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Purpose Intraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate. Methods This study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness. Discussion This is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy. We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety. Trial Registration ClinicalTrials.gov Identifier: NCT03975179; Clinical Research Information Service Identifier: KCT0004606

Background In estrogen receptor (ER)-positive breast cancer (BC), young age is associated with poor prognosis. While very young patients respond better to chemotherapy, chemotherapy is less effective in ER-positive tumors than in ER-negative tumors. The authors tried to evaluate chemotherapy response of very young patients with ER-positive BC by pathologic complete response (pCR) after neoadjuvant chemotherapy excluding the effect of endocrine treatment to the extent possible. Methods We collected individual patient data from 1992 to 2013 from the Korean Breast Cancer Society (KBCS). Total 1048 ER-positive and 797 ER-negative patients aged Results The proportion of patients aged P = 0.001). Breast conservation rates were not significantly different according to age (44.2% vs. 46.8% in ER-positive group, 55.2% vs. 48.0% in ER-negative group). pCR rate was not different according to age in ER-positive group (P = 0.71) but significantly better in patients aged P = 0.009). After adjusting for confounding variables, young patients maintained the higher probability of pCR than older patients in ER-negative tumors. However, pCR rate did not differ according to age in ER-positive tumors. In multivariate analysis, young age (P = 0.003, HR = 1.98) and there was only one event in a few patients achieved pCR in ER-positive group. Conclusions Chemotherapy response based on pCR was not better in young patients ( Trial registration Retrospectively registered.

Background There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody–drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer. Methods Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan–Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups. Results HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49–0.93; P = 0.019). Conclusions These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer.

We report the development of a label-free, simple, and high efficiency breast cancer detection platform with multimodal biomarker analytic algorithms on a portable 785 nm Raman setup with an endoscopic Raman-lensed fiber optic probe. We propose a multimodal biomarker extraction algorithm (PCMA) implemented by combining a multivariate statistics principal component analysis (PCA) algorithm and a multivariate curve resolution-alternating least squares (MCR-ALS) computational model for extraction of the biomarker information hidden in Raman spectrochemical data. We show that the six Raman spectrochemical peaks at 1009, 1270, 1305/1443, 1658, and 1750 cm-1 assigned to phenylalanine, amide III in proteins, CH2 deformation in lipids, amide I in proteins, and carbonyl, respectively, can be used as a biomarker for breast cancer diagnosis using the biomarker-dominated PCMA spectrochemical spectra of breast tissues. From 20 human breast tissues, the PCMA-linear discriminant analysis (PCMA-LDA) identification method achieved high classification performance with a sensitivity and specificity >99% along with an improvement of approximately 4.5% compared to the performance without the PCMA mixture analysis algorithm. Our label-free breast cancer detection method has the potential for clinical application to diagnose breast cancer in real-time during surgery.

Surface-enhanced Raman scattering (SERS) is an ultrasensitive molecular screening technique with greatly enhanced Raman scattering signals from trace amounts of analytes near plasmonic nanostructures. However, research on the development of a sensor that balances signal enhancement, reproducibility, and uniformity has not yet been proposed for practical applications. In this study, we demonstrate the potential of the practical application for detecting or predicting asymptomatic breast cancer from human tears using a portable Raman spectrometer with an identification algorithm based on multivariate statistics. This potentiality was realized through the fabrication of a plasmonic SERS substrate equipped with a well-aligned, gold-decorated, hexagonal-close-packed polystyrene (Au/HCP-PS) nanosphere monolayer that provided femtomole-scale detection, giga-scale enhancement, and

Many studies have reported that Aldehyde dehydrogenase 1 (ALDH1) and tumor-infiltrating lymphocytes (TIL) are related to breast cancer prognosis. However, the clinical significance of ALDH1 and tumor-infiltrating immune cells in breast cancer has not been fully investigated in patients who received neoadjuvant chemotherapy (NAC). We studied the significance of the expression of ALDH1 and the population of TIL for predicting the prognosis and chemotherapeutic response of patients with breast cancer who had received NAC. Forty patients who underwent NAC were enrolled in this study. ALDH1 and TIL (T cells and tumor associated macrophages) were evaluated before and after NAC. The influences of ALDH1 expression status and TIL populations on both prognosis and chemotherapeutic response were evaluated. ALDH1 positivity was related to estrogen receptor (p = 0.026) and progesterone receptor negativity (p = 0.025). Positive change of ALDH1 after NAC tended to be associated with a poor NAC response (p = 0.078). Patients with more CD8+ T cells before NAC and fewer CD68 (+) macrophages after NAC tended to have better OS, respectively (p = 0.086, p = 0.096). The chemotherapeutic response and prognosis of patients with breast cancer who received NAC are thought to be determined by the tumor microenvironment. Further research with more patients and a longer study period is needed.

Purpose Breast cancer is one of the most common malignancies worldwide and the second most common cancer among Korean women. The prognosis of breast cancer is poor in patients with other primary cancers. However, there have been few clinical studies regarding this issue. Therefore, we analyzed the characteristics and prognosis of patients with breast cancer with multiple primary cancers (MPCs). Methods Data from the Korean Breast Cancer Society Registry were analyzed. Data from enrolled patients who underwent surgery for breast cancer were analyzed for differences in prognosis dependent on the presence of MPCs, and which MPC characteristics affected their prognosis. Results Among the 41,841 patients analyzed, 913 patients were found to have MPCs, accounting for 950 total MPCs. There was a significant difference in survival rates between the breast cancer only group and the MPC group. The 5-year survival rates were 93.6% and 86.7% and the 10-year survival rates were 87.5% and 70.4%, respectively. Among the 913 patients with MPCs, patients with two or more MPCs had significantly worse prognoses than patients with a single MPC. With respect to the time interval between breast cancer and MPC occurrence, patients with a 5-year or greater interval had significantly better prognoses than patients with less than 1 year between occurrences. Among MPCs, thyroid cancer was the most common primary cancer. However, this type was not related to the prognosis of breast cancer. Gynecologic cancer, colorectal cancer, upper gastrointestinal cancer, and lung cancer were related to breast cancer prognosis. Conclusion MPCs were a poor prognostic factor for patients with breast cancer. Two or more MPCs and a shorter time interval between occurrences were worse prognostic factors. Although MPCs were a poor prognostic factor, thyroid cancer did not affect the prognosis of patients with breast cancer.

We aimed to investigate the prognostic influence of primary tumor site on the survival of patients with breast cancer.Data of 63,388 patients with primary breast cancer from the Korean Breast Cancer Registry were analyzed. Primary tumor sites were classified into 5 groups: upper outer quadrant, lower outer quadrant, upper inner quadrant, lower inner quadrant (LIQ), and central portion. We analyzed overall survival (OS) and breast cancer-specific survival (BCSS) according to primary tumor site.Central portion and LIQ showed lower survival rates regarding both OS and BCSS compared with the other 3 quadrants (all P .05) and hazard ratios were 1.267 (95% CI, 1.180-1.360, P .001) and 1.215 (95% CI, 1.097-1.345, P .001), respectively. Although central portion showed more unfavorable clinicopathologic features, LIQ showed more favorable features than the other 3 quadrants. Primary tumor site was a significant factor in univariate and multivariate analyses for OS and BCSS (all P .001). For lymph node-negative patients, LIQ showed a worse OS than the other primary tumor sites in the subgroup with no chemotherapy (P .001), but that effect disappeared in the subgroup with chemotherapy (P = .058).LIQ showed a worse prognosis despite having more favorable clinicopathologic features than other tumor locations and it was more prominent for lymph node-negative patients who received no chemotherapy. The hypothesis of possible hidden internal mammary node metastasis could be suggested to play a key role in LIQ lesions.

Purpose Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1-RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. Methods Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-μm tissue sections from each TMA block. The χ² test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. Results Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. Conclusion Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.

Purpose In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. Methods In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. Results Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. Conclusion Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression. Trial registration ClinicalTrials.gov Identifier: NCT01069211.

Purpose There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. Methods Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. Results All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p

The purpose of this study was to compare the characteristics of quantitative perfusion parameters obtained from dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) in patients with mammographically occult (MO) breast cancers and those with mammographically visible (MV) breast cancers. Quantitative parameters (AUC, Ktrans,kep,ve,vp, and wi) from 13 MO breast cancers and 16 MV breast cancers were mapped after the DCE‐MRI data were acquired. Various prognostic factors, including axillary nodal status, estrogen receptor (ER), progesterone receptor (PR), Ki‐67, p53, E‐cadherin, and human epidermal growth factor receptor 2 (HER2) were obtained in each group. Fisher's exact test was used to compare any differences of the various prognostic factors between the two groups. The Mann‐Whitney U test was applied to compare the quantitative parameters between these two groups. Finally, Spearman's correlation was used to investigate the relationships between perfusion indices and four factors — age, tumor size, Ki‐67, and p53 — for each group. Although age, tumor size, and the prognostic factors were not statistically different between the two groups, the mean values of the quantitative parameters, except wi in the MV group, were higher than those in the MO group without statistical significance (p=0.219). The kep value was significantly different between the two groups (p=0.048), but the other parameters were not. In the MO group, vp with size, ve with p53, and Ktrans and vp with Ki‐67 had significant correlations (p

Cancer cells show a higher rate of anaerobic respiration than normal cells. The exact mechanisms for this higher glycolysis rate in cancer cells remain to be elucidated. The results of recent studies have indicated that p53, the most commonly mutated tumor suppressor gene, may have important functions in the regulation of energy-generating metabolic pathways that switch from oxidative phosphorylation to glycolysis via the synthesis of cytochrome c oxidase 2 (SCO2), p53-transactivated TP53-induced glycolysis (TIGAR), and apoptosis regulator. We evaluated the expression of p53, SCO2, TIGAR, and COX in 113 cases of invasive breast cancer using immunohistochemistry. A high expression of p53, SCO2, TIGAR, and COX was noted in 27.5% (31 cases), 84.1% (95 cases), 74.3% (84 cases), and 73.4% (83 cases) of the breast tumors, respectively. A high p53 expression was significantly associated with low expression levels of SCO2 (P = .008), COX (P < .0001), and TIGAR (P = .007). On the survival analysis, the low SCO2-expressing breast cancer patients showed a significantly poorer prognosis than that of the high SCO2-expressing breast cancer patients (P = .0078). These results suggest that p53 can modulate the metabolic pathways via the proteins SCO2 and TIGAR in human breast cancer.

Previous investigations have indicated that stromal CD10 expression, and altered levels of both E-cadherin and beta-catenin, are associated with the biological aggressiveness of human carcinoma. The aim was to evaluate stromal CD10 expression and the association of stromal CD10 with E-cadherin and beta-catenin in breast carcinoma.The expression of CD10, E-cadherin and beta-catenin was immunohistochemically analysed in tissue microarrays containing 104 cases of invasive ductal carcinoma (IDC) and 10 cases of ductal carcinoma in situ (DCIS). Stromal CD10 was detected in 49.5% (50/101) of the IDC. No immunoreactivity was identified in the stromal cells of normal breast, DCIS or intraductal components of IDC. Accumulation of the cytoplasmic beta-catenin was found in 87.0% (87/100) of the IDC. Stromal CD10 expression in IDC was significantly correlated with tumour size (P = 0.027), stage (P0.001) and histological grade (P = 0.006), the presence of nodal (P = 0.048) and distant (P = 0.015) metastases, oestrogen receptor-negative status (P = 0.016), cytoplasmic beta-catenin accumulation (P = 0.031) and lower overall survival rate (P = 0.041).Stromal CD10 expression in IDC may constitute an important prognostic marker. Stromal CD10 expression with associated aggressive features might be related to aberrant beta-catenin expression.

The human beclin-1 gene, located on chromosome 17q21, has been identified as the mammalian orthologue of Atg6 (autophagy-related gene) and may be a haploinsufficient tumor suppressor gene. The function and expression of beclin-1 in human breast cancer are largely unknown. We investigated the expression of beclin-1 and bcl-2 in human breast cancer. Tissue samples from 125 cases of invasive breast cancer were used for the present study. Immunohistochemical staining for beclin-1 and bcl-2 was evaluated using tissue microarray, then the 2 proteins were correlated with clinicopathologic parameters. Positive beclin-1 expression and bcl-2 expression in breast cancer tissue were observed in 53 cases (42.4%) and 48 cases (38.4%), respectively. Beclin-1 expression was inversely correlated with bcl-2 expression in breast cancer tissue (P = .035). Beclin-1 expression significantly correlated with nuclear pleomorphism and mitotic count. Bcl-2 expression in breast cancer tissue significantly correlated with histologic grade, tubule formation, nuclear pleomorphism, mitotic count, estrogen receptor, and distant metastasis. Our results suggest that beclin-1 might play a role in the inhibition of the development of breast cancer and that inhibition might be due to an interaction with bcl-2 protein.

Purpose A chemotherapy response assay test is performed to evaluate the degree of tumor growth inhibition by a chemotherapeutic agent. Several studies have been done on its usefulness; however, to the best of our knowledge, only a few studies concerning the relationship between chemotherapy response assay test results and breast cancer patients' prognoses have been conducted. Thus, we performed this study to analyze this relationship. Methods Among breast cancer patients who underwent curative surgery and neoadjuvant or adjuvant chemotherapy between August 2004 and December 2009, 102 were enrolled in this study. Chemotherapeutic regimens for patients were doxorubicin plus taxane or doxorubicin plus cyclophosphamide followed by taxane. We divided these patients into two groups (sensitive group [n=19] and resistant group [n=83]) and analyzed the relationship between chemosensitivity results and patient prognosis. Results The sensitive group was associated with poor disease-free survival (DFS) (p=0.003) and overall survival (OS) (p

Purpose: Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMPs). MMPs contribute to invasion and metastasis of tumor cells by degrading the surrounding basement membrane and extracellular matrix barriers, which enables the easy migration and spread of cancer cells. We examined whether hypoxia increases tumor cell invasion, and whether increased invasiveness was due to HIF-1α and MMP-9 expression. Methods: Transwell invasion assays were performed to demonstrate whether hypoxia enhance tumor invasion by use of MDA-MB-231 breast cancer cells. An immunofluorescence assay was used to demonstrate expression of HIF1α and MMP-9 under hypoxic conditions. Luciferase and ChiP assays were performed to demonstrate that MMP-9 promoter activity was regulated by HIF-1α. Results: HIF-1α was stabilized under hypoxic conditions and stimulated MMP-9 expression, which affected the tumor invasiveness of breast cancer cells. HIF-1α transactivated the MMP-9 promoter by forming a transcriptional unit with p300, thus increasing expression of MMP-9 transcripts. Zymography indicated that MMP-9 had more gelatinase activity under hypoxic conditions than normoxic conditions. Furthermore, the small GTPase Ras was also activated in response to hypoxia, which then aids stabilization of HIF-1α, and in turn upregulates MMP-9 expression. We also demonstrate that MMP-9 is upregulated concurrently with HIF-1α in tumor tissues from patients with breast cancer. Conclusion: These results suggest that HIF-1α promotes cell invasion through a MMP-9-dependent mechanism and that future antitumor agents could be used to target HIF-1α and MMP-9.