Surveillance for Distant Metastasis in Breast Cancer Patients Who Underwent Contemporary Management: A Report from the Korean Breast Cancer Society Survivor Research Group.

BACKGROUND: Current guidelines recommend against the use of routine imaging tests to detect distant metastasis in asymptomatic breast cancer patients. However, recent advancements in effective therapeutics and diagnostic accuracy have raised the need to reassess the clinical efficacy of intensive metastasis surveillance. We report the results of a multicenter retrospective study to investigate the association between intensive imaging studies and survival outcomes. PATIENTS AND METHODS: We retrospectively reviewed the data of 4130 patients who underwent surgery from 11 hospitals in Korea between January 2010 and December 2011. Patients were divided into two groups on the basis of the intensity of metastasis imaging studies during their disease-free period. The types and intervals of the imaging studies were based on each physician's decisions. RESULTS: High-intensive screening showed a shorter distant metastasis-free survival [p < 0.001, hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.29-2.04], especially for patients in whom bone or lung was the first site of metastasis. With a median follow-up period of 110.0 months, the 5-year breast cancer-specific survival (BCSS) rate was 96.5%. The high-intensity screening group showed significantly poorer BCSS compared with the low-intensity screening group (p < 0.001, HR 3.13; 95% CI 2.32-4.21). However, both multivariable analysis and propensity score matching analysis showed no significant association between the screening intensity and BCSS. CONCLUSIONS: Frequent imaging studies to detect distant metastasis were associated with earlier detection of distant metastasis, especially for lung and bone metastasis. However, intensive surveillance showed no apparent association with BCSS despite the use of currently available treatments.

Comparison of long-term oncologic outcomes of central lumpectomy and conventional breast-conserving surgery for invasive breast cancer: propensity score matching analysis.

PURPOSE: Central lumpectomy (CL) is a breast-conserving surgical (BCS) technique that involves excision of the nipple-areolar complex with breast tumor in centrally located breast cancers. We aimed to investigate the long-term clinical outcomes of CL in comparison with conventional BCS (cBCS). METHODS: Patient records who underwent BCS with clear resection margins for invasive breast cancer between 2004 and 2018 were retrospectively reviewed. Of the total 6,533 patients, 106 (1.6%) underwent CL. Median follow-up duration was 73.4 months. 1:3 propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize selection bias. RESULTS: The CL group showed a significantly higher ipsilateral breast tumor recurrence (IBTR) rate than the cBCS group (10-year IBTR rate: 5.8% vs. 3.1%, p = 0.004), even after adjusting for other variables (hazard ratio (HR), 2.65; 95% confidence interval (CI), 1.07-6.60, p = 0.048). However, there were no significant differences observed in regional recurrence, distant metastasis, or overall survival rates between the two groups. Both PSM and IPTW analyses showed significantly higher IBTR in the CL group (PSM HR, 3.27; 95% CI, 0.94-11.36; p = 0.048 and IPTW HR, 4.66; 95%CI, 1.85-11.77; p < 0.001). Lastly, when analyzing 2,213 patients whose tumors were located within 3 cm of the nipple, the CL group showed a significantly higher IBTR than the cBCS group before and after PSM. CONCLUSION: CL was associated with a higher rate of IBTR compared to cBCS, while other survival outcomes were comparable. For centrally located tumors, CL may be considered for patients preferring breast preservation. However, higher risk for IBTR should be informed and careful surveillance may be necessary during the early post-operative follow-up periods.

Survival Outcomes in Premenopausal Patients With Invasive Lobular Carcinoma.

Importance: The disparate prognostic implications between invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) have been demonstrated. However, information on premenopausal patients remains insufficient. Objective: To examine long-term survival outcomes of ILC and IDC in premenopausal patients using national databases. Design, Setting, and Participants: This cohort study used the Surveillance, Epidemiology, and End Results (SEER), Korean Breast Cancer Registry (KBCR), and Asan Medical Center Research (AMCR) databases to identify premenopausal patients with stage I to III ILC or IDC between January 1, 1990, and December 31, 2015. The median follow-up time was 90 (IQR, 40-151) months in the SEER database, 94 (IQR, 65-131) months in the KBCR database, and 120 (IQR, 86-164) months in the AMCR database. Data were analyzed from January 1 to May 31, 2023. Main Outcomes and Measures: The primary outcome was breast cancer-specific survival (BCSS), which was analyzed according to histological type, and the annual hazard rate was evaluated. Survival rates were analyzed using a log-rank test and a Cox proportional hazards regression model with time-varying coefficients. Multivariable analysis was performed by adjusting for tumor characteristics and treatment factors. Results: A total of 225 938 women diagnosed with IDC or ILC and younger than 50 years were identified. Mean (SD) age at diagnosis was 42.7 (5.3) years in the SEER database, 41.8 (5.5) years in the KBCR database, and 41.8 (5.5) years in the AMCR database. In terms of race (available for the SEER database only), 12.4% of patients were Black, 76.1% were White, 11.0% were of other race (including American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander), and 0.5% were of unknown race). Patients with ILC had better BCSS in the first 10 years after diagnosis than those with IDC (hazard ratios [HRs], 0.73 [95% CI, 0.68-0.78] in the SEER database, 1.20 [95% CI, 0.91-1.58] in the KBCR database, and 0.50 [95% CI, 0.29-0.86] in the AMCR database), although BCSS was worse after year 10 (HRs, 1.80 [95% CI, 1.59-2.02] in the SEER database, 2.79 [95% CI, 1.32-5.88] in the KBCR database, and 2.23 [95% CI, 1.04-4.79] in the AMCR database). Similar trends were observed for hormone receptor-positive tumors (HRs, 1.55 [95% CI, 1.37-1.75] in the SEER database, 2.27 [95% CI, 1.01-5.10] in the KBCR database, and 2.12 [95% CI, 0.98-4.60] in the AMCR database). Considering the annual hazard model of BCSS, IDC events tended to decline steadily after peaking 5 years before diagnosis. However, the annual peak event of BCSS was observed 5 years after diagnosis for ILC, which subsequently remained constant. Conclusions and Relevance: These findings suggest that premenopausal women with ILC have worse BCSS estimates than those with IDC, which can be attributed to a higher late recurrence rate of ILC than that of IDC. Histological subtypes should be considered when determining the type and duration of endocrine therapy in premenopausal women.

Prognostic Implication of Focal Breast Edema on Preoperative Breast Magnetic Resonance Imaging in Breast Cancer Patients.

PURPOSE: In this study, we investigated the prognostic implications of focal breast edema on preoperative breast magnetic resonance imaging (MRI) in patients with breast cancer. METHODS: Data of 899 patients with breast cancer at a single institution were retrospectively analyzed. The patients were divided into an edema-positive group (EPG) and an edema-negative group (ENG) based on the presence of peritumoral, prepectoral, or subcutaneous edema. Two radiologists evaluated the presence or absence of focal edema and its subtypes on preoperative breast MRI. Clinicopathologic characteristics and survival outcomes were compared between the two groups and among the three subtypes using Pearson's χ² test, Kaplan-Meier estimator, and Cox proportional hazards model. RESULTS: There were 399 (44.4%) and 500 (55.6%) patients in the EPG and ENG, respectively. The EPG showed significantly higher rates of axillary lymph node metastasis (55.6% vs. 19.2%, p < 0.001) and lymphovascular invasion (LVI) (57.9% vs. 12.6%, p < 0.001) than the ENG. Patients in the EPG showed significantly worse overall survival (OS) rate (log-rank p < 0.001; hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.56-9.11) and recurrence-free survival rate (log-rank p < 0.001; HR, 3.00; 95% CI, 1.94-4.63) than those in the ENG. After adjusting for other variables, focal breast edema remained a significant factor affecting the OS rate, regardless of the edema type. Specifically, the presence of subcutaneous edema emerged as the strongest predictor for OS with the highest HR (p < 0.001; HR, 9.10; 95% CI, 3.05-27.15). CONCLUSION: Focal breast edema on preoperative breast MRI implies a higher possibility of LVI and axillary lymph node metastasis, which can lead to a poor prognosis. A detailed description of focal breast edema, especially subcutaneous edema, on preoperative breast MRI may provide prognostic predictions. More intensive surveillance is required for patients with breast cancer and focal preoperative breast edema.

Diagnostic accuracy of a three-protein signature in women with suspicious breast lesions: a multicenter prospective trial.

BACKGROUND: Mammography screening has been proven to detect breast cancer at an early stage and reduce mortality; however, it has low accuracy in young women or women with dense breasts. Blood-based diagnostic tools may overcome the limitations of mammography. This study assessed the diagnostic performance of a three-protein signature in patients with suspicious breast lesions. FINDINGS: This trial (MAST; KCT0004847) was a prospective multicenter observational trial. Three-protein signature values were obtained using serum and plasma from women with suspicious lesions for breast malignancy before tumor biopsy. Additionally, blood samples from women who underwent clear or benign mammography were collected for the assays. Among 642 participants, the sensitivity, specificity, and overall accuracy values of the three-protein signature were 74.4%, 66.9%, and 70.6%, respectively, and the concordance index was 0.698 (95% CI 0.656, 0.739). The diagnostic performance was not affected by the demographic features, clinicopathologic characteristics, and co-morbidities of the participants. CONCLUSIONS: The present trial showed an accuracy of 70.6% for the three-protein signature. Considering the value of blood-based biomarkers for the early detection of breast malignancies, further evaluation of this proteomic assay is warranted in larger, population-level trials. This Multi-protein Assessment using Serum to deTermine breast lesion malignancy (MAST) was registered at the Clinical Research Information Service of Korea with the identification number of KCT0004847 ( https://cris.nih.go.kr ).

Association of body composition fat parameters and breast density in mammography by menopausal status.

We investigated the relationship between body fat-driven obesity and breast fat density in mammography according to menopausal status. We retrospectively analyzed 8537 women (premenopausal, n = 4351; postmenopausal, n = 4186). Body fat parameters included BMI (body mass index), waist circumference (WC), waist-hip ratio (WHR), fat mass index (FMI), Percentage of body fat (PBF), and visceral fat area (VFA). Body fat-driven obesity was defined as follows: overall obesity, BMI ≥ 25 kg/m2; central obesity, WC > 85 cm; abdominal obesity, WHR > 0.85; excessive FMI, the highest quartile (Q4) of FMI; excessive PBF, the highest quartile (Q4) of VFA; visceral obesity, and the highest quartile (Q4) of VFA). Breast density was classified according to BI-RADS (grade a, b, c, and d), which defined as an ordinal scale (grade a = 1, grade b = 2, grade c = 3, and grade d = 4). All body fat-driven obesity parameters were negatively associated with the grade of breast density in both groups of women (p < 0.001): The more fatty parameters are, the less dense breast is. In multivariable binary logistic regression, all body fat-driven obesity parameters also showed a negative association with grade d density (vs. grade a, b, or c). In premenopausal women, BMI was a more associated parameter with grade d density than those of the other fat-driven parameters (OR 0.265, CI 0.204-0.344). In postmenopausal women, WC was more associated with grade d density than the others (OR 0.315, CI 0.239-0.416). We found that BMI, WC, WHR, FMI, PBF and VFA were negatively correlated with dense breast, and the association degree pattern between body fat-driven obesity and dense breast differs according to menopausal status.

Racial differences in predictive value of the 21-gene recurrence score assay: a population-based study using the SEER database.

PURPOSE: The 21-gene recurrence score (RS) assay is currently used for predicting chemotherapeutic benefits for hormone receptor-positive (HR +) early-stage breast cancer patients without consideration regarding racial differences in that predictive value. This study aimed at demonstrating racial differences in the predictive values of the 21-gene RS assay. METHODS: The study cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) database. Breast cancer-specific mortality (BCSM) was compared between patients who received chemotherapy (the "CTx group") and those who did not (the "no CTx group") to estimate the predictive value of the assay. This comparison was repeated for each racial group. RESULTS: Among 88,498 T1 - 2N0 HR + breast cancer patients who had results of 21-gene RS, 13,123 patients had RS > 25, which included 10,697 Whites, 1282 Blacks, and 1,144 Asian Americans/Pacific Islanders (AAPIs). Chemotherapy was administered to 8364 patients (63.4%). The adjusted hazard ratio for BCSM in the CTx group (vs. no CTx group) was 0.734 (95% confidence interval [CI] 0.588-0.917) in Whites, 0.748 (95% CI 0.428-1.307) in Blacks, and 1.343 (95% CI 0.558-3.233) in AAPIs. No subgroup within patients with RS > 25 among non-White women showed a significant predictive value of the 21-gene RS assay, except for Black women with grade 3 tumors. CONCLUSION: The predictive value of the 21-gene RS assay for assessing chemotherapy benefit was validated in White women based on the SEER database, although the predictive value was not warranted in non-White women.

Psychological Impact of Type of Breast Cancer Surgery: A National Cohort Study.

BACKGROUND: The present study assessed the impact of different types of breast surgery on rates of psychological disorders in breast cancer patients. METHODS: This nationwide cohort study, based on Korean Health Insurance Review and Assessment Service claims data, included 26,259 breast patients who underwent surgery from June 1, 2017, to December 31, 2018. Associations between the incidence of psychological disorders and variables were evaluated by time dependent Cox regression analyses. RESULTS: Of the 26,259 patients, 9394 (35.8%) underwent total mastectomy (TM) and 16,865 (64.2%) underwent partial mastectomy (PM); of the former, 4056 (43.2%) underwent breast reconstruction surgery (RS). A total of 4685 patients (17.84%) were newly diagnosed with psychological disorders after surgery. Multivariable analysis showed that axillary lymph node dissection was significantly associated with increased rates of overall psychological disorders (p < 0.0001), depression (p = 0.0462), anxiety (p < 0.0001) and insomnia (p < 0.0001). The rates of overall psychological disorders (p = 0.0002) and insomnia (p = 0.01) were significantly lower in patients who underwent TM than PM. RS tended to associated with reduced rates of overall psychological disorders in patients who underwent TM. Subgroup analysis showed that, compared with PM, RS after TM significantly associated with a reduced incidence of overall psychological disorders and insomnia in younger patients (< 50 years) and those who underwent sentinel lymph node biopsy. CONCLUSION: In contrast to general belief, rates of overall psychological disorders and insomnia were lower in patients who underwent TM than PM. Moreover, RS after TM confers psychological benefit in younger patients with early stage breast cancer compared with PM.

Maternal lipid profiles vs. fetal growth and cord blood hematopoietic cells: weak associations in healthy Korean newborn-mother pairs.

BACKGROUND: We aimed to define the maternal lipid profiles that are associated with fetal growth and cord blood (CB) hematopoietic cells in healthy Korean full-term newborns. METHODS: A total of 608 fetal-maternal pairs were enrolled; mothers voluntarily donated CB with informed consent. We analyzed birth weight (BW) as a marker of fetal growth, and we examined total nucleated cells (TNCs) and CD34+ cell concentrations of CB as markers of hematopoietic progenitor cell (HPC) contents. We also analyzed maternal lipid levels and investigated their associations with BW, TNCs and CD34+ cells. RESULTS: Maternal triglycerides (TG) showed a significant positive association with BW and CD34+ cells, and low-density lipoprotein (LDL) showed a negative association with BW and CD34+ cells. Though not statistically significant, higher maternal TG showed a tendency toward higher levels of TNCs. Maternal TG was independently and positively correlated with BW, and maternal LDL was independently and negatively correlated with CD34+ cells, although the impacts were not as strong, as indicated by small beta coefficients (0.157 and -0.226, respectively). CONCLUSIONS: We were able to investigate the association of maternal lipid profiles with BW and CB HPCs in healthy Korean newborn-mother pairs in this study. Both BW and the HPC contents showed independent associations with maternal TG and LDL, although the effect of maternal lipid levels on fetal growth and HPCs was not strong in the normal healthy population. Because maternal lipid levels were assessed once in the healthy fetal-maternal pairs, we could not investigate those associations across pregnancy.

Application of patch stimulator for intraoperative neuromonitoring during thyroid surgery: maximizing surgeon's convenience.

BACKGROUND: Intraoperative neuromonitoring (IONM) is frequently used in thyroid surgery to reduce recurrent laryngeal nerve (RLN) injury by providing the surgeon with real-time feedback on nerve stimulation during dissection. We applied a disposable adhesive patch electrode to a dissecting instrument to transfer electrical stimulation to the dissecting instrument for IONM during thyroid surgery. This study aimed to evaluate the feasibility of using the patch stimulator approach for IONM during thyroid surgery. METHODS: We reviewed the medical records of patients who underwent thyroidectomy using both conventional stimulator and adhesive patch stimulator for IONM. The electromyography (EMG) amplitudes of the vagal and the RLNs before (V1, R1) and after thyroid resection (V2, R2) were alternatively checked with each type of stimulator at the same location of each nerve. RESULTS: Fifteen consecutive patients (4 males, 11 females) were included in this analysis, and a total of 38 nerves (19 vagus nerves and 19 RLNs) were evaluated. No statistically significant differences were seen in the mean amplitudes evoked by the patch stimulator and the conventional probe stimulator for the V1 signal (825.5±394.6 vs. 821.8±360.9 µV, P=0.954), R1 signal (1,044.8±471.2 vs. 1,039.2±507.4 µV, P=0.898), R2 signal (1,037.8±495.0 vs. 938.2±415.8 µV, P=0.948), or V2 signal (812.5±391.9 vs. 787.3±355.7 µV, P=0.975). CONCLUSIONS: The patch stimulator was safely and effectively used for IONM during thyroid surgery and provided similar nerve monitoring responses as the conventional stimulator. This approach may be used to enhance the surgeon's convenience during thyroid surgery.

Microbiota of Breast Tissue and Its Potential Association with Regional Recurrence of Breast Cancer in Korean Women.

Recent studies have reported dysbiosis of the microbiome in breast tissue collected from patients with breast cancer and the association between the microbiota and disease progression. However, the role of the microbiota in breast tissue remains unclear, possibly due to the complexity of breast cancer and various factors, including racial and geographical differences, influencing microbiota in breast tissue. Here, to determine the potential role of microbiota in breast tumor tissue, we analyzed 141 tissue samples based on three different tissue types (tumor, adjacent normal, and lymph node tissues) from the same patients with breast cancer in Korea. The microbiota was not simply distinguishable based on tissue types. However, the microbiota could be divided into two cluster types, even within the same tissue type, and the clinicopathologic factors were differently correlated in the two cluster types. Risk of regional recurrence was also significantly different between the microbiota cluster types (p = 0.014). In predicted function analysis, the pentose and glucuronate interconversions were significantly different between the cluster types (q < 0.001), and Enterococcus was the main genus contributing to these differences (q < 0.01). Results showed that the microbiota of breast tissue could interact with the host and influence the risk of regional recurrence. Although further studies would be recommended to validate our results, this study could expand our understanding on the breast tissue microbiota, and the results might be applied to develop novel prediction methods and treatments for patients with breast cancer.

Hormone Receptor Subtype in Ductal Carcinoma in Situ: Prognostic and Predictive Roles of the Progesterone Receptor.

BACKGROUND: We investigated the prognostic and predictive roles of the hormone receptor (HRc) subtype in patients with ductal carcinoma in situ (DCIS). We focused on identifying the roles of the progesterone receptor (PR) independent of estrogen receptor (ER) status. METHODS: Nationwide data of 12,508 female patients diagnosed with DCIS with a mean follow-up period of 60.7 months were analyzed. HRc subtypes were classified as ER-/PR-, ER-/PR+, ER+/PR-, and ER+/PR+ based on ER and PR statuses. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The ER+/PR+ group showed better prognoses than the ER+/PR- and ER-/PR- groups in the patients who received tamoxifen therapy (p = .001 and p = .031, respectively). HRc subtype was an independent prognostic factor (p = .028). The tamoxifen therapy group showed better survival than the patients who did not receive tamoxifen, but only in the ER+/PR+ subgroup (p = .002). Tamoxifen therapy was an independent prognostic factor (HR, 0.619; 95% CI, 0.423 - 0.907; p = .014). PR status was a favorable prognostic factor in patients with DCIS who received tamoxifen therapy (p < .001), and it remained a prognostic factor independent of ER status (HR, 0.576; 95% CI, 0.349 - 0.951; p = .031). CONCLUSION: The HRc subtype can be used as both a prognostic and predictive marker in patients with newly diagnosed DCIS. Tamoxifen therapy can improve overall survival in the ER+/PR+ subtype. PR status has significant prognostic and predictive roles independent of ER status. Testing for the PR status in addition to the ER status is routinely recommended in patients with DCIS to determine the HRc subtype in clinical settings. IMPLICATIONS FOR PRACTICE: The hormone receptor (HRc) subtype was an independent prognostic factor, and the estrogen receptor (ER)+/progesterone receptor (PR) + subtype showed a better survival in patients with ductal carcinoma in situ (DCIS) who received tamoxifen therapy. PR was an independent prognostic factor independent of ER, and PR was a favorable prognostic factor in patients with DCIS who received tamoxifen therapy. The HRc subtype could be used as both a prognostic and predictive marker in patients with newly diagnosed DCIS. Testing of PR status in addition to ER status is routinely recommended for patients with DCIS to determine the HRc subtype in clinical settings.

Prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer.

We investigated the prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer patients. BCL1 and BCL2 expression statuses were assessed by immunohistochemistry using tissue microarrays from 393 breast cancer patients. The Kaplan-Meier estimator and log-rank test were used for survival analyses. The Cox proportional hazards model was used to calculate hazard ratio (HR) and the 95% confidence interval (CI) of survival analyses. BCL1 expression revealed no impact on survival. The high BCL2 group showed superior disease-free survival compared with the low BCL2 group (p = 0.002), especially regarding local recurrence-free survival (p = 0.045) and systemic recurrence-free survival (p = 0.002). BCL2 expression was a significant prognostic factor by univariable analysis (HR, 0.528; 95% CI, 0.353-0.790; p = 0.002) and by multivariable analysis (HR, 0.547; 95% CI, 0.362-0.826; p = 0.004). High BCL2 expression was associated with higher disease-free survival in the hormone receptor (HRc)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HRc(+)/HER2(-)) subtype only (p = 0.002). The high BCL2 group was associated with positive estrogen receptor (ER), positive progesterone receptor (PR), low histologic grade, and age ≤ 50 years. BCL1 expression had no prognostic impact, but BCL2 expression was a significant independent prognostic factor. High BCL2 expression was associated with higher disease-free survival, especially regarding local recurrence and systemic recurrence. The prognostic effect of BCL2 expression was effective only in the HRc(+)/HER2(-) subtype. Favorable clinicopathologic features and a strong association with the ER/PR status could partly explain the superior prognosis of the high BCL2 group. BCL2 expression could be utilized to assess the prognosis of breast cancer patients in clinical settings.

Clinical Databases for Breast Cancer Research.

Clinical database is a collection of clinical data related to patients, which can be used for analysis and research. Clinical data can be classified into several categories: patient-related, tumor-related, diagnostics-related, treatment-related, outcome-related, administration-related, and other clinical data. Clinical databases can be classified according to the data types of clinical databases, ranges of institutes, and accessibility to data. The numbers of papers and clinical trials are rapidly increasing. Recently, more than 9000 papers related to breast cancer have been published annually, and more than 7000 papers related to human breast cancer are published annually. The speed of increase is expected to be faster and faster in future. Now, almost 8000 clinical trials are registered world widely. Main research areas of breast cancer can be classified into followings; epidemiology, screening and prevention, diagnosis, treatment, and prognosis. Clinical databases that are available for breast cancer research are also introduced in this chapter. The analysis of big data is expected to be the mainstream of breast cancer research using clinical databases. As the technology of artificial intelligence (AI) is rapidly evolving, the technology of deep learning starts to be applied for breast cancer research. In near future, AI technology is predicted to penetrate deeply the field of breast cancer research.

Increased expression of thyroid hormone receptor alpha and estrogen receptor alpha in breast cancer associated with thyroid cancer.

INTRODUCTION: Breast cancer co-occurred with thyroid cancer might be associated with thyroid hormone receptor (TR) and estrogen receptor (ER), but few have been reported. We aimed to investigate the expression and prognostic significance of ERs and TRs in such settings. MATERIAL AND METHODS: Tissue microarrays were constructed from 75 patients with breast and thyroid cancer (BC + TC) who were retrospectively recruited between 1999 and 2012 and 147 with breast cancer only (BC controls). The ERα, ERß, TRα, and TRß expression levels were analyzed by immunohistochemistry. RESULTS: TRα expression was more frequently observed in the BC + TC group than the BC control group both in the normal (51.5% vs 23.3%, respectively, p = 0.009) and cancer tissues (21.6% vs 6.8%, respectively, p = 0.001). The BC + TC group showed greater ERα-positivity in the cancer tissues (79.7% vs 58.7%, respectively, p = 0.002) than the BC control group. The degree of ERα- and TRα-positivity was unchanged by radioactive treatment or serum thyroid stimulating hormone levels. In the BC + TC group, ERα-positivity was associated with earlier disease stage I/IIA (81.0% vs 50.0%; p = 0.031) and lower recurrence rates (8.5% vs 40.0%; p = 0.002). TRα-positivity alone was not associated with any recurrence-free survival-related differences, and ERα- and TRα-negativity were associated with significantly shorter recurrence-free survival (p < 0.001). CONCLUSION: Enhanced ERα and TRα expression in breast cancer is associated with thyroid cancer occurrence, and the observed association with prognosis suggests the possible role of ERs and TRs in the link between breast cancer and thyroid cancer.

Wip1 controls the translocation of the chromosomal passenger complex to the central spindle for faithful mitotic exit.

Dramatic cellular reorganization in mitosis critically depends on the timely and temporal phosphorylation of a broad range of proteins, which is mediated by the activation of the mitotic kinases and repression of counteracting phosphatases. The mitosis-to-interphase transition, which is termed mitotic exit, involves the removal of mitotic phosphorylation by protein phosphatases. Although protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) drive this reversal in animal cells, the phosphatase network associated with ordered bulk dephosphorylation in mitotic exit is not fully understood. Here, we describe a new mitotic phosphatase relay in which Wip1/PPM1D phosphatase activity is essential for chromosomal passenger complex (CPC) translocation to the anaphase central spindle after release from the chromosome via PP1-mediated dephosphorylation of histone H3T3. Depletion of endogenous Wip1 and overexpression of the phosphatase-dead mutant disturbed CPC translocation to the central spindle, leading to failure of cytokinesis. While Wip1 was degraded in early mitosis, its levels recovered in anaphase and the protein functioned as a Cdk1-counteracting phosphatase at the anaphase central spindle and midbody. Mechanistically, Wip1 dephosphorylated Thr-59 in inner centromere protein (INCENP), which, subsequently bound to MKLP2 and recruited other components to the central spindle. Furthermore, Wip1 overexpression is associated with the overall survival rate of patients with breast cancer, suggesting that Wip1 not only functions as a weak oncogene in the DNA damage network but also as a tumor suppressor in mitotic exit. Altogether, our findings reveal that sequential dephosphorylation of mitotic phosphatases provides spatiotemporal regulation of mitotic exit to prevent tumor initiation and progression.

Causal Bayesian gene networks associated with bone, brain and lung metastasis of breast cancer.

Using a machine learning method, this study aimed to identify unique causal networks of genes associated with bone, brain, and lung metastasis of breast cancer. Bayesian network analysis identified differentially expressed genes in primary breast cancer tissues, in bone, brain, and lung breast cancer metastatic tissues, and the clinicopathological features of patients obtained from the Gene Expression Omnibus microarray datasets. We evaluated the causal Bayesian networks of breast metastasis to distant sites (bone, brain, or lung) by (i) measuring how well the structures of each specific type of breast cancer metastasis fit the data, (ii) comparing the structures with known experimental evidence, and (iii) reporting predictive capabilities of the structures. We report for the first time that the molecular gene signatures are specific to the different types of breast cancer metastasis. Several genes, including CHPF, ARC, ANGPTL4, NR2E1, SH2D1A, CTSW, POLR2J4, SPTLC1, ILK, ALDH3B1, PDE6A, SCTR, ADM, HEY1, KCNF1, and UVRAG, were found to be predictors of the risk for site-specific metastasis of breast cancer. Expression of POLR2JA, SPTLC1, ILK, ALDH3B1, and the estrogen receptor was significantly associated with breast cancer bone metastasis. Expression of PDE6A and NR2E1 was causally linked to breast cancer brain metastasis. Expression of HEY1, KCNF1, UVRAG, and the estrogen and progesterone receptors was strongly associated with breast cancer lung metastasis. The causal Bayesian network structures of these genes identify potential interactions among the genes in distant metastases of breast cancer, including to the bone, brain, and lung, and may serve as target candidates for treatment of breast cancer metastasis.

Metachronous Sporadic Sextuple Primary Malignancies Including Bilateral Breast Cancers.

Multiple primary malignancies are defined as the presence of more than one malignant neoplasm with a distinct histology occurring at different sites in the same individual. They are classified as synchronous or metachronous according to the diagnostic time interval of different malignancies. Diagnosis of multiple primary malignancies should avoid misclassification from multifocal/multicentric tumors or recurrent/metastatic lesions. In multiple primary malignancies, with increase in the number of primary tumors, the frequency rapidly decreases. Here, we report an exceptionally rare case of a woman who was diagnosed with metachronous sporadic sextuple primary malignancies including bilateral breast cancers (gastric cancer, ovarian Sertoli-Leydig cell tumor, left breast cancer, thyroid cancer, right breast cancer, and rectal neuroendocrine tumor). The sextuple primary malignancies in this case involved 5 different organs: the stomach, ovary, thyroid, rectum, and bilateral breasts. Further studies are needed to elucidate the current epidemiologic status of patients with multiple primary malignancies.

Influence of Metabolic Syndrome on Risk of Breast Cancer: A Study Analyzing Nationwide Data from Korean National Health Insurance Service.

BACKGROUND: To investigate the influence of metabolic syndrome and its components on the risk of breast cancer. METHODS: Retrospective nationwide cohort study analyzing data of 13,377,349 women older than 19 years from Korean National Health Insurance Service was performed. Cox proportional hazards model was used to calculate HR and 95% confidence interval (CI) of breast cancer risk. RESULTS: The presence of metabolic syndrome decreased the risk of all breast cancer types in all subjects (HR, 0.954; 95% CI, 0.939-0.970). In women with age ≤50 years, metabolic syndrome decreased the risk of all breast cancer types, with similar findings for all subject groups (HR, 0.915; 95% CI, 0.892-0.939). In women with age >50 years, metabolic syndrome increased the risk of all breast cancer types (HR, 1.146; 95% CI, 1.123-1.170), especially in age groups of more than 55 years. In women with age >50 years, HRs increased as the number of metabolic syndrome components increased, while HRs decreased as the number of metabolic syndrome components increased in women with age ≤50 years. CONCLUSIONS: The presence of metabolic syndrome increased the risk of breast cancers in postmenopausal women, but decreased the risk in premenopausal women. Every metabolic syndrome component played similar roles on the risk of breast cancer as metabolic syndrome, and their effects became stronger when the number of components increased. IMPACT: Metabolic syndrome is associated with the risk of breast cancer having different effect according to age groups.