Long-term outcome in patients with nodal-positive breast cancer treated with sentinel lymph node biopsy alone after neoadjuvant chemotherapy.

PURPOSE: Sentinel lymph node biopsy (SLNB) has yet to be accepted as the standard staging procedure in node positive (cN1) breast cancer patients who had clinical complete response in the axilla (cN0) following neoadjuvant chemotherapy (NAC), due to the presumed high false negative rate associated with SLNB in such scenario. This study aimed to determine whether there is a significant difference in the axillary recurrence rate (ARR) and long-term survival in this group of patients, receiving SLNB alone versus axillary lymph node dissection (ALND). METHODS: A retrospective cohort of cN1 patients who were rendered cN0 by NAC from January 2014 to December 2018 were identified from the Asan Medical Center database. Patients' characteristics and outcomes were collected and analyzed. RESULTS: 902 cN1 patients treated with NAC and turned cN0 were identified. 477 (52.9%) patients achieved complete pathological response in the axilla (ypN0). At a median follow up of 65 months, ARR was 3.2% in the SLNB only group and 1.8% in the ALND group (p = 0.398). DFS and OS were significantly worse in patients with ALND as compared to patients with SLNB only (p = 0.011 and 0.047, respectively). We noted more patients in the ALND group had T3-4 tumor. In the subgroup analysis, we showed that in the T1-2 subgroup (n = 377), there was no statistically significant difference in DFS and OS (p = 0.242 and 0.671, respectively) between SLNB only and ALND group. CONCLUSION: Our findings suggest that cN1 patients who were converted to ypN0 following NAC may be safely treated with SLNB only.

Comparison of long-term oncological outcomes after central lumpectomy versus nipple-sparing breast-conserving surgery for centrally located breast cancer: a propensity score-matched study.

PURPOSE: To compare the oncological safety of nipple-sparing breast-conserving surgery (BCS) versus central lumpectomy for centrally located breast cancer (CLBC). METHODS: Patients who underwent BCS for CLBC at Asan Medical Center from 2007 to 2018 were reviewed retrospectively. The oncological outcomes of nipple-sparing BCS (NS-BCS) and central lumpectomy were compared using univariate and multivariate Cox regression analyses and compared again after 1:1 propensity score matching (PSM). RESULTS: The study included 306 patients who underwent NS-BCS and 106 patients who underwent central lumpectomy (median follow-up: 111 months). On multivariate analysis, central lumpectomy had a lower risk of local recurrence compared to NS-BCS, albeit without statistical significance (HR 0.14, 95% CI 0.02-1.24; p = 0.077). There was no significant difference in the risk of death (HR 0.14, 95% CI 0.01-1.68, p = 0.12). After PSM, each group had 106 patients. The 5-year and 10-year local recurrence-free survival rates were 94.2% and 92.9% for NS-BCS, and 99.1% and 99.1% for central lumpectomy, respectively (p = 0.031). There were no significant differences in overall survival, regional recurrence-free survival, or distant recurrence-free survival. Fifteen patients (4.9%) who underwent NS-BCS had ipsilateral breast tumor recurrence (IBTR), of which 40% were in the nipple-areolar complex and previous surgical sites. One patient (0.9%) who underwent central lumpectomy experienced an IBTR in a different quadrant. CONCLUSION: NS-BCS showed more local recurrence than central lumpectomy. When deciding whether to spare the nipple during BCS in CLBC, patients should be sufficiently informed about the risk of IBTR.

Characteristics and risk factors of axillary lymph node metastasis of microinvasive breast cancer.

PURPOSE: To select patients who would benefit most from sentinel lymph node biopsy (SLNB) by investigating the characteristics and risk factors of axillary lymph node metastasis (ALNM) in microinvasive breast cancer (MIBC). METHODS: This retrospective study included 1688 patients with MIBC who underwent breast surgery with axillary staging at the Asan Medical Center from 1995 to 2020. RESULTS: Most patients underwent SLNB alone (83.5%). Seventy (4.1%) patients were node-positive, and the majority had positive lymph nodes < 10 mm, with micro-metastases occurring frequently (n = 37; 55%). Node-positive patients underwent total mastectomy and axillary lymph node dissection (ALND) more than breast-conserving surgery (BCS) and SLNB compared with node-negative patients (p < 0.001). In the multivariate analysis, independent predictors of ALNM included young age [odds ratio (OR) 0.959; 95% confidence interval (CI) 0.927-0.993; p = 0.019], ALND (OR 11.486; 95% CI 5.767-22.877; p < 0.001), number of lymph nodes harvested (≥ 5) (OR 3.184; 95% CI 1.555-6.522; p < 0.001), lymphovascular invasion (OR 6.831; 95% CI 2.386-19.557; p < 0.001), presence of multiple microinvasion foci (OR 2.771; 95% CI 1.329-5.779; p = 0.007), prominent lymph nodes in preoperative imaging (OR 2.675; 95% CI 1.362-5.253; p = 0.004), and hormone receptor positivity (OR 2.491; 95% CI 1.230-5.046; p = 0.011). CONCLUSION: Low ALNM rate (4.1%) suggests that routine SLNB for patients with MIBC is unnecessary but can be valuable for patients with specific risk factors. Ongoing trials for omitting SLNB in early breast cancer, and further subanalyses focusing on rare populations with MIBC are necessary.

Comparative Associations of Nonalcoholic Fatty Liver Disease and Metabolic Dysfunction-Associated Fatty Liver Disease With Coronary Artery Calcification: A Cross-Sectional and Longitudinal Cohort Study.

BACKGROUND: In cross-sectional and retrospective cohort studies, we examined comparative associations between nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) and risk of having or developing coronary artery calcification (CAC). METHODS: Participants who had health examinations between 2010 and 2019 were analyzed. Liver ultrasonography and coronary artery computed tomography were used to diagnose fatty liver and CAC. Participants were divided into a MAFLD and no-MAFLD group and then NAFLD and no-NAFLD groups. Participants were further divided into no fatty liver disease (reference), NAFLD-only, MAFLD-only, and both NAFLD and MAFLD groups. Logistic regression modeling was performed. Cox proportional hazard model was used to examine the risk of incident CAC in participants without CAC at baseline and who had at least two CAC measurements. RESULTS: In cross-sectional analyses, 162 180 participants were included. Compared with either the no-NAFLD or no-MAFLD groups, the NAFLD and MAFLD groups were associated with a higher risk of prevalent CAC (NAFLD: adjusted odds ratio [OR], 1.34 [95% CI, 1.29-1.39]; MAFLD: adjusted OR, 1.44 [95% CI, 1.39-1.48]). Among the 4 groups, the MAFLD-only group had the strongest association with risk of prevalent CAC (adjusted OR, 1.60 [95% CI, 1.52-1.69]). Conversely, the NAFLD-only group was associated with a lower risk of prevalent CAC (adjusted OR, 0.76 [95% CI, 0.66-0.87]). In longitudinal analyses, 34 233 participants were included. Compared with either the no-NAFLD or no-MAFLD groups, the NAFLD and MAFLD groups were associated with a higher risk of incident CAC (NAFLD: adjusted hazard ratio, 1.68 [95% CI, 1.43-1.99]; MAFLD: adjusted hazard ratio, 1.82 [95% CI, 1.56-2.13]). Among these 4 groups, the MAFLD-only group had the strongest associations with risk of incident CAC (adjusted hazard ratio, 2.03,[95% CI, 1.62-2.55]). The NAFLD-only group was not independently associated with risk of incident CAC (adjusted hazard ratio, 0.88 [95% CI, 0.44-1.78]) Conclusions: Both NAFLD and MAFLD are significantly associated with an increased prevalence and incidence of CAC. These associations tended to be stronger for MAFLD.

Influence of MAFLD and NAFLD on arterial stiffness: A longitudinal cohort study.

BACKGROUND AND AIMS: This cohort study investigated associations of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with risk of increase in arterial stiffness (AS), measured as brachial-ankle pulse wave velocity (baPWV). METHODS AND RESULTS: Participants who had health examinations between 2006 and 2019 were analyzed for fatty liver and increased baPWV using liver ultrasonography and automatic volume plethysmography device. Participants were classified based on presence of MAFLD or NAFLD and further divided into subgroups: no fatty liver disease (reference), NAFLD-only, MAFLD-only, and both NAFLD and MAFLD. Subgroups were additionally stratified by sex. Cox proportional hazard model was utilized to analyze the risk of developing baPWV ≥1400 cm/s in participants without baseline elevation of the baPWV. The NAFLD and MAFLD groups exhibited higher risks of increased baPWV (NAFLD: adjusted hazard ratio (aHR), 1.35 [95% CI, 1.29-1.42]; MAFLD: aHR, 1.37 [95% CI, 1.31-1.43]) compared to group without the conditions. Incidence of NAFLD or MAFLD were higher in men than in women but aHR of developing the increase in AS was higher in women. In subgroup analysis, the MAFLD-only group presented the strongest associations with increase in AS (aHR, 1.53 [95% CI, 1.43-1.64]), with the trend more pronounced in women than in men (Women, aHR, 1.63 [95% CI, 1.08-2.46]; Men, aHR 1.45 [95% CI, 1.35-1.56]). CONCLUSIONS: Both NAFLD and MAFLD are significantly associated with elevated AS. These associations tended to be stronger in MAFLD than in NAFLD, in women than in men.

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 ).

An integrative approach for exploring the nature of fibroepithelial neoplasms.

BACKGROUND: Malignant phyllodes tumour (MPT) is a rare breast malignancy with epithelial and mesenchymal features. Currently, there are no appropriate research models or effective targeted therapeutic approaches for MPT. METHODS: We collected fresh frozen tissues from nine patients with MPT and performed whole-exome and RNA sequencing. Additionally, we established patient-derived xenograft (PDX) models from patients with MPT and tested the efficacy of targeting dysregulated pathways in MPT using the PDX model from one MPT. RESULTS: MPT has unique molecular characteristics when compared to breast cancers of epithelial origin and can be classified into two groups. The PDX model derived from one patient with MPT showed that the mouse epithelial component increased during tumour growth. Moreover, targeted inhibition of platelet-derived growth factor receptor (PDGFR) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) by imatinib mesylate and PKI-587 showed in vivo tumour suppression effects. CONCLUSIONS: This study revealed the molecular profiles of MPT that can lead to molecular classification and potential targeted therapy, and suggested that the MPT PDX model can be a useful tool for studying the pathogenesis of fibroepithelial neoplasms and for preclinical drug screening to find new therapeutic strategies for MPT.

Clinical significance of microinvasive breast cancer across the different subtypes and human epidermal growth factor receptor 2 expression levels.

PURPOSE: The clinical behavior, prognosis, and management of microinvasive breast cancer (MiBC) is controversial. We aimed to clarify its significance across different subtypes and the role of human epidermal growth factor receptor 2 (HER2) expression in MiBC. METHODS: We analyzed 1530 patients with T1mi (tumor size ≤ 0.1 cm), node-negative breast cancer who underwent breast conserving surgery or total mastectomy between 2001 and 2020 at the Asan Medical Center (AMC). RESULTS: When divided into four subtypes, hormone receptor (HR)+/HER2-, HR+ /HER2+ , HR-/HER2+ , and HR-/HER2-, HR-/HER2+ had the highest prevalence rate of 38.5% in MiBC patients. In a median follow-up period of 74 months (0-271 months), 103 (6.7%) patients had recurrent tumor, and 95 (6.2%) had local recurrence. Disease-free survival (DFS) and local recurrence-free survival (LRFS) were worst in the HR-/HER2+ group. The five-year DFS for the HR-/HER2+ group was 92.2%, while it was 97.1% for the HR+/HER2- group (p = 0.024 The five-year LRFS for HER2- patients were better than that of HER2+ MiBC patients, which were 97.1 and 93.8%, respectively (p = 0.010). Univariate and multivariate Cox regression analyses showed that the HR-/HER2+ group had relatively higher risk of recurrence compared to the HR+/HER2- group (hazard ratio [HR] = 2.332, 95% confidence interval [CI] 1.412-3.852, p = 0.001 unadjusted; HR = 3.346, 95% CI 1.408-7.953, p = 0.006 adjusted). CONCLUSION: HER2 overexpression was significantly associated with adverse clinicopathologic parameters and increased local recurrence risk in MiBC. Therefore, more understanding of the clinical behavior of HER2 in MiBC will enable tailoring of adjuvant therapy for these patients.

Impact of mental disorders on the risk of heart failure among Korean patients with diabetes: a cohort study.

BACKGROUND: Few studies have assessed the correlation between coexisting mental disorders in participants with diabetes mellitus (DM) and the risk of heart failure (HF). Herein, we conducted a cohort study to determine the association between the accumulation of mental disorders in participants with DM and the risk of HF. METHODS: The Korean National Health Insurance Service records were assessed. 2,447,386 adults with DM who underwent health screening between 2009 and 2012 were analyzed. Participants with major depressive disorder, bipolar disorder, schizophrenia, insomnia, or anxiety disorders were included. In addition, participants were categorized based on the number of coexisting mental disorders. Each participant was followed until December 2018 or until the onset of HF. Cox proportional hazard modelling with confounding factors adjustment was conducted. In addition, a competing risk analysis was conducted. Subgroup analysis assessed the impact of clinical variables on the association between the accumulation of mental disorders and the risk of HF. RESULTS: The median follow-up duration was 7.09 years. The accumulation of mental disorders was associated with a risk of HF (zero mental disorder (0), reference; 1 mental disorder, adjusted hazard ratio (aHR): 1.222, 95% confidence intervals (CI): 1.207-1.237; 2 mental disorders, aHR: 1.426, CI: 1.403-1.448; ≥3 mental disorders, aHR: 1.667, CI: 1.632-1.70. In the subgroup analysis, the strength of association was the strongest in the younger age group (< 40 years, 1 mental disorder, aHR 1.301, CI 1.143-1.481; ≥2 mental disorders, aHR 2.683, CI 2.257-3.190; 40-64 years, 1 mental disorder, aHR 1.289, CI 1.265-1.314; ≥2 mental disorders, aHR 1.762, CI 1.724-1.801; ≥65 years, 1 mental disorder, aHR 1.164, CI 1.145-1.183; ≥2 mental disorders, aHR 1.353, CI 1.330-1.377; Pinter<0.001). In addition, income, BMI, hypertension, chronic kidney disease, history of cardiovascular disease, insulin use, and duration of DM showed significant interactions. CONCLUSIONS: Comorbid mental disorders in participants with DM are associated with an increased risk of HF. In addition, the association was stronger in a younger age group. Participants with DM and mental disorders should be monitored with increased frequency for signs of HF; for which they have a higher risk than the general population.

Comparison of cardiovascular mortality between MAFLD and NAFLD: A cohort study.

BACKGROUND AND AIMS: A new diagnostic criterion of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. However, only few studies have shown that MAFLD predicts cardiovascular disease (CVD) mortality better than non-alcoholic fatty liver disease (NAFLD). Therefore, a cohort study was conducted to assess this relationship. METHODS AND RESULTS: Health examination data from health care centers in South Korea were assessed after excluding participants with missing covariates and cancer history (n = 701,664). Liver ultrasonography reports, laboratory and anthropometric data were extracted. Diagnoses of NAFLD and MAFLD were performed according to standard definitions. Participants were categorized based on the presence of NAFLD and MAFLD. In addition, participants were classified into five categories: no fatty liver disease (no FLD), NAFLD-only, MAFLD-only, both FLDs, and alcoholic FLD (AFLD) and non-MAFLD. Multivariable regression modeling was performed. The median follow-up duration was 8.77 years, and 52.56% of participants were men. After stratifying the cohort into no-MAFLD and MAFLD groups, MAFLD was associated with increased CVD mortality (adjusted HR 1.14, 95% CI 1.02-1.28). When participants were divided into no-NAFLD and NAFLD groups, there was a non-significant trend towards an increase in CVD mortality in NAFLD group (adjusted HR 1.07, 95% CI 0.95-1.21). When participants were divided into five categories, MAFLD-only group showed increased CVD mortality (adjusted HR 1.35, 95% CI 1.07-1.70) while NAFLD-only group showed no significant association with CVD mortality (adjusted HR 0.67, 95% CI 0.38-1.19). CONCLUSIONS: In conclusion, MAFLD is associated with increased CVD mortality in a relatively young Korean population.

A Cross-Sectional Investigation of the Association between Arterial Stiffness and Depressive Symptoms, Anxiety Symptoms, and Quality of Life.

Background and Objectives: Previous studies have assessed the association between arterial stiffness and depressive and anxiety symptoms, but the results were inconsistent. We aimed to conduct a cross-sectional study to assess the relationship between arterial stiffness, depressive and anxiety symptoms, and quality of life. Materials and Methods: We analyzed the 2014-2015 Korea Institute of Sport Science Fitness Standards project data. Brachial-ankle pulse wave velocity (baPWV) was measured to assess arterial stiffness. High baPWV was defined as a baPWV higher than 1400 cm/s. Participants completed Beck's depressive symptoms inventory (BDI), Beck's anxiety symptoms inventory (BAI), and the World Health Organization's Quality of Life Questionnaire (WHOQOL-Bref). We performed a logistic regression analysis by adjusting confounding factors and used the inverse probability of treatment weighting (IPTW) method. Results: 1936 participants were included in the analysis (men 43.9%, median age 47). Participants with a high baPWV had higher odds of depressive symptoms compared to those with a normal baPWV (aOR 1.920, 95% CI 1.062-3.472, p = 0.031; IPTW OR 2.637, 95% CI 1.219-5.704, p = 0.014). In addition, baPWV was significantly associated with depressive symptoms in the IPTW model in men but not in women (OR 2.497, 95% CI 1.004-6.207, p = 0.049). High baPWV was not associated with anxiety symptoms in all models, but it was associated with poor QOL in women (OR 4.561, 95% CI 1.465-14.199, p = 0.009). Conclusions: High baPWV was associated with higher odds of depressive symptoms, especially in men. Our study suggests a modest association between arterial stiffness and depressive symptoms in Korean adults.

Association of Cardiovascular Mortality with Concurrent Coronary Artery Calcification and Physical Activity: A Cohort Study.

Background: Increased coronary artery calcification (CAC) has been reported in individuals with high levels of physical activity (PA). However, the association between increased CAC in a physically active population and cardiovascular mortality has not yet been well-established. This study aimed to investigate the association between PA levels and the presence or absence of CAC and cardiovascular mortality. Methods: A cohort study was conducted from 1 January 2011 to 30 December 2019. Mortality data were updated until 30 December 2020. The study population comprised 56,469 individuals who had completed the International Physical Activity Short Form Questionnaire and had undergone CAC score evaluation using a CT scan. We divided the participants into four groups: physically inactive individuals without CAC, physically inactive individuals with CAC, moderately active and health-enhancing physically active (HEPA) individuals without CAC, and moderately active and HEPA individuals with CAC. The primary outcome was cardiovascular mortality. The Cox proportional hazard model with confounding factor adjustment was conducted. Inverse probability of treatment weighting-based marginal-structural modelling was conducted. Results: The median follow-up duration was 6.60 years. The mean (SD) age of the study participants was 41.67 (±10.91) years, with 76.78% (n = 43,359) men. Compared with individuals without CAC, individuals with CAC demonstrated higher cardiovascular disease mortality regardless of PA level (Inactive and CAC > 0, HR 2.81, 95% CI: 1.76-19.19; moderately active and HEPA HR 3.27, 95% CI: 1.14-9.38). Conclusions: The presence of CAC might be associated with cardiovascular mortality regardless of PA level.

A triple-negative breast cancer surrogate subtype classification that correlates with gene expression subtypes.

BACKGROUND: This study developed a triple-negative breast cancer (TNBC) surrogate subtype classification that represents TNBC subtypes based on the Vanderbilt subtype classification. METHODS: Patients who underwent primary curative surgery for TNBC were included. Representative FFPE blocks were used for gene expression analysis and tissue microarray construction for immunohistochemical (IHC) staining. The Vanderbilt subtypes were re-classified into four groups: basal-like (BL), mesenchymal-like (M), immunomodulatory (IM) and luminal androgen receptor (LAR) subtype. Classification and regression tree (CART) modeling was applied to develop a surrogate subtype classification. RESULTS: A total of 145 patients were included. The study cohort was allocated to the Vanderbilt 4 subtypes as LAR (n = 22, 15.2%), IM (n = 32, 22.1%), M (n = 38, 26.2%), BL (n = 25, 17.2%) and unclassified (n = 28, 19.3%). After excluding nine (6.2%) patients due to poor IHC staining quality, CART modeling was performed. TNBC surrogate subtypes were defined as follows: LAR subtype, androgen receptor Allred score 8; IM subtype, LAR-negative with a tumor-infiltrating lymphocyte (TIL) score > 70%; M subtype, LAR-negative with a TIL score < 20%; BL subtype, LAR-negative with a TIL score 20-70% and diffuse, strong p16 staining. The study cohort was classified by the surrogate subtypes as LAR (n = 26, 17.9%), IM (n = 21, 14.5%), M (n = 44, 30.3%), BL1 (n = 27, 18.6%) and unclassified (n = 18, 12.4%). Surrogate subtypes predicted TNBC Vanderbilt 4 subtypes with an accuracy of 0.708. CONCLUSION: We have developed a TNBC surrogate subtype classification that correlates with the Vanderbilt subtype. It is a practical and accessible diagnostic test that can be easily applied in clinical practice.

Impact of Sex on the Association between Flexibility and Arterial Stiffness in Older Adults.

Background and Objectives: Flexibility is one of the most important physical fitness parameters in the geriatric population. Brachial-ankle pulse wave velocity (baPWV) is a measure of systemic arterial stiffness. However, data on the association between flexibility and arterial stiffness in the older adult population are limited. Therefore, we aim to investigate this association by using the sit-and-reach test (SRT) and measuring baPWV. Materials and Methods: We reviewed data from the 2014-2015 Korean Institute of Sports Science Fitness Standards Project. Individuals older than 65 years with SRT and baPWV data were included. A generalized linear regression analysis was conducted to assess the association between flexibility and arterial stiffness. Multiple relevant confounding factors were adjusted. Results: A total of 615 individuals were included in the analysis. The mean age of the male and female participants was 71.44 ± 4.42 and 70.64 ± 4.13 years, respectively. The mean SRT result was 6.58 ± 9.97 and 18.04 ± 7.48 cm, respectively. After multivariable adjustment among the male participants, the higher SRT result tertiles were inversely associated with baPWV (ß (95% confidence interval): 3.11-11.00 cm, -74.45 (-140.93, -8.55); ≥11.01 cm, -108.17 (-177.65, -38.70)) in comparison with the lowest tertile. The female participants did not show any significant correlation between the SRT result and baPWV. Conclusions: Our results suggest an inverse association between trunk flexibility and systemic arterial stiffness, expressed as the SRT result and baPWV, respectively, in older Korean men but no association in older Korean women. Sex differences might influence the association between flexibility and arterial stiffness in the older adult population.

Cardiovascular events and mortality in a population-based cohort initially diagnosed with ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) patients are usually diagnosed through cancer screening programs, suggesting a healthy user effect. In this population-based cohort, we assessed the risk of cardiovascular events and mortality in DCIS patients. METHODS: Using the Korean National Health Insurance Service database, 13,740 women, who were initially diagnosed with DCIS between 2007 and 2013, were analyzed. A control group was matched according to age and the year of diagnosis at a 3:1 ratio (n = 41,220). Follow-up was performed until 2016. Subgroup analysis was performed according to the subsequent diagnosis of invasive breast cancer within 1 year: pure DCIS and DCIS+Invasive group. RESULTS: DCIS patients were more likely to have underlying diseases, higher incomes, and to live in urban districts compared to the control group. Women diagnosed of DCIS had lower myocardial infarct risk (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.46-0.90) and lower stroke risk (HR 0.77; 95% CI 0.60-0.98) compared to the control group. This trend of lower risk was sustained after adjusting for age, income, residence and comorbidities. The mortality rate was similar between the control group and pure DCIS patients but was higher in the DCIS+Invasive group (HR 1.63; 95% CI 1.34-1.98). However, after adjusting for age, income, residence and comorbidities, mortality did not differ between the control group and DCIS+Invasive group (HR 0.99; 95% CI 0.78-1.24). CONCLUSIONS: DCIS patients were at lower risk for MI and stroke compared to a control group despite a higher rate of comorbidities, which may reflect changes in health behaviour. The importance of managing pre-existing comorbidities along with DCIS treatment should be emphasized.

Liquid Biopsy in Breast Cancer: Circulating Tumor Cells and Circulating Tumor DNA.

Cancer is associated with gene mutations, and the analysis of tumor-associated mutations is increasingly used for diagnostic, prognostic, and treatment purposes. These molecular landscapes of solid tumors are currently obtained from surgical or biopsy specimens. However, during cancer progression and treatment, selective pressures lead to additional genetic changes as tumors acquire drug resistance. Tissue sampling cannot be performed routinely owing to its invasive nature and a single biopsy only provides a limited snapshot of a tumor, which may fail to reflect spatial and temporal heterogeneity. This dilemma may be solved by analyzing cancer cells or cancer cell-derived DNA from blood samples, called liquid biopsy. Liquid biopsy is one of the most rapidly advancing fields in cancer diagnostics and recent technological advances have enabled the detection and detailed characterization of circulating tumor cells and circulating tumor DNA in blood samples.Liquid biopsy is an exciting area with rapid advances, but we are still at the starting line with many challenges to overcome. In this chapter we will explore how tumor cells and tumor-associated mutations detected in the blood can be used in the clinic. This will include detection of cancer, prediction of prognosis, monitoring systemic therapies, and stratification of patients for therapeutic targets or resistance mechanisms.

The prognostic value of HER2 status and efficacy of anti-HER2 therapy in patients with HR-positive mucinous breast cancer: a nationwide study from the Korean Breast Cancer Society.

PURPOSE: The effect of human epidermal growth factor receptor 2 (HER2) status on mucinous carcinoma (MC) of the breast is unknown due to the rarity of HER2-positive cases. We evaluated the prognostic value of HER2 status and the efficacy of anti-HER2 therapy in patients with hormone receptor (HR)-positive MC. METHODS: From the data of 154,661 patients recorded in the Korean Breast Cancer Registry between January 1990 and August 2016, 3076 (2.0%) were diagnosed with MC. Overall survival (OS) according to HER2 status and anti-HER2 therapy was analyzed using Kaplan-Meier estimates. Multivariate analysis was performed using the Cox proportional hazards model to estimate the adjusted hazards ratio (HR) for clinicopathologic factors. RESULTS: A total of 2716 HR-positive MC patients were enrolled and followed up for a median 100.1 months. Of these, 2094 (77.1%) were HER2-negative and 228 (8.4%) were HER2-positive. HR-positive, HER2-positive MC patients had more advanced pathologic tumor stages (T3 or T4) (p = 0.001), more axillary lymph node involvement (p < 0.001), higher nuclear grade (p < 0.001), and more lymphovascular invasion (p = 0.012) than HER2-negative patients. Subgroup analysis of HR-positive, node-positive MC showed that HER2-positive MC was an independent prognostic factor for OS (HR = 2.657; 95% CI, 1.665-4.241; p < 0.001). HR-positive, node-positive, and HER2-negative MC had significantly longer OS than HER2-positive MBC (p = 0.017). The node-positive subgroup that received anti-HER2 therapy had increased OS, although not significantly (p = 0.224). CONCLUSION: Our nationwide database study revealed that HER2-positive status was associated with worse prognosis in HR-positive and node-positive MC. Anti-HER2 therapy might be beneficial in HR-positive, node-positive, and HER2-positive MC.

Axillary lymph node dissection is not obligatory in breast cancer patients with biopsy-proven axillary lymph node metastasis.

PURPOSE: The ACOSOG Z0011 trial demonstrated that axillary lymph node dissection (ALND) is unnecessary in select patients with cT1-2N0 tumors undergoing breast-conserving therapy with 1-2 positive sentinel lymph nodes (SLNs). However, patients with preoperatively confirmed ALN metastasis were not included and may be subjected to unnecessary ALND. The aim of this study is to identify patients who can be considered for ALND omission when the preoperative ALN biopsy results are positive. METHODS: Breast cancer patients who underwent preoperative ALN biopsy and primary surgery were retrospectively reviewed. Among patients with positive ALN biopsy results, clinicopathological and imaging characteristics were compared according to LN disease burden (1-2 positive LNs vs. ≥ 3 positive LNs). RESULTS: A total of 542 patients were included in the analysis. Among them, 225 (41.5%) patients had a preoperative positive ALN biopsy. More than 40% of the patients (n = 99, 44.0%) with a positive biopsy had only 1-2 positive ALNs. The association between nodal burden and imaging factors was strongest when ≥ 2 suspicious LNs were identified on PET/CT images (HR 8.795, 95% CI 4.756 to 13.262). More than one imaging modality showing ≥ 2 suspicious LNs was also strongly correlated with ≥ 3 positive ALNs (HR 5.148, 95% CI 2.881 to 9.200). CONCLUSIONS: Nearly half of patients with a preoperative biopsy-proven ALN metastasis had only 1-2 positive LNs on ALND. Patients meeting ACOSOG Z0011 criteria with only one suspicious LN on PET/CT or those presenting with few abnormal ALNs on only one imaging modality appear appropriate for SLNB and consideration of ALND omission.

Identifying long-term survivors among metastatic breast cancer patients undergoing primary tumor surgery.

PURPOSE: The prognostic role of primary tumor surgery in women with metastatic breast cancer at diagnosis is contentious. A subset of patients who will benefit from aggressive local treatment is needed to be identified. Using a nationwide database, we developed and validated a predictive model to identify long-term survivors among patients who had undergone primary tumor surgery. METHODS: A total of 150,043 patients were enrolled in the Korean Breast Cancer Registry between January 1990 and December 2014. Of these, 2332 (1.6%) presented with distant metastasis at diagnosis. Using Cox proportional hazards regression, we developed and validated a model that predicts survival in patients who undergo primary tumor surgery, based on the clinicopathological features of the primary tumor. RESULTS: A total of 2232 metastatic breast cancer patients were reviewed. Of these, 1541 (69.0%) patients had undergone primary tumor surgery. The 3-year survival rate was 62.6% in this subgroup. Among these patients, advanced T-stage, high-grade tumor, lymphovascular invasion, negative estrogen receptor status, high Ki-67 expression, and abnormal CA 15-3 and alkaline phosphatase levels were associated with poor survival. A prediction model was developed based on these factors, which successfully identified patients with remarkable survival (score 0-3, 3-year survival rate 87.3%). The clinical significance of the model was also validated with an independent dataset. CONCLUSIONS: We have developed a predictive model to identify long-term survivors among women who undergo primary tumor surgery. This model will provide guidance to patients and physicians when considering surgery as a treatment modality for metastatic breast cancer.