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Purpose: Mastocheck®, a proteomic-based blood assay, has been developed for early diagnosis of breast cancer. The purpose of this study is whether Mastocheck® is useful as a postoperative follow-up. Methods: A total of 255 patients were analyzed. The patients were classified into longitudinal monitoring and recurrence/nonrecurrence cohorts. The longitudinal monitoring cohort consisted of 111 patients. In this cohort, blood analyses were performed three times (before surgery, 8 weeks after surgery, and between 6 months and one year after surgery), and a comparative analysis of the values of Mastocheck® and individual proteins at each time point was performed. The recurrence/nonrecurrence cohort consisted of 144 patients who had been followed up for more than 1 year, and the blood marker values at the time of local recurrence were compared to those of nonrecurrence patients. Results: In the longitudinal monitoring cohort analysis, in 81 of 111 patients were diagnosed with breast cancer with Mastocheck® and the sensitivity was 73.0%. Of 111 patients in the longitudinal monitoring cohort, 108 had two blood analyses (before and 8 weeks after surgery), and three serial blood analyses were performed on 53 patients. The Mastocheck® value that were in the cancer range of 73.0% (in 81 of 111 patients) of patients before surgery, was within the normal range of 68.5% (in 74 of 108 patients) at 8 weeks after surgery and 88.7% (in 47 of 53 patients) from 6 months to 1 year after surgery. The value of Mastocheck® was significantly decreased after surgery compared to before surgery (p < 0.001). In the recurrence/nonrecurrence cohort analysis, the Mastocheck® values were in the cancer range in 38 out of 63 recurrence patients and within the normal range in 66 of 81 nonrecurrence patients (sensitivity of 60.3% and specificity of 80.2%). Conclusions: Mastocheck® is expected to be used as a blood marker tool to aid in the early detection of recurrence during follow-up after breast cancer surgery. [ABSTRACT FROM AUTHOR]

Mass spectrometry (MS) based proteomics is widely used for biomarker discovery. However, often, most biomarker candidates from discovery are discarded during the validation processes. Such discrepancies between biomarker discovery and validation are caused by several factors, mainly due to the differences in analytical methodology and experimental conditions. Here, we generated a peptide library which allows discovery of biomarkers in the equal settings as the validation process, thereby making the transition from discovery to validation more robust and efficient. The peptide library initiated with a list of 3393 proteins detectable in the blood from public databases. For each protein, surrogate peptides favorable for detection in mass spectrometry was selected and synthesized. A total of 4683 synthesized peptides were spiked into neat serum and plasma samples to check their quantifiability in a 10 min liquid chromatography-MS/MS run time. This led to the PepQuant library, which is composed of 852 quantifiable peptides that cover 452 human blood proteins. Using the PepQuant library, we discovered 30 candidate biomarkers for breast cancer. Among the 30 candidates, nine biomarkers, FN1, VWF, PRG4, MMP9, CLU, PRDX6, PPBP, APOC1, and CHL1 were validated. By combining the quantification values of these markers, we generated a machine learning model predicting breast cancer, showing an average area under the curve of 0.9105 for the receiver operating characteristic curve. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Based on the American College of Surgeons Oncology Group (ACOSOG)-Z0011, a useful nomogram has been constructed to identify patients who do not require intraoperative frozen sections to evaluate sentinel lymph nodes in the previous study. This study investigated the developed nomogram by ultrasonography (US) and positron emission tomography (PET)/computed tomography (CT) as a modality. In the training set, 89/1030 (8.6%) patients had three or more positive nodes. Larger tumor size, higher grade ultrasonographic ALN classification, and findings suspicious of positive ALN on PET/CT were associated in multivariate analysis. The areas under the receiver operating characteristic curve (AUC) of the nomogram were 0.856 [95% CI 0.815–0.897] in the training set. The AUC in the validation set was 0.866 [95% CI 0.799–0.934]. Application of the nomogram to 1067 patients who met the inclusion criteria of ACOSOG-Z0011 showed that 90 (8.4%) patients had scores above the cut-off and a false-negative result was 37 (3.8%) patients. And the specificity was 93.8%, and the negative predictive value was 96.4%. The upgraded nomogram improved the predictive accuracy, using only US and PET/CT. This nomogram is useful for identifying patients who do not require intraoperative analysis of sentinel lymph nodes and considering candidates for identifying neoadjuvant chemotherapy. The patients consisted of clinical T1-2 and node-negative invasive breast cancer. The training and validation set consisted of 1030 and 781 patients, respectively. A nomogram was constructed by analyzing factors related to three or more axillary lymph node metastases. The patients who matched the ACOSOG-Z0011 criteria were selected and applied to the new nomogram. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the combined use of blood-based 3-protein signature and breast ultrasound (US) for validating US-detected lesions. Methods: From July 2011 to April 2020, women who underwent whole-breast US within at least 6 months from sampling period were retrospectively included. Blood-based 3-protein signature (Mastocheck®) value and US findings were evaluated. Following outcome measures were compared between US alone and the combination of Mastocheck® value with US: sensitivity, specificity, positive predictive value (PPV), negative predictive value, area under the receiver operating characteristic curve (AUC), and biopsy rate. Results: Among the 237 women included, 59 (24.9%) were healthy individuals and 178 (75.1%) cancer patients. Mean size of cancers was 1.2 ± 0.8 cm. Median value of Mastocheck® was significantly different between nonmalignant (− 0.24, interquartile range [IQR] − 0.48, − 0.03) and malignant lesions (0.55, IQR − 0.03, 1.42) (P <.001). Utilizing Mastocheck® value with US increased the AUC from 0.67 (95% confidence interval [CI] 0.61, 0.73) to 0.81 (95% CI 0.75, 0.88; P <.001), and specificity from 35.6 (95% CI 23.4, 47.8) to 64.4% (95% CI 52.2, 76.6; P <.001) without loss in sensitivity. PPV was increased from 82.2 (95% CI 77.1, 87.3) to 89.3% (95% CI 85.0, 93.6; P <.001), and biopsy rate was significantly decreased from 79.3 (188/237) to 72.1% (171/237) (P <.001). Consistent improvements in specificity, PPV, and AUC were observed in asymptomatic women, in women with dense breast, and in those with normal/benign mammographic findings. Conclusion: Mastocheck® is an effective tool that can be used with US to improve diagnostic specificity and reduce false-positive findings and unnecessary biopsies. [ABSTRACT FROM AUTHOR]

We investigated the molecular mechanisms of paclitaxel resistance in TNBC using seven patient-derived xenograft (PDX) models and TNBC cell lines. Among the seven PDX models, four models showed resistance to paclitaxel. Dysregulation of JAK/STAT pathways and JAK2 copy number gains were observed in the four paclitaxel-resistant PDX tumors. In TNBC cell lines, silencing the JAK2 gene showed a significant but mild synergistic effect when combined with paclitaxel in vitro. However, JAK1/2 inhibitor treatment resulted in restoration of paclitaxel sensitivity in two out of four paclitaxel-resistant PDX models and JAK1/2 inhibitor alone significantly suppressed the tumor growth in one out of the two remaining PDX models. Transcriptome data derived from the murine microenvironmental cells revealed an enrichment of genes involved in the cell cycle processes among the four paclitaxel-resistant PDX tumors. Histologic examination of those PDX tumor tissues showed increased Ki67-positive fibroblasts in the tumor microenvironment. Among the four different cancer-associated fibroblast (CAF) subtypes, cycling CAF exhibiting features of active cell cycle was enriched in the paclitaxel-resistant PDX tumors. Additionally, fibroblasts treated with the conditioned media from the JAK2-silenced breast cancer cells showed downregulation of cell cycle-related genes. Our data suggest that the JAK2 gene may play a critical role in determining responses of TNBC to paclitaxel by modulating the intrinsic susceptibility of cancer cells against paclitaxel and also by eliciting functional transitions of CAF subtypes in the tumor microenvironment. Key messages: We investigated the molecular mechanisms of paclitaxel resistance in TNBC. JAK2 signaling was associated with paclitaxel resistance in TNBC PDX models. Paclitaxel-resistant PDX tumors were enriched with microenvironment cCAF subpopulation. JAK2 regulated paclitaxel-resistant CAF phenotype transition. [ABSTRACT FROM AUTHOR]

Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis. We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015. Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 225 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2 + tumors and patients who developed lung metastasis in the LSG had better overall survival than those in the ISG did. Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques. [ABSTRACT FROM AUTHOR]

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell–cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell–cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to examine profiles of depressive symptoms and the association with anxiety and quality of life (QOL) in breast cancer survivors.Methods: A cross-sectional multicenter survey involving 5 hospitals in Korea was implemented between February 2015 and January 2017. A self-report survey included the Patient Health Questionnaire-9, Short Form 36, and State and Trait Anxiety Scale. Data from 347 patients were analyzed.Results: Latent profile analysis identified five profiles of depressive symptoms: (1) "no depression" (63.98%); (2) "mild depression with sleep problems" (16.43%); (3) "mild depression" (8.65%); (4) "moderate depression with anhedonia" (7.78%); and (5) "moderately severe depression" (3.17%). Results from Fisher's exact test and analysis of variance (ANOVA) to examine whether sociodemographic and clinical characteristics distinguish the classes indicated that marital status, income and education as well as C-reactive protein distinguished a few classes. Multivariate analysis of covariance and analysis of covariance results indicated that both types of anxiety as well as several dimensions of QOL differed between the identified classes.Conclusions: The current results suggest that although identified classes were characterized overall by severity of depression, a few classes also reflected pronounced individual symptom patterns, warranting tailored interventions for these symptom patterns, along with overall severity of depression. [ABSTRACT FROM AUTHOR]

Background: Our main objective of this research was to analyze the effect of BMI on breast cancer risk according to various subtypes of breast cancer stratified with menopausal status. Methods: By using a case–control study setting, we recruited a total of 16,190 female breast cancer patients aged between 35 and 80 years from 2003 to 2010. These breast cancer patients were then individually matched by age to control female group (1:2 ratios of cases and controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via multivariable logistic regression by setting normal BMI range (18.5–22.9) as the reference group. Results: In premenopausal women, the risk of breast cancer of triple-negative subtype increased (OR 1.60, 95% CI 1.27–2.02) in obese II (BMI ≥ 30) women and in underweight women, it was Luminal A (OR 1.24, 95% CI 1.06–1.45) and HER2 express subtype (OR 1.43, 95% CI 1.26–1.62) that showed increased risk of breast cancer. In postmenopausal women, Luminal A (OR 2.35, 95% CI 2.01–2.75), Luminal B HER2 negative (OR 1.81, 95% CI 1.46–2.25) and triple-negative subtype (OR 2.25, 95% CI 1.85–2.72) showed higher risk of breast cancer in obese II women. Conclusion: Our findings suggest that the effect of BMI on breast cancer differs according to various subtypes and hormone receptors and to menopausal status. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant chemotherapy studies have consistently reported a strong correlation between pathologic response and long-term outcome in triple-negative breast cancer (TNBC). We aimed to define minimal gene signatures for predicting chemoresponse by a three-step approach and to further develop a risk-stratification method of TNBC. Methods: The first step involved the detection of genes associated with resistance to docetaxel in eight TNBC cell lines, leading to identification of thousands of candidate genes. Through subsequent second and third step analyses with gene set enrichment analysis and survival analysis using public expression profiles, the candidate gene list was reduced to prognostic core gene signatures comprising ten or four genes. Results: The prognostic core gene signatures include three up-regulated (CEBPD, MMP20, and WLS) and seven down-regulated genes (ASF1A, ASPSCR1, CHAF1B, DNMT1, GINS2, GOLGA2P5, and SKA1). We further develop a simple risk-stratification method based on expression profiles of the core genes. Relative expression values of the up-regulated and down-regulated core genes were averaged into two scores, Up and Down scores, respectively; then samples were stratified by a diagonal line in a xy plot of the Up and Down scores. Based on this method, the patients were successfully divided into subgroups with distinct chemoresponse and prognosis. The prognostic power of the method was validated in three independent public datasets containing 230, 141, and 117 TNBC patients with chemotherapy. In multivariable Cox regression analysis, the core gene signatures were significantly associated with prognosis independent of tumor stage and age at diagnosis. In meta-analysis, we found that five core genes (CEBPD, WLS, CHAF1B, GINS2, and SKA1) play opposing roles, either tumor promoter or suppressor, in TNBC and non-TNBC tumors respectively, depending on estrogen receptor status. Conclusions: The results may provide a promising prognostic tool for predicting chemotherapy responders among TNBC patients prior to initiation of chemotherapeutic treatment. [ABSTRACT FROM AUTHOR]

Background: Immune cells in the tumour microenvironment play an essential role in tumorigenesis. This study aimed to evaluate the immunoregulatory protein expression of breast cancer and reveal their prognostic role.Methods: Expression of 10 immune markers (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/ B7-H3/B7-H4) with known/possible clinical relevance was identified in stromal tumour-infiltrating lymphocytes or tumour tissue of stage I-III breast cancer patients.Results: A total of 392 patients, including 271(69.1%) luminal A, 36(9.2%) luminal B, 32(8.2%) HER2-positive and 53(13.5%) triple negative disease, were included. Expression of PD-1 and PD-L1 was higher in HER2-positive and triple negative disease. By contrast, expression of TIM-3, OX40 and OX40L were higher in luminal disease. We devised an immune recurrence score (IRS) using seven markers with prognostic value (B7-H2/B7-H3/B7-H4/OX40/OX40L/PD-L1/PD-L2). Patients were classified as high-risk (7.9%), intermediate-risk (67.6%), or low-risk (24.5%). In the multivariate analysis, IRS low-risk (adjusted HR 0.14, p = 0.001) and intermediate-risk (adjusted HR 0.32, p = 0.002) had significantly lower risk of recurrence compared with high-risk. The prognostic role of IRS was maintained in both luminal A and non-luminal A patients.Conclusions: This study identified immunoregulatory protein expression of breast cancer patients using 10 immune markers. In addition, we devised an IRS which may predict recurrence in stage I-III breast cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Although controversial, obesity and underweight may have a negative impact on breast cancer outcome. However, the relationship between body mass index (BMI) and breast cancer outcomes according to tumor subtype and menopausal status remains unclear. Methods: This study investigated the association between BMI and breast cancer outcome in stage I–III breast cancer patients. The relationships were further evaluated according to tumor subtype and menopausal status. Results: A total of 5919 patients, 3475 (58.7%) hormone receptor (HR)(+) human epidermal growth factor receptor 2 (HER2)(–), 608 (10.3%) HR(+)HER2(+), 621 (10.5%) HR(–)HER2(+), and 1079 (18.2%) HR(–)HER2(–) were included. Underweight and obesity had a negative impact on relapse-free survival but did not affect overall survival. Importantly, the prognostic role of BMI was different according to tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight was associated with poor relapse-free survival and overall survival in pre-menopausal women. In contrast, obesity had negative impact on relapse-free survival and overall survival in HR(+)HER2(–) post-menopausal patients. Underweight may have a negative prognostic role in HR(+)HER2(+) patients. However, BMI did not impact the outcome of HR(–)HER2(+) and HR(–)HER2(–) patients. Conclusions: The impact of BMI on breast cancer outcome was dependent on tumor subtype and menopausal status. In HR(+)HER2(–) patients, underweight and obesity had a negative prognostic role in pre-menopausal and post-menopausal women, respectively. These findings in Asian population should be further evaluated and compared in Western population. [ABSTRACT FROM AUTHOR]

Purpose: The Z0011 trial demonstrated that axillary dissection (ALND) could be omitted during breast-conserving therapy for cT1-2N0 breast cancers with 1–2 metastatic SLNs. However, that result has not been validated in a larger cohort and the significance of the small number of SLNs remains unclear. This study aimed to validate the Z0011 results within an Asian Z0011-eligible cohort and determine whether the number of sentinel lymph nodes (SLNs) influenced the Z0011-based outcomes. Methods: Data from Asian patients who fulfilled the Z0011 criteria were collected from five hospitals. Disease recurrence (DR) was compared between patients who underwent ALND or SLN dissection (SLND) alone. Propensity-score matching was performed to reduce the effects of potential selection biases. Results: During 2010–2016, 1750 Asian patients had 1–2 SLN metastases and fulfilled the Z0011 criteria. These patients included 707 cases treated using SLND alone (40%) and 967 patients with ≤ 2 SLNs (55%). Ninety-five patients (5.4%) experienced DR at a median interval of 50 months, although the rates of DR were similar in the ALND and SLND groups. The adjusted hazard ratios for DR after ALND omission were 0.95 (95% CI 0.55–1.64) among the entire cohort and 0.83 (95% CI 0.34–2.03) among patients with ≤ 2 SLNs. Conclusions: In this Asian Z0011-eligible cohort, ALND omission did not increase risk of DR, even among patients with ≤ 2 SLNs. Therefore, the Z0011 strategy might be safely applied in Asia, and a small number of SLNs did not significantly influence this strategy. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to explore the expression of DNA damage response machinery proteins and their integrated prognostic value in different subgroups of breast cancer. Methods: Expression of NBS1, BRCA1, BRCA2, ATM, and p53 was determined by immunohistochemistry in 419 surgically resected breast tumors. Results: Loss of NBS1, BRCA1, ATM, and abnormal p53 expression was significantly associated with lower disease-free survival rates. Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status. Most patients with luminal B (86.1%), HER2-enriched (94.4%), and triple-negative (86.8%) breast cancers had abnormal DNA damage response protein expression. In contrast, abnormal DNA damage response protein expression was found in only 53.8% of luminal A tumors. Abnormal DNA damage response protein expression was associated with significantly lower 5-year disease-free survival rates in all patients (95.6% vs. 84.8%, p = 0.001), as well as in the luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DNA damage response protein expression remained an independent predictor of shorter disease-free survival for luminal A subtype (hazard ratio 3.14, 95% confidence interval 1.16–8.47; p = 0.024). Conclusion: Abnormal DNA damage response protein expression is found in most luminal B and HER2-enriched breast cancers as frequently as in triple-negative breast cancer. In the luminal A subtype, abnormal DNA damage response protein expression is an independent prognostic marker. [ABSTRACT FROM AUTHOR]

Purpose: It has been reported that PI3K/AKT pathway is altered in various cancers and AKT isoforms specifically regulate cell growth and metastasis of cancer cells; AKT1, but not AKT2, reduces invasion of cancer cells but maintains cancer growth. We propose here a novel mechanism of the tumor suppresser, TIS21/BTG2, that inhibits both growth and invasion of triple negative breast cancer cells via AKT1 activation by differential regulation of mTORc1 and mTORc2 activity.Methods: Transduction of adenovirus carrying TIS21/BTG2 gene and transfection of short interfering RNAs were employed to regulate TIS21/BTG2 gene expression in various cell lines. Treatment of mTOR inhibitors and mTOR kinase assays can evaluate the role of mTORc in the regulation of AKT phosphorylation at S473 residue by TIS21/BTG2 in breast cancer cells. Open data and immunohistochemical analysis were performed to confirm the role of TIS21/BTG2 expression in various human breast cancer tissues.Results: We observed that TIS21/BTG2 inhibited mTORc1 activity by reducing Raptor-mTOR interaction along with upregulation of tsc1 expression, which lead to significant reduction of p70S6K activation as opposed to AKT1S473, but not AKT2, phosphorylation via downregulating PHLPP2 (AKT1-specific phosphatase) in breast cancers. TIS21/BTG2-induced pAKTS473 required Rictor-bound mTOR kinase, indicating activation of mTORc2 by TIS21/BTG2 gene. Additionally, the TIS21/BTG2-induced pAKTS473 could reduce expression of NFAT1 (nuclear factor of activated T cells) and its target genes, which regulate cancer microenvironment.Conclusions: TIS21/BTG2 significantly lost in the infiltrating ductal carcinoma, but it can inhibit cancer growth via the TIS21/BTG2-tsc1/2-mTORc1-p70S6K axis and downregulate cancer progression via the TIS21/BTG2-mTORc2-AKT1-NFAT1-PHLPP2 pathway. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to develop and validate a short form (SF) of the Smart Management Strategy for Health Assessment Tool (SAT) for cancer patients.Methods: Data for item reduction were derived from cancer patient data (n = 300) previously used to develop the original SAT. We used regression methods to select and score the new SAT-SF. To assess the instrument's reliability and validity, we recruited another 354 cancer patients from the same hospitals who were older than 18 years and accustomed to using the web. All results were compared with that of the long-form SAT (original SAT).Results: The SAT-SF used is the shorter version, a 30-item (from the original 91-item) instrument, to measure cancer patient's health. The 30-item SAT-SF explained 97.7% of total variance of the full 91-item long-form SAT. All SAT-SF subscales demonstrated a high reliability with good internal consistency compared with the original SAT. The total short-form scores of the three SAT sets (SAT-Core, SAT-Preparation, SAT-Implementation) differentiated participant groups according to their stage of goal implementation and percentage of actions taken in the 10 Rules for Highly Effective Health Behavior. We found acceptable correlations between the three SAT-SF sets and the additional assessment tools compared with the original SAT.Conclusions: The 30-item SAT-SF had a satisfactory internal consistency and validity for cancer patients with minimal loss of information compared with the original SAT. [ABSTRACT FROM AUTHOR]

Purpose: Many breast cancer patients with positive axillary lymph nodes achieve complete node remission after neoadjuvant chemotherapy. The usefulness of sentinel lymph node biopsy in this situation is uncertain. This study evaluated the outcomes of sentinel biopsy-guided decisions in patients who had conversion of axillary nodes from clinically positive to negative following neoadjuvant chemotherapy. Methods: We reviewed the records of 1247 patients from five hospitals in Korea who had breast cancer with clinically axillary lymph node-positive status and negative conversion after neoadjuvant chemotherapy, between 2005 and 2012. Patients who underwent axillary operations with sentinel biopsy-guided decisions (Group A) were compared with patients who underwent complete axillary lymph node dissection without sentinel lymph node biopsy (Group B). Axillary node recurrence and distant recurrence-free survival were compared. Results: There were 428 cases in Group A and 819 in Group B. Kaplan-Meier analysis showed that recurrence-free survivals were not significantly different between Groups A and B (4-year axillary recurrence-free survival: 97.8 vs. 99.0%; p = 0.148). Multivariate analysis also indicated the two groups had no significant difference in axillary and distant recurrence-free survival. Conclusions: For breast cancer patients who had clinical conversion of axillary lymph nodes from positive to negative following neoadjuvant chemotherapy, sentinel biopsy-guided axillary surgery, and axillary lymph node dissection without sentinel lymph node biopsy had similar rates of recurrence. Thus, sentinel biopsy-guided axillary operation in breast cancer patients who have clinically axillary lymph node positive to negative conversion following neoadjuvant chemotherapy is a useful strategy. [ABSTRACT FROM AUTHOR]

Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS ( n = 1230 for AM and n = 1458 for ANM), a Korean GWAS ( n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = −0.118 years, P = 3.4 × 10) and rs1023935 at 4p15.1 (beta = −0.145 years, P = 4.9 × 10) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = −0.276 years, P = 8.8 × 10). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations. [ABSTRACT FROM AUTHOR]

While p53 mutation is found in the majority of triple-negative breast cancer (TNBC) and despite recent developments in p53-targeting agents, their therapeutic application is still limited by the absence of standard biomarkers and ambiguousness of its essential biological role in cancer. Whole sections from 305 TNBC cases were stained for p53 to determine the correlation with lymph node metastasis and clinical outcomes in the whole cohort as well as in stratified patient groups according to AJCC stage and the use of adjuvant chemotherapy. Reduced immunohistochemical expression of p53 was an independent risk factor for lymph node metastasis. p53 overexpression was predictive of better clinical outcome in all patients ( P = 0.012, disease-free survival and P = 0.008, overall survival) and the stratified cohorts of those who had early breast cancer and received adjuvant chemotherapy. Suppression of endogenous mutant p53 by siRNA and induction of wild-type p53 repressed TNBC cell invasion in vitro. In TNBC, increased immunohistochemical expression of p53 may reflect the accumulation of wild-type p53 rather than the mutant form. Strong p53 protein expression may serve as a favorable prognostic indicator and provide evidence for the use of specific agents targeting p53. [ABSTRACT FROM AUTHOR]

Dysregulated energy metabolism is one of the main mechanisms for uncontrolled growth in solid tumors. Hypoxia-inducible factor 1-alpha (HIF1α) is a transcription factor implicated in regulating several genes that are responsible for cell metabolism, including carbonic anhydrase IX (CAIX). The aim of this study is to determine the clinical significance of immunohistochemical metabolic alteration in early-stage triple negative breast cancer (TNBC) patients who received cyclophosphamide-based chemotherapy or radiotherapy and those with basal phenotype. Immunohistochemical staining for HIF1α and CAIX was performed to determine the correlation with clinicopathologic variables and survival outcome on tissue microarrays from 270 early-stage TNBC patients. In vitro experiments with multiple human TNBC cell lines, suppression of HIF1α by small interfering RNA (siRNA) significantly reduced CAIX protein expression in all cell lines. In multivariate analyses for different therapeutic modalities and basal phenotype, combined HIF1α and CAIX protein overexpression was significantly associated with disease-free survival in the total cohort (OR = 2.583, P = 0.002), stratified cohorts expressing basal phenotype (OR = 2.234, P = 0.021), and in those patients who received adjuvant chemotherapy (OR = 3.078, P = 0.023) and adjuvant radiotherapy (OR = 2.111, P = 0.050), respectively. In early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic indicator particularly in patients treated with cyclophosphamide-based chemotherapy or radiotherapy as well as those with basal phenotype of breast cancer. [ABSTRACT FROM AUTHOR]

We investigated the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors. ATM loss was observed in 126/407 evaluable cases (31.0 %), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival rates than those in patients with intact ATM (5-year disease-free survival rate 81.2 vs. 90.7 %, p = 0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter disease-free survival [hazard ratio (HR) 3.48; 95 % confidence interval (CI), 1.48-8.17, p = 0.004]. A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached (HR 1.74; 95 % CI 0.95-3.20; p = 0.075). In subgroup analysis, ATM loss was associated with shorter disease-free survival in patients who did not receive adjuvant anthracycline chemotherapy (5-year disease-free survival rate 92.7 % in intact ATM group vs. 68.1 % in ATM loss group, p = 0.002), but this poor prognosis was overcome in patients who did (5-year disease-free survival rate 89.8 vs. 84.4 %, p = 0.243), suggesting more benefit from anthracycline-based chemotherapy. Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy. [ABSTRACT FROM AUTHOR]

Purpose: In stage II/III breast cancer, neoadjuvant chemotherapy (NAC) is a standard treatment. Although several biomarkers are used to predict prognosis in breast cancer, there is no reliable predictive biomarker for NAC success. Recently, the hepatocyte growth factor (HGF) and cMet signaling pathway demonstrated to be involved in breast cancer tumor progression, and its potential as a biomarker is under active investigation. In this study, we assessed the potential of serum HGF as a prognostic biomarker for NAC efficacy. Methods: Venous blood samples were drawn from patients diagnosed with stage II/III breast cancer and treated with NAC in Seoul National University Hospital from August 2004 to November 2009. Serum HGF level was determined using an ELISA system. We reviewed the medical records of the patients and investigated the association of HGF level with patients' clinicopathologic characteristics. Results: A total of 121 female patients (median age = 45 years old) were included. Median level of HGF was 934 pg/ml (lower quartile: 772, upper quartile: 1145 pg/ml). Patients with higher HGF level than median value were significantly more likely to have clinically detectable regional node metastasis ( p = 0.017, Fisher's exact test). Patients with complete and partial response according to the American Joint Committee on Cancer 7th Edition criteria tended to have higher HGF level ( p = 0.105 by t test). Patients with an HGF level higher than the upper quartile value had longer relapse-free survival than the other patients (106 vs. 85 months, p = 0.008). Conclusions: High serum HGF levels in breast cancer patients are associated with clinically detectable regional node metastasis and, paradoxically, with longer relapse-free survival in stage II/III breast cancer. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the biological role and clinical implications of silent mating type information regulation 2 homolog 1 (SIRT1) as a novel candidate for target therapy in triple negative breast cancer (TNBC) for which there is no specific agent. 344 patients who received surgical resection for TNBC from January 2003 to December 2006 at Seoul National University Hospital were enrolled, and the role of SIRT1 protein was evaluated via immunohistochemistry on tissue samples. In vivo experiments to evaluate tumor invasiveness were carried out with three human TNBC cell lines following SIRT1-siRNA transfection. Expression of SIRT1 significantly correlated with lymph node metastasis (p = 0.008). In multivariate analysis, SIRT1 expression (p = 0.011), T stage (p = 0.014), and lymphatic invasion (p < 0.001) were revealed to be independent predictive factors for lymph node metastasis. Combination of these three parameters revealed predictive performance for lymph node metastasis with an area under the curve (AUC) of 0.689 on receiver operating characteristics (ROC) curves analysis. SIRT1 expression correlated with shorter disease-free survival (P = 0.003) but not with overall survival. Inhibition of SIRT1 with small interfering RNA (siRNA) conspicuously suppressed the invasiveness of TNBC cell lines. This study reveals the role of SIRT1 on tumor invasiveness and unfavorable clinical outcomes, and we suggest its potential role as a prognostic indicator as well as a novel therapeutic target in TNBC. [ABSTRACT FROM AUTHOR]

Background: The association between chemotherapy-induced ovarian dysfunction (CIOD) and response to neoadjuvant chemotherapy (NAC) is not known. We therefore investigated the impact of CIOD on response to NAC in breast cancer patients according to estrogen receptor (ER) status. Methods: In total, 343 premenopausal breast cancer patients treated with NAC between 2006 and 2010 were analyzed. Clinical responses were determined based on changes in tumor size measured using breast MRI. Patients with complete response or partial response were considered to have clinical response. Results: After completion of NAC, 264 of 343 patients (76.9 %) developed CIOD. The clinical response rate was significantly higher in patients with CIOD than those without CIOD (65.2 vs. 51.9 %; p = 0.033). Additionally, the mean follicle-stimulating hormone (FSH) level after NAC was significantly higher in patients with clinical response (FSH 68.7 ± 34.5 vs. 59.8 ± 34.3 IU/L; p = 0.021). Multivariate analysis showed an independent association of CIOD to clinical response (OR 0.523, 95 % CI 0.297-0.918; p = 0.024). However, we observed no differences in the pathologic complete response (pCR) rate between patients with and without CIOD (8.7 vs. 6.3 %; p = 0.497). Subgroup analysis according to ER status showed that the association between CIOD and clinical response was significant in ER-positive but not ER-negative breast cancer ( p = 0.025 and 0.818, respectively). Conclusions: CIOD during NAC is significantly associated with clinical response, but not pCR. Moreover, this association is only observed in ER-positive breast cancer, suggesting that the moderate difference in response to NAC is possibly a hormonal effect of chemotherapy-induced ovarian dysfunction. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to evaluate the accuracy of shear-wave elastography (SWE) in the detection of residual breast cancer after neoadjuvant chemotherapy (NAC). Methods: Seventy-one women with stage II-III breast cancers who underwent B-mode ultrasound (US), SWE, and magnetic resonance imaging (MRI) after NAC were included. The presence of residual cancer was determined on B-mode US and MRI, and the maximum elasticity of residual lesions was assessed on SWE. The sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of B-mode US, SWE, and MRI were compared. Results: Sixty-one of 71 women (86 %) had residual cancer and showed higher maximum elasticity values (mean 116.0 ± 74.1 kPa) than those without residual cancer (26.4 ± 21.0 kPa; p < 0.001). B-mode US showed 72.1 % (44/61) sensitivity, 50.0 % (5/10) specificity, and 69.0 % (49/71) accuracy. The sensitivity, specificity, and accuracy of SWE were 83.6 % (51/61), 80.0 % (8/10), and 83.1 % (59/71) when a maximum elasticity value of >30 kPa was considered to indicate the presence of residual cancer. The combined AUC of B-mode US and SWE (0.877) was significantly higher than that of B-mode US (0.702) ( p = 0.014) and comparable to that of MRI (0.939) ( p = 0.147). Conclusions: SWE allowed relatively accurate assessment for the presence of residual lesion after NAC and improved the diagnostic performance of B-mode US. [ABSTRACT FROM AUTHOR]

We aimed to identify the factors affecting the successful tumor engraftment in breast cancer patient-derived xenograft (PDX) models. Further, we investigated the prognostic significance and the functional importance of the PDX engraftment-related genes in triple-negative breast cancers (TNBC). The clinico-pathologic features of 81 breast cancer patients whose tissues were used for PDX transplantation were analyzed to identify the factors affecting the PDX engraftment. A gene signature associated with the PDX engraftment was discovered and its clinical importance was tested in a publicly available dataset and in vitro assays. Nineteen out of 81 (23.4 %) transplanted tumors were successfully engrafted into the PDX models. The engraftment rate was highest in TNBC when compared to other subtypes ( p = 0.001) and in recurrent or chemotherapy-resistant tumors compared to newly diagnosed primary tumors ( p = 0.024). PDX tumors originated from the TNBC cases showed more rapid tumor growth in mice. Gene expression profiling showed that down-regulation of genes involved in the tumor-immune interaction was significantly associated with the successful PDX engraftment. The engraftment gene signature was associated with worse survival outcome when tested in publicly available mRNA datasets of TNBC cases. Among the engraftment-related genes, PHLDA2, TKT, and P4HA2 showed high expression in triple-negative breast cancer cell lines, and siRNA-based gene silencing resulted in reduced cell invasion and proliferation in vitro. Our results show that the PDX engraftment may reflect the aggressive phenotype in breast cancer. Genes associated with the PDX engraftment may provide a novel prognostic biomarker and therapeutic targets in TNBC. [ABSTRACT FROM AUTHOR]

Luminal A breast cancer can present with early, unexpected lymph node metastasis, and sentinel lymph node biopsy has been reported false negative in some cases. We aimed to construct a biomarker-based model that predicts lymph node metastasis in luminal A breast cancer, using expression of silent mating type information regulation 2 homolog 1 (SIRT1) and apoptosis-related factors, which are known to be closely related. We selected tissue samples of 278 cases of luminal A invasive ductal carcinoma, constructed tissue microarrays, and performed immunohistochemical staining for SIRT1 and four apoptosis-related proteins. In constructing the best predictive model for lymph node metastasis, six clinicopathological parameters and five molecular markers were considered. Independent factors predictive of lymph node metastasis were pT stage (OR 1.829, p = 0.027), lymphovascular invasion (OR 4.128, p < 0.001), and decreased expression of caspase-3 (OR 0.535, p = 0.034) and of SIRT1 (OR 0.526, p = 0.053). A combination nuclear grade, lymphovascular invasion, increased B-cell lymphoma 2 (Bcl-2) expression, and reduced expression of caspase-3 and of SIRT1 yielded the strongest predictive performance for lymph node metastasis with an area under the curve (AUC) of 0.696. This combination was also predictive of shortened disease-free survival (73.1 vs. 67.7 months, p = 0.003). Our data support a role of SIRT1 protein as tumor suppressor in luminal A breast cancer, in association with apoptosis-related proteins. Our model based upon a combination of these biomarkers is expected to increase accuracy of prediction of lymph node metastasis in luminal A breast cancer. This might serve as a valuable tool in determining the optimal surgical strategy in breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Young breast cancer patients have a poorer prognosis, especially when their tumors are hormone receptor positive. We analyzed the association between Ki67 and age and the impact of these factors on outcomes in hormone receptor-positive breast cancer. Methods: The records of 9,321 hormone receptor-positive invasive breast cancer patients from three large centers were retrospectively reviewed. Each institution separately assayed Ki67 level immunohistochemically. Univariate and multivariate analysis for recurrence-free survival (RFS) was performed on 4,738 patients from a single center. Results: Ki67 level was inversely proportional to age in all three data sets and was significantly higher for younger patients ( p < 0.001, 0.03, and <0.001, respectively). This correlation was seen only in the human epidermal growth factor receptor 2 ( HER2)-negative population. Survival analysis showed that both very young age (<35 years) and high Ki67 level (≥10 %) were independent prognostic factors. Although young age was a worse prognostic indicator regardless of HER2 status, Ki67 index was associated with worse prognosis only in HER2-negative patients. When patients were stratified into those with low and high Ki67, young age remained a significant factor for RFS, with hazard ratios in these two Ki67 groups of 2.15 and 2.57, respectively ( p < 0.001). Also, the young age/low Ki67 group had significantly poorer RFS than the older age/high Ki67 group ( p < 0.001). Conclusions: Ki67 level was higher in younger patients. However, very young patients had a poorer prognosis regardless of Ki67 level. Unknown biologic factors other than high cell proliferation might play a role in the aggressiveness of hormone receptor-positive breast cancer in very young patients. [ABSTRACT FROM AUTHOR]

Previous observational studies have suggested that metformin in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications. This randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients. Female breast cancer patients ( N = 105), at least 6 months post-mastectomy, with obesity (≥25 kg/m) and/or pre-diabetes (fasting blood sugar levels ≥100 mg/dL), were randomly assigned to three groups (placebo, metformin 500 mg, and metformin 1000 mg) stratified by tamoxifen use. A linear mixed model for repeated measurements among three groups and ANOVA for profile differences during 6 months of treatment were used for the intention-to-treat analysis. The metformin 1000 mg group had a significantly greater decline in glucose and HbA1c levels between treatment weeks 0 and 6 month ( p = 0.008 and 0.009, respectively), and the declines increased with an increase in body mass index (BMI) level ( p interaction with BMI = 0.007 and 0.067, respectively). A marginally significant different effect from the metformin 1000 mg treatment was detected for glucose and HbA1c levels ( p interaction = 0.084 and 0.063, respectively) in the intention-to-treat analysis. Metformin 1000 mg treatment had a favorable effect on controlling glucose and HbA1C levels in obese non-diabetic breast cancer patients, indicating prognostic importance. Further trials are needed to elucidate the risk-benefit ratio of long-term use of metformin. [ABSTRACT FROM AUTHOR]

Purpose: To ensure a surgical margin of ≥1 cm for the effective treatment of phyllodes tumors of the breast (PTB) a second resection has been recommended, but the outcomes of an extensive series of cases employing the aforementioned criterion cast doubt on this clinical approach. The aim of this study was to identify the local recurrence (LR) risk factors of PTB and determine future optimal surgical treatment according to verified risks. Methods: All cases given a diagnosis of PTB, and resected between 1989 and 2008, were retrospectively evaluated. Clinicopathologic data and clinical outcomes were analyzed and stratified according to the risks for LR. Results: All 285 cases were categorized as benign (191, 67.0 %), borderline (61, 21.4 %), or malignant (33, 11.6 %). Median follow-up was 6.7 years and there were 20 LRs during follow-up. All benign PTB recurred as benign PTB lesions. Mitoses ( p < 0.001) and tumor size ( p = 0.021) were independent prognostic factors for LR in multivariate analysis. Neither margin status ( p = 0.758) nor type of surgery ( p = 0.922) had any significance for LR. In the risk stratification for LR, PTB ≤5 cm in size with ≥10 mitoses/10 high-power fields (HPFs) had the highest LR rate (55.6 %) compared with all other subgroups ( p < 0.001). Conclusions: It is recommended a wide excision and clear margin of 1 cm be ascertained in only small PTB with frequent mitoses, if necessary by means of a second surgery, which could be considered in order to avoid the risk of LR in this distinct and limited group. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to determine whether triple-negative breast cancers (TNBCs) with and without androgen receptor (AR) expression have distinguishing imaging features on mammography, breast ultrasound (US), and magnetic resonance (MR) imaging. Methods: AR expression was assessed immunohistochemically in 125 patients with TNBC from a consecutive series of 1,086 operable invasive breast cancers. Two experienced radiologists blinded to clinicopathological findings reviewed all imaging studies in consensus using the BI-RADS lexicon. The imaging and pathological features of 33 AR-positive TNBCs were compared with those of 92 AR-negative TNBCs. Results: The presence of mammographic calcifications with or without a mass ( p < 0.001), non-mass enhancement on MR imaging ( p < 0.001), and masses with irregular shape or spiculated margins on US ( p < 0.001 and p = 0.002) and MR imaging ( p = 0.001 and p < 0.001) were significantly associated with AR-positive TNBC. Compared with AR-negative TNBC, AR-positive TNBC was more likely to have a ductal carcinoma in situ component (59.8 % vs. 90.9 %, p = 0.001) and low Ki-67 expression (30.4 % vs. 51.5 %, p = 0.030). Conclusion: AR-positive and AR-negative TNBCs have different imaging features, and certain imaging findings can be useful to predict AR status in TNBC. Key points: • Triple-negative breast cancers have distinguishing imaging features according to AR expression. • AR-positive TNBC is associated with calcifications, spiculated masses, and non-mass enhancement. • Multimodality imaging can help predict androgen receptor status in TNBC. [ABSTRACT FROM AUTHOR]

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene; P = 1.67 × 10−9) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P = 4.25 × 10−8). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P = 0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) accounts for 12-24 % of all breast cancers. Here, we studied 221 familial breast and/or ovarian cancer patients from 37 hospitals using a comprehensive approach to identify large genomic rearrangements (LGRs) as well as sequence variants, and investigated the association between BRCA1/2 mutational status and TNBC. We performed direct sequencing or mutation scanning followed by direct sequencing. Then, 143 BRCA1/2 mutation-negative patients were screened for LGRs. In this study, the prevalence of BRCA1/2 mutations was high (36.9 %). The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations: 49.4 versus 50.6 %, respectively. TNBC was diagnosed in 35.2 % of BRCA1/2 mutation carriers and 57.1 % of BRCA1 mutation carriers. Conversely, two-thirds of TNBC patients carried BRCA1/2 mutation(s), and about half were BRCA1 mutation carriers. When stratified by the mutated gene, TNBC prevalence in BRCA1 mutation carriers was significantly lower when there was a family history of ovarian cancer. Our multinomial logistic regression model demonstrated that no single factor was sufficient, and at least two factors, such as a patient with family history of both breast cancer and ovarian cancer or a patient diagnosed at a relatively young age (<40 years) with a TNBC phenotype, are necessary to indicate BRCA1/2 genetic testing in this population. Our results suggest that TNBC is a strong predictor for the presence of a BRCA1 mutation in this population, but additional risk factors should also be evaluated to ascertain a 10 % or higher prior probability of BRCA1/2 mutation testing. [ABSTRACT FROM AUTHOR]

Lifestyle factors have been chronologically changed into western style ones, which could result in the rapid increase of breast cancer incidence in Korea. It is plausible that reproductive factors through hormonal mechanisms are differentially related to the risk of breast cancer subtypes. We investigated the association of reproductive risk factors on breast cancer by birth year groups and also evaluated the differential associations on the hormone receptor-defined subtypes. Using the data from the Seoul Breast Cancer Study (SeBCS), a multicenter case-control study, 3,332 breast cancer patients and 3,620 control subjects were analyzed. The distribution of subtypes among cases was as follows: 61.0 % estrogen receptor (ER)-positive, 51.9 % progesterone receptor (PR)-positive, and 43.4 % both ER/PR-positive status, respectively. Polytomous logistic regression and Wald tests for heterogeneity have been used across the subtypes. The frequencies of reproductive-related risk factors including early age at menarche, nulligravid, age at first full-term pregnancy (FFTP), duration of estrogen exposure before FFTP (EEBF), less number of children, never breastfeeding, and short duration of breastfeeding has increased as women were born later in both cases and controls, respectively ( p < 0.0001. Among breast cancer patients, either ER- or PR-positive subtypes were increased in women born in 1960s compared to women born in 1940s. Early age at menarche increased the risk of breast cancer regardless of the subtypes while nulligravid, late age at FFTP, and longer duration of EEBP were associated with hormone receptor-positive cancer risk only ( p < 0.05), which associations were stronger among women born later. Our results suggest that the associations of age at menarche, parity, age at FFTP, and duration of EEBF with breast cancer risk were different based on the hormone receptor status and birth year groups in Korea. [ABSTRACT FROM AUTHOR]

Background: We conducted a retrospective study to evaluate the local recurrence (LR) rate depending on the use of neoadjuvant chemotherapy (NCT) and to determine the oncologic safety of breast-conserving surgery (BCS) after NCT by comparing LR between patients treated with BCS and mastectomy in clinical stage III breast cancer patients. Patients and Methods: Between 2004 and 2007, 166 patients underwent BCS or mastectomy after NCT (NCT group) and 193 patients underwent surgery first (surgery group) in clinical stage III breast cancer patients. Patients whose tumor size became ≤4 cm after NCT, 57 patients underwent mastectomy (mastectomy group) 39 patients underwent preplanned BCS (preplanned BCS group), and 33 patients underwent downstaged BCS (downstaged BCS group). The recurrence rates between the groups and risk factors for LR were analyzed. Results: The 5-year LR-free survival rates were 93.6 % in the NCT group and 95.9 % in the surgery group ( P = 0.108). In the NCT group, the 5-year LR-free survival rates were 96.3 % in the mastectomy group, 94.7 % in the preplanned BCS group and 90.9 % in the downstaged BCS group ( P = 0.669). High expression of Ki-67 was a predictor of LR in patients in three groups (Hazard ratio 8.300, P = 0.049). Conclusions: Our findings suggest that BCS after NCT in clinical stage III patients is oncologically safe in terms of LR if breast tumor size is ≤4 cm after NCT and Ki-67 is a predictor of LR after NCT. [ABSTRACT FROM AUTHOR]

Purpose: Recently, the American Joint Committee on Cancer (AJCC) 7th edition proposed new response criteria for neoadjuvant chemotherapy (NAC) in breast cancer. The purpose of this study was to evaluate the clinical usefulness of AJCC response criteria. Methods: A total of 398 consecutive stage II or III breast cancer patients who received NAC were enrolled in this study. AJCC response criteria were as follows: (1) complete response (CR)-absence of invasive carcinoma in the breast and node; (2) partial response (PR)-decrease in either or both T or N stage; (3) no response (NR)-no change or increase in either or both T or N stage. Results: Complete response, PR, and NR by AJCC criteria were 9.8, 59.3, and 30.7 %, respectively. Among the 398 patients, 337 patients were available for both paired pre- and post- breast MRI and chest CT. AJCC response criteria were significantly associated with RECIST criteria ( P < 0.001). AJCC response was significantly associated with relapse-free survival (RFS) and overall survival (OS). The 5-year RFS rates were 89.6 % in CR, 74.1 % in PR, and 62.6 % in NR ( P = 0.002). The 5-year OS rates were 97.4 % in CR, 88.6 % in PR, and 78.3 % in NR ( P = 0.012). When adjusting potential prognostic factors, AJCC response was independently associated with RFS and OS. Conclusions: AJCC response criteria for NAC in breast cancer have clinical usefulness in evaluating response of NAC, as well as predicting survival. AJCC response criteria can discriminate among patient subgroups with respect to survival. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to determine the usefulness of sequential FDG PET/CTs for prediction of axillary lymph node (ALN) status after neoadjuvant chemotherapy (NAC). Methods: Seventy-seven stage II or III breast cancer patients who received 3 cycles of neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for early metabolic response prediction. Results: Patients with pN0 had significantly lower post-NAC ALN standard uptake value (SUV) than those who were pN+ (1.22 ± 1.46 in pN0 vs. 2.13 ± 1.99 in pN+, P = 0.017). Post-NAC ALN size on CT also differed according to pathologic ALN status (6.3 mm in pN0 vs. 11.1 mm in pN+, P = 0.014). When serial FDG PET/CT and chest CT were used, patients with an SUV > 1.5 and post-NAC ALN size ≥10 mm on CT did not achieve pN0 (specificity 100% and positive predictive value 100%). Conclusions: The serial FDG PET/CT after NAC could predict the pathologic status of ALN before surgery in stage II/III breast cancer. Our findings suggest that the combined use of serial FDG PET/CTs and chest CT might provide better information regarding ALN before surgery. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to estimate the prevalence of BRCA1/2 mutations among familial breast cancer (BC) patients in Korea. We analyzed 775 familial BC patients who were enrolled in the Korean Hereditary Breast Cancer (KOHBRA) study and treated at 36 institutions between May 2007 and May 2010. Patients with familial BC were defined as BC patients with family histories of BC or ovarian cancer (OC) in any relatives. All probands received genetic counseling and BRCA genetic testing was performed after obtaining informed consent. The mean age of BC diagnosis was 43.6 years. The numbers of probands with family histories of BC only and OC only were 682 and 93, respectively. The overall prevalence of the BRCA mutation among familial BC patients was 21.7 % ( BRCA1 9.3 % and BRCA2 12.4 %). Subgroup analyses observed prevalences of the BRCA mutation as follows: 19.6 % among patients with BC family history only ( BRCA1 7.6 % and BRCA2 12.0 %) and 36.6 % among patients with OC family history only ( BRCA1 21.5 % and BRCA2 15.1 %). Most of the subgroups satisfied the 10 % probability criteria to undergo BRCA testing. However, the prevalence of the BRCA mutations among subgroups that had 2 BC patients in a family with both age at diagnosis of more than 50 years old did not reach the 10 % criteria (4.1 %). Korean familial BC patients are good candidates for BRCA testing even when they have family histories of single breast cancers. However, proband age at diagnosis should be carefully considered when selecting patients for testing. [ABSTRACT FROM AUTHOR]

A positive resection margin after breast-conserving surgery (BCS) is the most important risk factor for tumor recurrence. Re-excision after BCS often results in unnecessary wider excisions, or even mastectomies and poor cosmetic results, as well as increased medical costs and patients' anxiety. A nomogram for predicting positive resection margins may allow the surgeon to develop an individualized surgical plan. Data from 1,034 consecutive breast cancer patients with invasive or in situ breast cancer who initially underwent BCS between January 2008 and December 2009 were used to develop a nomogram for predicting positive resection margins. The nomogram was then validated independently using a cohort of 563 patients who underwent breast surgery in 2010. Multivariate logistic regression analysis showed that microcalcifications (OR 1.574, P = 0.034), grade 4 mammographic density (OR 4.515, P = 0.005), >0.5 cm difference in tumor size between magnetic resonance imaging and ultrasonography (OR 10.001, P < 0.0001), ductal carcinoma in situ (DCIS) on needle biopsy (OR 1.575, P = 0.044), and lobular component on needle biopsy (OR 3.985, P = 0.015) were independent predictors of positive resection margins. These significant variables were used to develop a nomogram for predicting positive resection margins after BCS; the AUCs of the study and the validation cohorts were 0.823 [95 % confidence interval (CI), 0.785-0.862] and 0.846 (95 % CI, 0.800-0.892), respectively. Our new nomogram using 5 variables that were determined before surgery to predict positive resection margins should aid the surgeon in developing individualized surgical plans for breast cancer patients who are scheduled for BCS. [ABSTRACT FROM AUTHOR]

Estrogen receptor (ER) expression status is an independent factor predicting response to neoadjuvant systemic treatment (NST). In the current study, we aimed to investigate the characteristics of NST response and benefits of extended NST cycles according to ER expression status. We investigated the outcomes of different durations of anthracycline-taxane-based NST in 377 operable breast cancer patients treated between Aug 2008 and June 2011. In 89 patients, the serial radiologic tumor response was assessed with either ultrasonography or computed tomography. Ninety-six patients (25.5 %) received extended cycles of anthracycline-taxane-based NST (6-8 cycles) and 281 patients (74.5 %) received 3-4 cycles of NST. Treatment with extended cycles of NST led to a significant increase in the pCR rate in ER-positive tumors only (2.1-11.7 %, p = 0.008 for ER-positive tumors and 20.0-19.4 %, p = 0.941 for ER-negative tumors). Serial assessment of radiologic tumor size during extended NST therapy revealed continuous shrinkage of ER-positive tumors during the chemotherapy cycles, while ER-negative tumors mainly achieved size reduction during the first 3-4 cycles with no significant additional tumor shrinkage during the extended cycles of NST. In this study, we report a distinct pattern of response to NST according to ER expression status in breast cancer. Our observation generates the hypothesis that the optimal duration of NST can be tailored to the molecular phenotypes of tumors. [ABSTRACT FROM AUTHOR]

Prevalence and phenotype of BRCA mutation can vary by race. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations in non-familial breast cancer patients with high risks in Korea. A subset of 758 patients was selected for this study from the KOHBRA nationwide multicenter prospective cohort study. Mutations in BRCA1/2 genes were tested using fluorescent-conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography or direct sequencing. Mutation of BRCA1/2 genes were identified in 65 (8.6%) patients among total 758 patients [ BRCA1 mutation: 25 (3.3%), BRCA2 mutation: 40 (5.3%)]. According to risk groups, mutation of BRCA1/2 genes were identified in 53 (8.5%) of 625 early onset patients (age ≤40), in 22 (17.7%) of 124 bilateral breast cancer patients, in 3 (50.0%) of 6 breast and ovarian cancer patients, in one (5.9%) of 17 male breast cancer patients, in 5 cases (7.6%) of 66 multiple organ cancer patients. The most common mutation was 509C>A for BRCA1 and 7708C>T for BRCA2. The prevalence of BRCA1/2 mutations by age in early onset patients was significantly different (age <35 vs age ≥35; 10.0 vs 2.9%, p = 0.0007). BRCA1/2 mutations for non-familial Korean breast cancer patients were detected at a high rate, particularly, in patients with early onset of less than 35 years of age, bilateral breast cancer, and breast and ovarian cancer. Individualized genetic counseling should be offered for non-familial breast cancer patients with these risk factors. [ABSTRACT FROM AUTHOR]

Background: Our aim was to compare the accuracy of magnetic resonance imaging (MRI) and ultrasonography (US) in measuring the size of invasive breast cancer (IBC) and carcinoma in situ (CIS). We also examined the utility of routinely performing MRI in addition to US before breast-conserving surgery (BCS). Patients and Methods: Data from 1558 consecutive patients diagnosed with IBC and/or CIS between 2003 and 2005 were reviewed. For comparing the accuracy of US and MRI, paired t test was done comparing pathologic and imaging (US and MRI) tumor size in 821 patients who received both breast US and MRI. In instance of attempted BCS ( n = 794), operative approach, resection margins, and clinical outcomes of non-MRI and MRI groups were compared. Results: For CIS, IBC without CIS, and IBC with CIS, MRI was more accurate in estimating tumor size than US. When BCS was attempted ( n = 794), the rate of tumor involvement in initial resection margins did not differ between non-MRI and MRI groups (23.0% and 23.4%, P = .926). Similarly, rates of re-excision (13.1% vs 17.5%, P = .130) and conversion to mastectomy (2.3% vs 2.1%, P = .893) were comparable, as were ipsilateral breast tumor recurrence, locoregional recurrence, and disease-free survival (log rank P = .284, .950, and .955, respectively). Conclusions: Breast MRI provided more accurate estimates of tumor size, correlating better with pathologic tumor size than US for both IBC and CIS. However, no clear benefit in terms of lower re-excision rate, higher breast conservation success, or reduced recurrence emerged for routine use of breast MRI before BCS. [ABSTRACT FROM AUTHOR]

An addition of trastuzumab preoperatively to chemotherapy for human epidermal growth factor receptor 2 (HER2) positive breast cancer improved relapse-free survival (RFS). This study was designed to evaluate the efficacy and safety of preoperative paclitaxel, gemcitabine, and trastuzumab (PGH) combination for HER2-positive breast caner. Pathologically, proven node positive stage II/III breast cancer patients with adequate organ function and no history of anti-cancer therapy were eligible. Patients received weekly trastuzumab with paclitaxel 80 mg/m and gemcitabine 1,200 mg/m on days 1 and 8, every 3 weeks for 6 cycles. Postoperatively, patients completed trastuzumab for 1 year and hormone therapy for 5 years if indicated. All patients received postoperative radiation therapy. Of 53 enrolled patients with a median tumor of 5.3 (range, 2.0 to >12) cm; 43.4%, T3/T4; 75.4%, N2/N3; and 45.3%, positive hormone receptors. The pathologic complete response (pCR) rate was 58.5% in both tumor and lymph nodes. Grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (0.6%), and transient elevation of AST/ALT (1.6%) during a total of 318 cycles. All patients maintained normal cardiac function. With a median follow-up of 40 months, 3-year RFS rate was 84% with 91.7% distant metastasis-free survival rates. Remarkable pCR rate was obtained with non-anthracycline-based PGH therapy for HER2-positive stage II/III breast cancer. Adverse events were mild with few incidences of febrile neutropenia. [ABSTRACT FROM AUTHOR]

To determine the significance of (Cyclooxygenase 2) COX2 for clinical outcome in breast cancer, we analyzed the correlation between COX2 overexpression and survival in 687 patients with invasive breast cancer. Cytoplasmic immunoreactivity of COX2 was determined as positive in 325 of 687 (47.3%) invasive breast cancers. COX2 positivity was significantly correlated with high histologic grade, negative estrogen receptor (ER), high Ki67, luminal B and triple-negative tumors, Bcl2 negativity, and p53 overexpression. In univariate analysis, COX2 overexpression resulted in significantly shorter relapse-free survival (RFS) [hazard ratio (HR) 1.487, 95% CI 1.035-2.110, P = 0.032]. Multivariate analysis revealed no significant association between COX2 overexpression and either overall survival (OS) or RFS. Kaplan-Meier analysis of the whole patient group showed significantly reduced RFS in patients with high COX2 expression, compared to those that did not overexpress COX2 (91 vs. 162 months, P = 0.031). Stratified subgroup analysis by TNM stage disclosed marked differences in OS and RFS rates in Stage III patients. We observed a significant association of COX2 overexpression with shorter RFS in the ER-negative subgroup of Stage III patients. The results show that COX2 overexpression is a significant unfavorable prognostic factor in Stage III breast cancer, and provide selective criteria for COX2 inhibitor combinations for invasive breast cancer therapy. [ABSTRACT FROM AUTHOR]

Central nerve system (CNS) metastases are a feared complication of breast cancer and are associated with poor prognosis. The purpose of this study is to investigate the clinical characteristics of CNS metastases and to clarify the prognostic factors after CNS metastases in breast cancer at a single institution over a long time period. We retrospectively reviewed the medical records of breast cancer patients diagnosed at Seoul National University Hospital from 1981 to 2009 and identified the patients who experienced CNS metastases. We collected the data, including demographics, clinico-pathologic characteristics, dates of diagnosis of original breast cancer and subsequent metastases, and date of death, and correlated the findings with the clinical outcome. A total of 400 patients were identified, of whom 17 (4.3%) were diagnosed with CNS metastases and primary breast cancer concurrently and 383 (95.7%) experienced CNS metastases subsequent to the diagnosis of primary breast cancer. Further, 318 patients (79.5%) had only brain parenchymal metastases, 30 (7.5%) had only leptomeningeal metastases, and 52 (13%) had both. After the diagnosis of CNS metastasis, 170 patients (42.5%) received systemic chemotherapy (CTx) and 143 (35.8%) received CTx after whole brain radiation therapy (WBRT). The patients with good performance status (PS), initial CNS metastasis as recurrence, absence of extracranial metastases, non-visceral extracranial metastases, longer interval from the date of primary breast cancer to the date of CNS metastasis, and CTx after WBRT and gamma-knife surgery (GKS), had better outcomes in univariate analyses. In multivariate analysis, good PS, systemic CTx after WBRT, GKS, and longer interval to CNS metastasis, were independent prognostic factors for overall survival after CNS metastases. Our results suggest that appropriate palliative systemic therapy after WBRT or GKS, and adequate palliative treatment via combined modalities are helpful for breast cancer patients, even after the detection of CNS metastases. [ABSTRACT FROM AUTHOR]