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Background: Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women., Methods: We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI's performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A-D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories., Results: Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]), PPV (1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]), recall rate (7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]), and AUC values (0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category., Conclusions: AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue., (© 2024. The Author(s).)

Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed., Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US., Design, Setting, and Participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023., Main Outcomes and Measures: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation., Results: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001)., Conclusions and Relevance: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.

Objective: To investigate the association between body composition parameters and breast cancer (BC) risk in premenopausal women., Design, Setting, and Participants: Prospective cohort study using data from the Kangbuk Samsung Cohort Study. Participants were women aged 20 to 54 years who were enrolled from 2011 to 2019 and followed up for BC development until December 31, 2020. Data were analyzed from June to August 2023., Exposures: Trained nurses conducted anthropometric measurements and assessed body composition using segmental bioelectric impedance analysis. The analysis encompassed adiposity measures such as body mass index (BMI), waist circumference, and body composition parameters, including muscle mass, fat mass, ratio of muscle mass to weight, ratio of fat mass to weight, and fat mass index., Main Outcomes and Measures: Adjusted hazard ratios (aHR) for BC during the follow-up period., Results: Among 125 188 premenopausal women, the mean (SD) age was 34.9 (6.3) years. During a mean (range) follow-up of 6.7 (0.5-9.9) years, 1110 incident BC cases were identified. The mean (SD) BMI and waist circumference were 21.6 (3.1) and 75.3 (8.2) cm, respectively. Higher BMI and waist circumference were associated with decreased risk, with an aHR of 0.89 (95% CI, 0.84-0.95) per SD increase in BMI and 0.92 (95% CI, 0.86-0.98) per SD increase in waist circumference. A higher ratio of fat mass to weight was associated with decreased BC risk (aHR, 0.92; 95% CI, 0.86-0.99 per SD increase), whereas the opposite trend was observed for the ratio of muscle mass to weight, with an aHR of 1.08 (95% CI, 1.02-1.15) per SD increase. The results remained consistent even after additional adjustments for height in the model. The fat mass index was also inversely associated with BC risk, with an HR of 0.90 (95% CI, 0.85-0.97) per SD increase., Conclusions and Relevance: In this cohort study of premenopausal women, a higher level of adiposity, represented by increased BMI, waist circumference, and fat mass, was consistently associated with decreased breast cancer risk. Conversely, muscle mass and its ratio to weight displayed opposite or inconsistent patterns. These findings suggest an inverse association between excess adiposity and the risk of BC in premenopausal women, confirming earlier findings that BMI is an indirect measure of adiposity.

Background: Residual microcalcifications after neoadjuvant chemotherapy (NAC) are challenging for deciding extent of surgery and questionable for impact on prognosis. We investigated changes in the extent and patterns of microcalcifications before and after NAC and correlated them with pathologic response. We also compared prognosis of patients depending on presence of residual microcalcifications after NAC., Methods: A total of 323 patients with invasive breast carcinoma treated with neoadjuvant chemotherapy at Kangbuk Samsung Hospital and Samsung Medical center from March 2015 to September 2018 were included. Patients were divided into four groups according to pathologic response and residual microcalcifications. Non-pCR w/mic group was defined as breast non-pCR with residual microcalcifications. Non-pCR w/o mic group was breast non-pCR without residual microcalcifications. pCR w/mic group was breast pCR with residual microcalcifications. pCR w/o mic group was breast pCR without residual microcalcifications. The first aim of this study is to investigate changes in the extent and patterns of microcalcifications before and after NAC and to correlate them with pathologic response. The second aim is to evaluate oncologic outcomes of residual microcalcifications according to pathologic response after NAC., Results: There were no statistical differences in the extent, morphology, and distribution of microcalcifications according to pathologic response and subtype after NAC (all p > 0.05). With a median follow-up time of 71 months, compared to pCR w/o mic group, the hazard ratios (95% confidence intervals) for regional recurrence were 5.190 (1.160-23.190) in non-pCR w/mic group and 5.970 (1.840-19.380) in non-pCR w/o mic group. Compared to pCR w/o mic group, the hazard ratios (95% CI) for distant metastasis were 8.520 (2.130-34.090) in non-pCR w/mic group, 9.120 (2.850-29.200) in non-pCR w/o mic group. Compared to pCR w/o mic , the hazard ratio (95% CI) for distant metastasis in pCR w/mic group was 2.240 (0.230-21.500) without statistical significance (p = 0.486)., Conclusions: Regardless of residual microcalcifications, patients who achieved pCR showed favorable long term outcome compared to non-pCR group., (© 2024. The Author(s).)

Introduction: SB3 is a trastuzumab biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the USA. This real-world study evaluated safety and effectiveness of SB3 as part of the Korean post approval safety management system., Methods: This post-marketing surveillance in Korea included patients in line with approved indications, i.e., patients with early or metastatic breast cancer or metastatic gastric cancer. Safety outcomes were adverse events (AEs) and adverse drug reactions. Effectiveness outcomes were tumor response and event-free survival., Results: 424 patients were evaluated: 366 patients (86%) with early breast cancer, 53 patients (13%) with metastatic breast cancer, and 5 patients (1%) with metastatic gastric cancer. Among patients with breast cancer, AEs (mostly mild) and adverse drug reactions were reported by 158 (37.7%) and 57 (13.6%) patients, respectively. Most patients with an AE (141, 89.2%) had no change in treatment schedule. Treatment was temporarily suspended in 14 (8.9%) patients with an AE and completely discontinued in 7 (4.4%). Among patients with early and metastatic breast cancer who were evaluated for efficacy, objective response rates were 82.7% and 38.3%, respectively. Pathological complete response was 64.6% in patients with early breast cancer., Discussion/conclusion: Safety and efficacy of SB3 demonstrated in this real-world study were comparable with previous studies of reference trastuzumab., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Objectives: Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment., Methods: Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as "one primary only." Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival., Results: Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period ( P =0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P <0.001) and 23% received chemotherapy (vs. 45% for PBA, P =0.11)., Conclusions: We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma., Competing Interests: E.T.L.—Clinical trial funding from BioAtla, Ayala, and SpringWorks. L.D.C.—Clinical trial funding from Eli Lilly, AADi, BluePrint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma. Honoraria or has served on advisory boards for Daaichi Sankyo. M.J.W.—Clinical trial support from Deciphera, Adaptimmune, GSK, Athenex, Foghorn Therapeutics, Shaqsi, Presage Biosciences, Inhibrx, and Incyte. Consulting fees from Adaptimmune, Epizyme, Aadi, and Deciphera. H.M.L.—Research funding from Tolmar, EliLilly, GE Healthcare, Sanofi, and Zymeworks. Consulting for GE Healthcare, Novartis, Sanofi, and Eli Lilly. J.M.S.—Research funding from Celcuity, Genentech, Xencor, Pfizer, SeaGen, Merck, Carisma, and Lyell. Consultant/advisory boards: A2 Biotherapeutics, Volastra Therapeutics, GE Healthcare, Sensei Therapeutics, and GlaxoSmithKline. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although breast MRI is known to be the best imaging modality for assessing the response after neoadjuvant chemotherapy (NAC), discordance still remains between MRI findings and final pathology findings., Purpose: To evaluate imaging and clinicopathologic factors associated with radiologic-pathologic discordance in breast cancer patients after NAC., Material and Methods: This retrospective study included 104 breast cancer patients (mean age: 50.2 years) who underwent breast MRI examinations before and after NAC between June 2015 and December 2019. Radiologic complete response (rCR) was defined as equal or lesser enhancement compared with breast tissue in post-NAC MRI. Pathologic CR (pCR) was defined as absence of invasive cancer in final pathology. Imaging and clinicopathologic factors associated with radiologic-pathologic discordance were analyzed with logistic regression analysis., Results: Overall rCR and pCR rates were 37.5% (39/107) and 40.2% (43/107), respectively. Multivariate analysis revealed that the presence of non-mass enhancement (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.1-11.2; P = 0.03) and multicentric lesions on pre-NAC MRI (OR, 4.2; 95% CI, 1.2-14.9; P = 0.03) were independently associated with radiologic-pathologic discordance. False-positive rate for predicting residual tumor was the most prevalent in HER2-positive cancers (86.7%)., Conclusion: When determining rCR, the presence of non-mass enhancement and multicentric lesions on pre-NAC MRI, and HER2-positive cancers should be interpreted with caution., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Since the publication of the Z0011 trial, practice-changing clinical guidelines for breast surgery have been developed. Although recent studies confirmed the feasibility of the Z0011 strategy in Asian populations, there has been no study on the trends of axillary surgery in Asian cohort. This study aimed to investigate the time trend of axillary surgery for breast cancer from a Korean Breast Cancer Registry to understand the impact of the Z0011 trial in Asian patients., Methods: We collected prospectively constructed data from the nationwide Korean Breast Cancer Registry (KBCR). We identified patients who underwent sentinel node biopsy followed by breast-conserving surgery from 2011 to 2018 and were found to have pathological stage T1-2N1-3M0 disease. Regression analyses were performed to compare the downward trend of axillary lymph node dissection (ALND) in Korean cohort with that previously reported in a Dutch cohort., Results: From KBCR data, 7478 patients met the inclusion criteria. The proportion of ALND significantly decreased from 2011 (76.6%) to 2018 (47.5%). Multivariate analysis revealed that earlier years at diagnosis, larger tumor size, and lymphatic invasion were associated with a higher odds ratio of performing ALND. Compared to the Dutch cohort, the downward trend of ALND in Korea was significantly more gradual (annual percent change: 37.2 vs. 5.8%, p < 0.001)., Conclusions: This study demonstrated a downward trend of ALND in Korean patients with breast cancer. However, the rate of decrease was significantly slower than that in the Dutch cohort., (© 2022. The Author(s).)

Purpose: While increased breast density is a risk factor for breast cancer, the effect of fatty liver disease on breast density is unknown. We investigated whether fatty liver is a risk factor for changes in breast density over ~ 4 years of follow-up in pre- and postmenopausal women., Methods: This study included 74,781 middle-aged Korean women with mammographically determined dense breasts at baseline. Changes in dense breasts were identified by more screening mammograms during follow-up. Hepatic steatosis (HS) was measured using ultrasonography. Flexible parametric proportional hazards models were used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), and a Weibull accelerated failure time model (AFT) was used to determine the time ratios (TRs) and 95% CIs., Results: During a median follow-up of 4.1 years, 4022 women experienced resolution of the dense breasts. The association between HS and dense breast resolution differed by the menopause status (P for interaction < 0.001). After adjusting for body mass index and other covariates, the aHRs (95% CI) for dense breast resolution comparing HS to non-HS were 0.81 (0.70-0.93) in postmenopausal women, while the association was converse in premenopausal women with the corresponding HRs of 1.30 (1.18-1.43). As an alternative approach, the multivariable-adjusted TR (95% CI) for dense breast survival comparing HS to non-HS were 0.81 (0.75-0.87) and 1.19 (1.06-1.33) in premenopausal and postmenopausal women, respectively., Conclusion: The association between HS and changes in dense breasts differed with the menopause status. HS increased persistent dense breast survival in postmenopausal women but decreased it in premenopausal women., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The risk of breast cancer related to changes in breast density over time, including its regression and persistence, remains controversial. The authors investigated the relationship between breast density and its changes over time with the development of breast cancer in premenopausal and postmenopausal women., Methods: The current cohort study included 74,249 middle-aged Korean women (aged ≥35 years) who were free of breast cancer at baseline and who underwent repeated screening mammograms. Mammographic breast density was categorized according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). A dense breast was defined as heterogeneously dense or extremely dense, and changes in dense breasts between baseline and subsequent follow-up were classified as none, developed, regressed, or persistent dense breast., Results: During a median follow-up of 6.1 years (interquartile range, 4.1-8.8 years), a total of 803 incident breast cancers were identified. Baseline breast density was found to be positively associated with incident breast cancer in a dose-response manner, and this association did not significantly differ by menopausal status. The multivariable-adjusted hazard ratios (HRs) for breast cancer comparing "heterogeneously dense" and "extremely dense" categories with the nondense category were 1.96 (95% confidence interval [95% CI], 1.40-2.75) and 2.86 (95% CI, 2.04-4.01), respectively. With respect to changes in dense breasts over time, multivariable-adjusted HRs for breast cancer comparing persistent dense breast with none were 2.37 (95% CI, 1.34-4.21) in premenopausal women and 3.61 (95% CI, 1.78-7.30) in postmenopausal women., Conclusions: Both baseline dense breasts and their persistence over time were found to be strongly associated with an increased risk of incident breast cancer in premenopausal and postmenopausal women., Lay Summary: Both baseline breast density and its changes over time were found to be independently associated with the risk of breast cancer in both premenopausal and postmenopausal women. The risk of incident breast cancer increased in women with persistent dense breasts, whereas the breast cancer risk decreased as dense breasts regressed. The findings of the current study support that both dense breasts at baseline and their persistence over time are independent risk factors for developing breast cancer., (© 2020 American Cancer Society.)

This study aimed to investigate the diagnostic performance of chest computed tomography (CT) for opportunistic screening and longitudinal follow-up of osteoporosis in breast cancer patients, compared to dual-energy X-ray absorptiometry (DXA). The association between L1 vertebral attenuation on chest CT and incidental fracture was also evaluated. We retrospectively reviewed 414 consecutive breast cancer patients who underwent both non-enhanced chest CT and DXA within a 3-month interval and had at least two DXA and two chest CT examinations over more than 1 year. The attenuation value of the L1 trabecular bone was measured on an axial CT image and compared to the corresponding DXA T-score. The diagnostic performance of L1 vertebral attenuation on CT for osteoporosis was calculated at different thresholds (90 HU, 100 HU, 110 HU), and the correlation between L1 vertebral attenuation values and DXA T-scores was statistically analyzed. Overall fracture-free survival was estimated and compared with the threshold of 90 HU on CT and -2.5 T-score on DXA. Of 414 patients (median age, 53.0 years), 88 (21.3%) had either vertebral or non-vertebral fractures. The median follow-up duration between initial and final DXA was 902.9 days. There was a moderate correlation between L1 vertebral attenuation value and DXA T-score (ρ = 0.684, CI 0.653-0.712). Fracture-free survival was significantly lower in patients with attenuation values ≤90 HU on CT and T-scores ≤-2.5 on DXA (P < .001). Multivariate analysis revealed that attenuation values ≤90 HU on CT (P < .001), T-scores ≤-2.5 on DXA (P = .003), and age ≥65 years (P = .03) were independent significant prognostic factors associated with overall fracture-free survival. The sensitivities and specificities of L1 attenuation value were 54.9% and 85.8% at 90-HU threshold, 74.0% and78.4% at 100-HU threshold, and 83.9% and 70.1% at 110-HU threshold, respectively. In conclusion, CT can be used for predicting osteoporosis and discriminating incidental fracture risk in breast cancer patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: To assess the predictive value of preoperative residual mammographic microcalcifications for residual tumours after neoadjuvant chemotherapy (NAC) for breast cancer., Materials and Methods: This single-centre retrospective study included breast cancer patients who underwent NAC and demonstrated suspicious microcalcifications within or near the tumour bed on mammography from June 2015 to August 2018. The residual microcalcifications and remnant lesion on magnetic resonance imaging (MRI) were correlated with histopathological findings of residual tumours and immunohistochemical markers., Results: A total of 96 patients were included. Ten patients achieved pathological complete response (pCR) and previous suspicious microcalcifications were associated with benign pathology in 10.4% (10/96) of the patients. In the remaining 86 patients who did not achieve pCR, 61.5% (59/96) of the residual microcalcifications were associated with invasive or in situ carcinoma and 28.1% (27/96) with benign pathology. Hormone receptor-positive (HR + ) patients had the highest proportion of residual malignant microcalcifications compared to HR - patients (48.9% versus 13.5%, respectively; p=0.019). MRI correlated better than residual microcalcifications on mammography in predicting residual tumour extent in all subtypes (ICC=0.709 versus 0.365). MRI also showed higher correlation with residual tumour size for the HR - /HER2 + and HR - /HER2 - subtype (ICC=0.925 and 0.876, respectively)., Conclusion: The extent of microcalcifications on mammography after NAC did not correlate with the extent of residual cancer in 38.5% of women. Regardless of the extent of microcalcifications, residual tumour extent on MRI after NAC and molecular subtype could be an accurate tool in evaluating residual cancer after NAC., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Antimicrobial peptides (AMP) with anticancer activity have drawn remarkable attention in modern treatments. However, long peptide length and protease instability are the most addressing factors, which hampers their further development as therapeutic agents. In view of this, herein, we designed and synthesized a series of AZT-based cationic small molecule incorporating a variety of hydrophobic groups and cationic charges, including amine and guanidine groups to mimic the amphipathic structure of AMPs. These compounds were evaluated for their antibacterial activity against Gram-positive and Gram-negative bacteria. Through an extensive structure activity relationship study (SAR), we identified ADG-2e as the most potent antibacterial agent, which exhibited remarkable potency against drug resistant bacterial strains such as MRSA and MDRPA. Further, ADG-2e was examined for their anti-metastatic ability by investigating the cancer cell migration and invasiveness through scratch wound-healing assay and transwell invasive assay, respectively. In addition, time-lapse cell tracking analysis also performed for analyzing the cell movement pattern. Treatment of ADG-2e against metastatic breast cancer cells (MDA-MB-231) suppressed tumor cell migration by multi-directional lamellipodium formation, indicating their anti-metastatic potential. Thus, our cationic AZT based small molecules may evolve as an appealing class of antibacterial agents with anti-metastasis potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The interleukin-22 (IL-22) signaling pathway is well known to be involved in the progression of various cancer types but its role in bone metastatic breast cancer remains unclear. We demonstrate using human GEO profiling that bone metastatic breast cancer displays elevated interleukin-22 receptor 1 (IL-22R1) and sphingosine-1-phosphate receptor 1 (S1PR1) expression. Importantly, IL-22 stimuli promoted the expression of IL-22R1 and S1PR1 in aggressive MDA-MB-231 breast cancer cells. IL-22 treatment also increased sphingosine-1-phosphate production in mesenchymal stem cells (MSCs) and induced the sphingosine-1-phosphate (S1P)-mediated chemotactic migration of MDA-MB-231 cells. This effect was inhibited by an S1P antagonist. In addition to the S1PR1 axis, IL-22 stimulated the expression of matrix metalloproteinase-9 (MMP-9), thereby promoting breast cancer cell invasion. Moreover, IL-22 induced IL22R1 and S1PR1 expression in macrophages, myeloid cell, and MCP1 expression in MSCs to facilitate macrophage infiltration. Immunohistochemistry indicated that IL-22R1 and S1PR1 are overexpressed in invasive malignant breast cancers and that this correlates with the MMP-9 levels. Collectively, our present results indicate a potential role of IL-22 in driving the metastasis of breast cancers into the bone microenvironment through the IL22R1-S1PR1 axis., Competing Interests: The authors declare no conflict of interest.

The impact of variations in serum thyroid hormone concentration within the euthyroid range on breast cancer risk remains unclear. We investigated the effect of serum thyrotropin (TSH) and thyroid hormone concentration on breast cancer risk. This cohort study involved 62,546 Korean women, aged ≥40 years, who were free of breast cancer at baseline and underwent health examination with determination of free thyroxine (FT4) and TSH. A parametric proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI). During a median follow-up of 4.8 years (interquartile range: 2.8-7.3 years), 834 incident breast cancers were identified. Compared to normal FT4 level, abnormally high serum FT4 level was associated with an increased risk of incident breast cancer with a corresponding multivariable aHR (95% CI) of 1.98 (1.02-3.83). This association tended to be stronger in postmenopausal women than in premenopausal women. Within the euthyroid range, the highest TSH tertile was associated with a lower risk of breast cancer than the lowest TSH tertile with a corresponding aHR (95% CI) of 0.68 (0.55-0.84). In contrast, highest FT4 tertile was associated with a higher risk of breast cancer than the lowest FT4 tertile. Abnormally high FT4 as well as higher FT4 within the euthyroid range were positively associated with breast cancer risk, while higher TSH concentration within the euthyroid range was negatively associated with breast cancer risk. Our findings indicate that thyroid function within both the abnormal and euthyroid ranges may contribute to the development of breast cancer., (© 2019 UICC.)

Background: In patients diagnosed with ductal carcinoma in situ (DCIS) with needle biopsy before surgery, invasive component (IC) is often found in the postoperative tissue, which results in altered post-surgical care. However, there are no clinically available factors to predict IC, and few MRI studies are available for the detection of IC in DCIS patients. The purpose of this study was to evaluate which risk factors can predict IC preoperatively., Methods: Patients with a DCIS diagnosis based on preoperative biopsy, who underwent breast surgery Kangbuk Samsung Hospital between Jan 2005 and June 2018, were retrospectively evaluated. Clinico-pathological and breast MRI factors were compared between DCIS and DCIS with IC in postsurgical specimens., Results: Of the 431 patients with a preoperative diagnosis of DCIS, 34 (7.9%) showed IC during the postoperative pathological investigations, and 217 (50.3%) underwent breast MRI. Among MRI-related factors, Mass-like enhancement on MRI was the sole but significant predictor of IC (HR = 0.26, C.I. = 0.07-0.93, p = 0.038), while nipple-areolar complex invasion, enhancement peak and pattern were not statistically significant. Nuclear grade was the only significant predictor of IC in the analysis of other clinico-pathological factors (HR = 2.39, C.I. = 1.05-5.42, p = 0.038 in univariate analysis, HR = 2.86, C.I. = 1.14-7.14, p = 0.025 in multivariate analysis)., Conclusions: Mass-like enhancement on MRI and high nuclear grade were associated with IC in patients with preoperative diagnosis of DCIS. Considering the high sensitivity of breast MRI for IC, further evaluation of the predictive value of MRI in preoperative DCIS patients is desirable.

Objective: To compare the accuracy of contrast-enhanced digital mammography (CEDM) and MRI, including maximal intensity projection (MIP) images, for measuring the tumour size of breast cancer., Methods: We included 52 females (mean age, 50.9 years) with surgery due to breast cancer, and measured maximum diameter of main mass on mediolateral oblique (MLO) and craniocaudal (CC) views of mammography and CEDM; sagittal, axial MIP images, and early dynamic contrast-enhanced MRI (CEMRI) before surgery. Bland-Altman plot, intraclass correlation coefficient, and univariate linear regression analysis were used to evaluate the maximum size between imaging and pathology including only invasive component (OP invasive ) or with carcinoma in situ (OP max )., Results: Mean OP invasive was 15.5 mm, and overestimation rate was similar or higher than underestimation rate on all images except CC view of mammography and axial MIP image of CEDM. Mean OP max was 21.7 mm, and underestimation rate was higher than the overestimation rate. All parameters of CEDM and CEMRI showed good agreement ( k > 0.75) with OP invasive , with the most favourable result being the CC view of CEDM and axial MIP image of CEMRI., Conclusion: All views of CEDM and MRI provided accurate measurements of tumour size. Axial plane CEDM and MRI would be the first choice for image review and treatment planning, with the highest accuracy obtained by using CC view of CEDM., Advances in Knowledge: Previous studies have not compared the measurement of the tumour size using detailed sequences; in our study, we discovered that CEDM can be an alternative modality to CEMRI.

Breast cancer exhibits high lethality in women because it is frequently detected at an advanced stage and aggressive forms such as triple-negative breast cancer (TNBC), which are often characterized by metastasis through colonization of secondary tumors. Thus, developing therapeutic agents that target the metastatic process is crucial to successfully treat aggressive breast cancer. We evaluated SP-8356, an anti-inflammatory synthetic verbenone derivative, with respect to its regulation of breast cancer cell behavior and cancer progression. Treatment of SP-8356 arrested cell cycle and reduced growth in various types of breast cancer cells with mild cytotoxicity. Particularly, SP-8356 significantly reduced the motility and invasiveness of TNBC cells. Assays using an in vivo xenograft mouse model confirmed the cell-specific anti-proliferative and anti-metastatic activity of SP-8356. Functional studies revealed that SP-8356 suppressed serum response element-dependent reporter gene expression and NF-κB-related signaling, resulting in downregulation of many genes related to cancer invasion. We conclude that SP-8356 suppresses breast cancer progression through multimodal functions, including inhibition of NF-κB signaling and growth-related signaling pathways.

Background: Carcinogenesis and tumor growth are associated with chronic inflammation and the host immune system. Here, we investigated the clinical significance and relationship between tumor-infiltrating lymphocytes (TILs) and hematologic parameters in patients with breast cancer., Methods: Invasive ductal breast cancer patients (N = 145) who underwent surgery were retrospectively evaluated. Samples were obtained using a core needle biopsy for CD8+, FOXP3+ TIL assessment. Blood lymphocytes, neutrophils, monocytes, and platelets were obtained by peripheral venous punctures., Results: CD8 + TILs were significantly associated with absolute lymphocyte count (ALC) and the absolute monocyte count (AMC). Low LMR (ALC/AMC) (cut-off - 5.3, range = 0.73-12.31) was associated with poor overall survival (OS) (p = 0.010), disease-free survival (DFS) (p = 0.005). However, in subgroup analysis, LMR did not have any value as a prognostic factor in HER2-positive breast cancers. TILs had different prognostic impacts across breast cancer subtypes, although they were not statistically significant. The treatment response after NAC tended to improve in breast cancer patients with high FOXP3+ TILs, low NLR (neutrophil count/ALC) (FOXP3 p for trend = 0.006, NLR p for trend = 0.063)., Conclusions: A relevance between TILs and hematologic parameters in breast cancer was demonstrated. The influence of the immune system on breast cancer progression may differ by subtype.

Background: The aim of this study was to determine the feasibility of image-guided marker-clip placement in axillary lymph nodes (ALNs) for breast cancer upon initial presentation and to assess the reliability of this method with sentinel lymph node biopsy (SLNB) for axillary restaging after neoadjuvant chemotherapy (NAC)., Methods: Between June 2015 and August 2016, a marker clip was placed at a clinically positive ALN under ultrasonography (US) guidance before initiation of NAC in 20 patients. Preoperative localization of marker-clipped LNs was performed, and the localized LNs were removed by SLNB. We compared the postoperative results of the marker-clipped LNs, SLNs and ALNs., Results: Image-guided marker-clip placements and localization of marker-clipped LNs were performed successfully in 20 patients. A total of 24 marker clips were inserted, and 23 marker-clipped LNs were successfully retrieved during surgery (identification rate, 23/24, 95.8%). In the 11 patients with pathologically confirmed metastatic marker-clipped LNs, four became negative after NAC, and seven maintained metastatic residues on the marker-clipped LNs. Three of the seven patients had metastatic residues on the ALNs, and two of the three patients also had negative SLNs. Marker-clipped nodes accurately predicted the axillary nodal status in these two patients compared with SLNs alone., Conclusion: Image-guided marker-clip placement on positive ALNs before NAC and removal with SLNB is technically feasible. This technique can improve the accuracy of the residual disease evaluation on the axilla, especially in patients with negative SLNB results, and can identify candidates for limited axillary surgery after NAC.

Brachyury has been characterized as a driver of epithelial-mesenchymal transition process which is regarded as an important mechanism of cancer cell invasion and metastatic progression. The status of tumor-infiltrating lymphocytes has been proposed to predict response to neoadjuvant chemotherapy in breast cancer. We investigated the clinical significance and value of tumor-infiltrating lymphocytes and brachyury as biomarkers to predict treatment responses to neoadjuvant chemotherapy in breast cancer. We also examined the correlation of the Neo-Bioscore with tumor-infiltrating lymphocytes and brachyury to indirectly predict long-term outcome. This retrospective study included a series of 44 consecutive patients treated between January 2011 and December 2015. All patient samples were obtained using core needle biopsy before neoadjuvant chemotherapy. The relationship of expression of Brachyury and tumor-infiltrating lymphocyte subsets (CD8+, forkhead box protein 3 tumor-infiltrating lymphocytes) with clinicopathological factors was assessed to identify its predictive role with respect to tumor response to neoadjuvant chemotherapy and the outcome. Of 44 patients, 6 showed no response, 31 had partial response, and 7 demonstrated pathological complete response. Forkhead box protein 3 was significantly higher in the response group than in the no response group (no response = 2.6, partial response = 7.0, complete response = 9.7, p = 0.020). Brachyury expression was inversely associated with response to neoadjuvant chemotherapy, but the difference was not statistically significant ( p = 0.62). We also observed a significant association between forkhead box protein 3 ( p = 0.001) and the Neo-Bioscore, while only a marginal difference was observed with CD8+ expression ( p = 0.074). This study demonstrated that forkhead box protein 3 expression has value as the only independent marker that predicts a good response to neoadjuvant chemotherapy and that it is related with a good prognosis according to the Neo-Bioscore. Brachyury was significantly associated with estrogen receptor positive and human epidermal growth factor receptor 2 negative status; further study would be needed to clarify how it affects treatment prognosis.

Objectives: This study aims to comprehensively assess the publication of clinical trial results and factors associated with their publication., Study Design and Setting: Phase II and III trials of advanced breast cancer registered on ClinicalTrials.gov between October 1, 2000, and September 30, 2012, were identified. Publications were searched by using PubMed and reviewing those listed on the registry site. The main outcomes were publication rate, public availability of results, and time to publication., Results: Of 352 phase II and 74 phase III trials, 12.5% and 31.1% were published, whereas 46.9% and 58.1% had publicly available results, respectively. Compared to those with significant results, studies with nonsignificant results had delays in time to publication (P < 0.001). Even after adjusting for funding source and phase type, the significance of study outcomes was a significant factor that affected time to publication (hazard ratio = 6.02; 95% confidence interval: 3.59, 10.07; P < 0.001), with trials with significant outcomes taking less time to publish than those with nonsignificant outcomes., Conclusion: Underreporting of results and nonpublication or delays in the publication of negative results were identified in registered trials of advanced breast cancer. Thus, further initiatives appear necessary to urgently address such publication bias., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The selection of appropriate endpoints is crucial for the evaluation of clinical benefits and approval of novel anticancer agents. To our knowledge, this is the first study to evaluate endpoint selection and the shift in trends in phase II and phase III trials of advanced breast cancer treatment., Methods: All phase II and phase III trials of advanced breast cancer registered in the ClinicalTrials.gov registry between October 2000 and September 2012 were included in our study. Two study periods were considered for comparison: October 2000 to September 2007 (cohort A) and October 2007 to September 2012 (cohort B). Information on primary and secondary outcome measures, as well as trial characteristics, was extracted by two independent reviewers., Results: Of the 398 phase II and 120 phase III trials, the most frequently intended primary endpoint was progression-free survival (phase II: 28.1 %; phase III: 50.0 %). For phase II trials, a shifting trend in primary outcome was observed from cohort A to cohort B: the use of objective response rate, the most frequently intended primary outcome, significantly declined (cohort A: 60.6 %; cohort B: 39.0 %; P < 0.001), while the use of progression-free survival significantly increased (cohort A: 35.9 %; cohort B: 66.1 %; P < 0.001)., Conclusions: Progression-free survival is the most frequently intended primary outcome measure in phase II and phase III trials of advanced breast cancer treatment, with a shifting trend observed from objective response rate to progression-free survival in phase II trials.

Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.

Background: Little information is available on the use of chest computed tomography (CT) to predict breast tumor size in breast cancer, despite the fact that chest CT examinations are being increasingly used. The purpose of this study was to evaluate the value of chest CT for predicting breast tumor size using pathology measurements as reference standards., Methods: Tumor sizes (defined as greatest diameter) were retrospectively measured on the preoperative chest CT images of 285 patients with surgically proven unifocal, invasive breast carcinoma. Greatest tumor diameters as determined by chest CT and pathologic examinations were compared by linear regression and Spearman's rho correlation analysis. Concordance between CT and pathology results was defined as a diameter difference of <5 mm. Subgroup analyses were also performed with respect to tumor size (<20 mm or ≥20 mm) and histological subtype (invasive ductal carcinoma(IDC) or non-IDC)., Results: CT and pathology measured diameters were found to be linearly related (size at pathology = 1.086 × CT determined tumor size - 1.141; Spearman's rho correlation coefficient = 0.84, P<0.001). Most tumors (n = 228, 80.0%) were concordant by chest CT and pathology, but 36 tumors (12.7%) were underestimated by CT (average underestimation, 11 mm; range, 6-36 mm) and 21 tumors (7.4%) were overestimated (average overestimation by CT, 10 mm; range, 6-19 mm). The concordance rate between the two sets of measurements was greater for tumor of <20 mm and for IDC (P<0.001 and P = 0.011, respectively)., Conclusions: Tumor size by chest CT is well correlated with pathology determined tumor size in breast cancer patients, and the diameters of the majority of tumors by chest CT and pathology differed by <5 mm. In addition, the concordance rate was higher for breast tumors of <20 mm and for tumors of the IDC histologic subtype.

Azathioprine (AZA) treatment in transplant or autoimmune patients and subsequent appearance squamous cell carcinomas at various sites, particularly skin and cervix, has shown a close relationship. However, it remains uncertain whether this is true for the patients with Crohn's disease. We report a case of squamous cell carcinoma of the breast occurred in a 35-year-old female with Crohn's disease taking AZA. She was first diagnosed with Crohn's disease 10 years ago and has taken AZA with 5-aminosalicylic acid (5-ASA) on regular follow up in gastrointestinal department for 9 years. She had no family history of breast cancer. She visited breast cancer clinic due to incidentally found right breast mass. A mastectomy on the right breast was performed and 6.3×5.5 cm mass was removed. The mass was microscopically proven to be poorly differentiated squamous cell carcinoma with focal keratin pearl formation. At age of 25, she was first diagnosed with active Crohn's disease. 5-ASA and corticosteroid induced remission. Then, steroid was tapered off and AZA was maintained at 1 mg/kg due to leukopenia at higher dose. She stopped taking AZA at her discretion during her two pregnancies and reported total of 67 months of AZA medication on her breast cancer diagnosis.

Leukotriene B4 (LTB4) is an inflammatory mediator with potent biological activities in the pathogenesis of many inflammatory diseases. In the present study, we found that expression of BLT2, a low-affinity LTB4 receptor, is significantly upregulated in breast cancer cells. In addition, we observed that inhibition of BLT2 by a specific antagonist, LY255283, or by siBLT2 RNA interference caused dramatic apoptotic cell death in breast cancer cells, especially in the estrogen receptor (ER)-negative MDA-MB-468 and MDA-MB-453 cells, suggesting a role for BLT2 in survival of these breast cancer cells. In an approach to understand the downstream mechanism by which BLT2 mediates the potential pro-survival signaling, we found that the elevated reactive oxygen species (ROS) generation is associated with BLT2-mediated survival. Expression of Nox1, a member of the NADPH oxidase family, is also highly upregulated in a BLT2-dependent manner in these breast cancer cells, suggesting that 'Nox1-derived ROS' lie downstream of BLT2. Consistent with the proposed role of 'Nox1-ROS' in pro-survival signaling, knockdown of Nox1 with siNox1 or treatment with a ROS scavenging agent caused dramatic apoptotic death in these breast cancer cells. Taken together, our results demonstrate, for the first time, that the 'BLT2-Nox1-ROS'-linked cascade is involved in the pro-survival signaling, especially in ER-negative breast cancer cells.

Background: The aim was to prove the low identification rate of sentinel lymph node biopsy (SNB) and to determine the feasibility of replacing axillary lymph node dissection (AND) in axillary lymph node positive patients after chemotherapy., Methods: From October 2001 to July 2005, 875 consecutive patients with primary operable breast cancer underwent SNB and AND. Among them, 238 received pre-operative chemotherapy. We compared the identification rate, false negative rate (FNR), negative predictive value (NPV), and accuracy of SNB in clinically node-positive patients with or without chemotherapy., Results: The identification rate was significantly lower in patients received chemotherapy (77.6%) than in those not received it (97.0%) (P<0.001). In those received the therapy, the FNR was 5.6%, the NPV was 86.8%, and the accuracy was 95.9%. In those not received therapy, the FNR was 7.4% and the accuracy was 92.6% (differences not statistically significant)., Conclusion: The identification rate in confirmed axillary lymph node-positive patients was significantly lower in patients received pre-operative chemotherapy, but accuracy did not differ significantly between the two groups. Thus, for patients who achieve complete axillary clearance by chemotherapy, SNB could replace AND.