruction; 255 were prosthesis based and 59 were associated with autologous flaps. The positive surgical margin rate for endoscopy-assisted total mastectomy was 2.1 percent. In morbidity evaluation, there were 19 cases (5.4 percent) with partial nipple necrosis, two cases (0.6 percent) with total nipple necrosis, and three cases (0.7 percent) with implant loss. Compared with the early phase, surgeons operating on patients in the middle or late phase had significantly decreased operation time and blood loss. With regard to patient-reported cosmetic outcomes, approximately 94.4 percent were satisfied with the aesthetic results. Patients who underwent breast reconstruction with preservation of the nipple had higher satisfaction rates. Over a median follow-up of 54.1 ± 22.4 months, there were 14 cases of locoregional recurrence (3.2 percent), three distant metastases (0.7 percent), and one mortality (0.2 percent)., Conclusion: This multicenter study showed that endoscopy-assisted total mastectomy is a reliable surgical intervention for early breast cancer, with high patient satisfaction., Clinical Question/level of Evidence: Therapeutic, IV., Competing Interests: Disclosure:None of the authors has conflicts of interest or financial ties to disclose., (Copyright © 2020 by the American Society of Plastic Surgeons.)

Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients. As compared with paired normal tissues and healthy individuals, CCND2 promoter hypermethylation was detected in 40.9% of breast tumors and 44.4% of plasma circulating cell-free DNA of patients. The western cohort of The Cancer Genome Atlas also demonstrated CCND2 promoter hypermethylation in female lung cancer, lung adenocarcinoma, and breast cancer patients and that CCND2 promoter hypermethylation is an independent poor prognostic factor. The cell model assay indicated that CCND2 expression inhibited cancer cell growth and migration ability. The demethylating agent antroquinonol D upregulated CCND2 expression, caused cell cycle arrest, and inhibited cancer cell growth and migration ability. In conclusion, hypermethylation of CCND2 is a potential diagnostic, prognostic marker and drug target, and it is induced by antroquinonol D.

Introduction: Laparoscopic techniques are commonly used in abdominal and gynecologic surgery, while breast cancer surgery has remained largely unchanged. In Asia, especially in Japan, many surgeons have started to use endoscopic surgery for breast cancer. In Taiwan, endoscopy-assisted breast surgery started in 2010. The benefits of this surgical method include smaller incisions, an axillary anatomic approach, clear vision, no oncologic compromise, and good cosmetic outcomes. This is the first report to discuss the learning curve of endoscopy-assisted breast surgery, including the difficulties experienced., Materials and Methods: From June 2011 to December 2013, data were collected from 134 patients who received an endoscopic total mastectomy at the Taipei Medical University Hospital (TMUH) or Changhua Christian Hospital (CCH). We divided these patients into a learning group (TMUH, n = 15; CCH, n = 15) and a mature group (TMUH, n = 50; CCH, n = 54). Patient data and perioperative variables were recorded by retrospective chart review. Variables were compared using the χ2 test and Student's t-test., Results: There was a significant difference in operation time (275.3 vs. 228.9 minutes, p < 0.01) between the learning and mature groups. Perioperative variables (lymph node dissection method, nipple preservation, and reconstruction method) were also analyzed, but there were no demographic differences between the groups. The complication rate was higher in the learning group, although this difference was also not statistically significant., Conclusion: Our study is the first to discuss the learning curve of endoscopic total mastectomy. The operation time decreased significantly after 15 cases at each hospital. Although the operation is still more time-consuming than traditional methods, it has the benefit of smaller wounds and improved cosmetic outcomes if combined with immediate reconstruction.

Background: Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population., Methods: In total, 446 breast cancer patients and 514 healthy controls were recruited for this case-control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC)., Results: Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose-response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51-3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%., Conclusions: Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

Background: Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women., Methods: This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2., Results: Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1-3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study., Conclusions: A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.

Background: Endoscopy-assisted breast surgery (EABS) performed through minimal axillary and/or periareolar incisions is a possible alternative to open surgery for certain patients with breast cancer. In this study, we report the early results of an EABS program in Taiwan., Methods: The medical records of patients who underwent EABS for breast cancer during the period May 2009 to December 2014 were collected from the Taiwan Endoscopic Breast Surgery Cooperative Group database. Data on clinicopathologic characteristics, type of surgery, method of breast reconstruction, complications and recurrence were analyzed to determine the effectiveness and oncologic safety of EABS in Taiwan., Results: A total of 315 EABS procedures were performed in 292 patients with breast cancer, including 23 (7.8%) patients with bilateral disease. The number of breast cancer patients who underwent EABS increased initially from 2009 to 2012 and then stabilized during the period 2012-2014. The most commonly performed EABS was endoscopy-assisted total mastectomy (EATM) (85.4%) followed by endoscopy-assisted partial mastectomy (EAPM) (14.6%). Approximately 74% of the EATM procedures involved breast reconstruction, with the most common types of reconstruction being implant insertion and autologous pedicled TRAM flap surgery. During the six-year study period, there was an increasing trend in the performance of EABS for the management of breast cancer when total mastectomy was indicated. The positive surgical margin rate was 1.9%. Overall, the rate of complications associated with EABS was 15.2% and all were minor and wound-related. During a median follow-up of 26.8 (3.3-68.6) months, there were 3 (1%) cases of local recurrence, 1 (0.3%) case of distant metastasis and 1 (0.3%) death., Conclusion: The preliminary results from the EABS program in Taiwan show that EABS is a safe procedure and results in acceptable cosmetic outcome. These findings could help to promote this under-used surgical technique in the field of breast cancer.

Previous studies indicated that smoking exposure is associated with an increased risk of breast cancer, and α9-nicotine acetylcholine receptors (α9-nAChRs) are involved in breast tumorigenesis. However, no studies have explored the joint effect of α9-nAChRs (CHRNA9) genes and cigarette smoking exposure on breast cancer risk. A case-control study was conducted on 737 breast cancer patients and 719 age-matched healthy controls. Three single-nucleotide polymorphisms (SNPs) of CHRNA9 located in the promoter region were genotyped and compared between cases and controls to identify those SNPs associated with breast cancer susceptibility. A dual-luciferase reporter assay was used to analyze the promoter activities of these SNPs of the CHRNA9 gene. After a Bonferroni correction, the G allele of the CHRNA9 rs7329797 SNP was significantly associated with an increased risk of developing breast cancer compared with A/A genotype carriers (odds ratio, 1.8; 95% confidence interval, 1.2-2.6). A multiplicative interaction between passive smoking exposure and the CHRNA9 rs73229797 SNP on the risk of breast malignancy was observed. A functional assay further showed that rs73229797 was associated with increased promoter activity of the CHRNA9 gene. Our findings support a significant interaction effect existing between the CHRNA9 gene and smoking exposure on the risk of breast cancer development., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Metastasis is the most life-threatening complication in all cancers. The chemokine receptor 4 (CXCR4) is expressed at high levels in many breast-cancer tumors and may modulate metastasis. We compared the time-to-metastasis and the sites of metastasis between breast-cancer tumors expressing CXCR4 at high or low levels. We enrolled 191 early breast cancer patients in our study. The expression of CXCR4 was evaluated using immunohistochemical staining, and the patients were divided into low-level (CXCR4-) and high-level (CXCR4+) CXCR4 expression groups. Associations between the patients' level of CXCR4 expression and their basic clinical characteristics, time-to-metastasis, and metastatic sites were examined using a Cox proportional-hazards regression model. A total of 107 CXCR4+ patients (56 %) were identified. No statistical differences were evident in basic characteristics between the CXCR4+ and CXCR4- groups. The CXCR4+ group had a higher incidence of distant metastasis during the first year (10.3 % versus 1.1 %, P = 0.009) and shorter event-free survival (17.43 months versus 27.5 months, P = 0.026) than those of the CXCR4- group. The CXCR4+ group also had a higher incidence of bone metastasis (P = 0.008) than the CXCR4- group. No significant difference in metastasis sites in other organs was observed between the two groups. A high level of CXCR4 expression in breast cancer is associated with early distant and bone metastases. The CXCR4+ phenotype may be a useful predictor for the prevention of early treatment failure and bone metastasis in breast cancer patients. This retrospective study shows that a high expression of CXCR4 in breast cancer is associated with earlier distant metastasis and bone metastasis in breast cancer.

Background: Lymphedema is a common complication of axillary dissection for breast cancer. We investigated whether manual lymphatic drainage (MLD) could prevent or manage limb edema in women after breast-cancer surgery., Methods: We performed a systematic review and meta-analysis of published randomized controlled trials (RCTs) to evaluate the effectiveness of MLD in the prevention and treatment of breast-cancer-related lymphedema. The PubMed, EMBASE, CINAHL, Physiotherapy Evidence Database (PEDro), SCOPUS, and Cochrane Central Register of Controlled Trials electronic databases were searched for articles on MLD published before December 2012, with no language restrictions. The primary outcome for prevention was the incidence of postoperative lymphedema. The outcome for management of lymphedema was a reduction in edema volume., Results: In total, 10 RCTs with 566 patients were identified. Two studies evaluating the preventive outcome of MLD found no significant difference in the incidence of lymphedema between the MLD and standard treatment groups, with a risk ratio of 0.63 and a 95% confidence interval (CI) of 0.14 to 2.82. Seven studies assessed the reduction in arm volume, and found no significant difference between the MLD and standard treatment groups, with a weighted mean difference of 75.12 (95% CI, -9.34 to 159.58)., Conclusions: The current evidence from RCTs does not support the use of MLD in preventing or treating lymphedema. However, clinical and statistical inconsistencies between the various studies confounded our evaluation of the effect of MLD on breast-cancer-related lymphedema.

Objective: The optimal duration of adjuvant trastuzumab treatment in patients with HER2-positive breast cancer is not known. The aim of this study was to evaluate the efficacy of 6 months of adjuvant trastuzumab treatment in patients with stage II or III HER2-positive breast cancer., Methods: The records of patients with HER2-positive stage II or III breast cancer who were admitted to the Breast Center of Taipei Medical University Hospital and Yuan's General Hospital between 2000 and 2008 were reviewed. All patients received adjuvant trastuzumab at an initial dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg/week for 22 weeks in combination with chemotherapy., Results: A total of 51 patients were included with a mean age of 46.9 years. Approximately 55% of the patients had stage III disease. The mean follow-up time from initiation of treatment was 45.2 months (range, 0.9 to 85 months). During follow-up, 46 patients (90.2%) did not experience tumor recurrence. The mean estimated disease free survival was 80.2 months. The estimated 1- , 2-, 5-, and 7-year survival rates were 97.9%, 93.1%, 93.1%, and 93.1%, respectively. The most common adverse effects were gastrointestinal symptoms (21.6%), chills (17.6%), dizziness (9.8%), and bone pain (7.8%). No cardiac or hematologic adverse events occurred., Conclusion: Adjuvant therapy with trastuzumab for 6 months resulted in a clinical benefit in patients with HER2-positive breast cancer.

Background: Bevacizumab is a monoclonal antibody that prevents angiogenesis by inhibiting vascular endothelial growth factor (VEGF) activity. Clinically, it has been used to treat a diverse range of cancer types. In this pilot phase II study, we investigated the efficacy and safety profiles of bevacizumab in combination with docetaxel plus cisplatin for patients with advanced HER2-negative metastatic breast cancer., Patients and Methods: Between 2005 and 2008, 20 patients with advanced breast cancer were recruited from the Taipei Medical University Hospital. Bevacizumab was administered every two weeks in a 12-cycle treatment with docetaxel plus cisplatin. The primary end-point for this study was the overall response rate. The secondary end-points were progression-free survival and the safety profiles of the combined therapy., Results: The average number of treatment cycles was 10.5 with a response rate of 80%. Neutropenia and neuropathy were the most commonly observed adverse events. Seven patients achieved complete remission and nine patients achieved partial remission. For the overall patient group in this study, the median time-to-progression and overall survival were 28.0 weeks and 52 weeks, respectively. The median time-to-progression and overall survival for the 10 patients that completed all 12 cycles of treatment were 64.0 weeks and 80 weeks, respectively. In one patient, a very rapid reduction in the level of breast cancer lung metastases was observed one week post-treatment., Conclusion: Based on this pilot study, bevacizumab in combination with docetaxel and cisplatin is likely to be an effective treatment option for metastatic breast cancer that warrants further study.