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Purpose This study investigated pathological complete response (pCR) according to androgen receptor (AR) in breast cancer patients undergoing neoadjuvant chemotherapy and estimated the relationship between AR expression and clinicopathological factors.Materials and Methods We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center in Goyang, Korea from April 2016 to October 2019. We retrospectively collected the clinicopathologic information and AR expression results and analyzed the data according to cancer stage, hormonal receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, tumor subtype, and pCR.Results Among the 624 breast cancer patients, 529 (84.8%) were AR-positive (AR+) patients and 95 (15.2%) were AR-negative (AR–) patients. AR+ patients showed more estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, HER2-positivity, and HR-positive and HER2-negative (HR+/HER2–) subtype. The rate of pCR was 31.4% (196/624). AR– patients had a significantly higher rate of pCR than AR+ patients (AR– 43.2% vs. AR+ 29.3%, p=0.007). The tumor factors associated with pCR were early stage, histologic grade 3, ER-negative, PR-negative, AR-negative, HER2-positive, and high Ki-67 values. In univariable analysis, AR+ significantly decreased the state of pCR (odds ratio, 0.546; 95% confidence interval, 0.349 to 0.853; p=0.008). According to tumor subtype, AR– tumor showed higher pCR rate in HR+/HER2– subtype (AR– 28.6% vs. AR+ 7.3%, p=0.022).Conclusion AR expression is predominant in the HR+/HER2– subtype. AR– is significantly associated with the pCR rate in breast cancer patients, especially within HR+/HER2– subtype. When determining neoadjuvant chemotherapy for the HR+/HER2– subtype, AR expression can be considered as a pCR predictive marker.

Background: Androgen receptors (AR) has emerged as a prognostic factor predicting survival and recurrence in breast cancer. However, the role of AR as a predictor of pathological complete response (pCR) rate after neoadjuvant chemotherapy by subtypes is unclear. This study aimed to investigate according to AR in breast cancer patients undergoing neoadjuvant chemotherapy as a predictor. Furthermore, we estimated the relationship between AR expression and clinicopathological factors. Method: We identified 624 breast cancer patients who underwent surgery after neoadjuvant chemotherapy at the National Cancer Center from April 2016 to October 2019. We retrospectively collected the medial records that the clinicopathologic information and AR expression analyzed according to cancer stage, hormonal receptor status, HER2 status, tumor subtype, pCR. Results: Among the 624 breast cancer patients, 529 (84.8%) were AR positive patients and 95 (15.2%) were AR negative patients. The mean age of the patients was 50.0 years. The rate of pCR was 31.4% (196/624). AR negative patients had significantly high rate of pCR than AR positive patients. (AR (-) 43.2% vs. AR (+) 29.3%, p = 0.0074). AR positive patients showed more ER positivity, PR positivity, HER2 positivity and luminal A subtype. A higher proportion of AR positive patients compared to AR negative patients received target therapy and hormonal therapy (target therapy, AR (-) 15.8% vs. AR (+) 43.9%, hormonal therapy, 14.7% vs. 71.0%, p Citation Format: Eun-Gyeong Lee, Dong-Eun Lee, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, Eun Sook Lee, Youngmee Kwon, Hyun Hee Kim, Hee Jung Chae, Sung Hoon Sim, Keun Seok Lee, So-Youn Jung. Androgen receptor as predictive marker for pathologic complete response in breast cancer with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-23.

Purpose The programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC. Methods Thirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training. Results The adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584-0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%-66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345-0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%-100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610. Conclusion The concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.

Given the recent advances in management and understanding of breast cancer, a standardized pathology report reflecting these changes is critical. To meet this need, the Breast Pathology Study Group of the Korean Society of Pathologists has developed a standardized pathology reporting format for breast cancer, consisting of 'standard data elements,' 'conditional data elements,' and a biomarker report form. The 'standard data elements' consist of the basic pathologic features used for prognostication, while other factors related to prognosis or diagnosis are described in the 'conditional data elements.' In addition to standard data elements, all recommended issues are also presented. We expect that this standardized pathology report for breast cancer will improve diagnostic concordance and communication between pathologists and clinicians, as well as between pathologists inter-institutionally.

The heterogeneity of triple-negative breast cancer (TNBC) poses difficulties for suitable treatment and leads to poor outcome. This study aimed to define a consensus molecular subtype (CMS) of TNBC and thus elucidate genomic characteristics and relevant therapy. We integrated the expression profiles of 957 TNBC samples from published datasets. We identified genomic characteristics of subtype by exploring the pathway activity, microenvironment, and clinical relevance. In addition, drug response (DR) scores (n = 181) were computationally investigated using chemical perturbation gene signatures and validated in our own patient with TNBC (n = 38) who received chemotherapy and organoid biobank data (n = 64). Subsequently, cooperative functions with drugs were also explored. Finally, we classified TNBC into four CMSs: stem-like; mesenchymal-like; immunomodulatory; luminal-androgen receptor. CMSs also elucidated distinct tumor-associated microenvironment and pathway activities. Furthermore, we discovered metastasis-promoting genes, such as secreted phosphoprotein 1 by comparing with primary. Computational DR scores associated with CMS revealed drug candidates (n = 18), and it was successfully evaluated in cisplatin response of both patients and organoids. Our CMS recapitulated in-depth functional and cellular heterogeneity encompassing primary and metastatic TNBC. We suggest DR scores to predict CMS-specific DRs and to be successfully validated. Finally, our approach systemically proposes a relevant therapeutic prediction model as well as prognostic markers for TNBC. Implications: We delineated the genomic characteristic and computational DR prediction for TNBC CMS from gene expression profile. Our systematic approach provides diagnostic markers for subtype and metastasis verified by machine-learning and novel therapeutic candidates for patients with TNBC.

This study aimed to compare the sentinel lymph node (SLN) identification rates for breast cancer patients after neoadjuvant chemotherapy (NAC) between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. This randomized study enrolled 130 patients who received NAC for breast cancer and 122 patients who received SLN biopsy (SLNB) using either DM (n = 58) or RI only (n = 64). The study compared the identification rate, number of SLNs, and detection time of SLNB. Among the 122 patients, 113 (92.6%) were clinically node-positive before NAC. The SLN identification rate was 98.3% in the DM group and 93.8% in the RI group (p = 0.14). The DM group and the RI group were similar in the average number of SLNs (2.2 ± 1.13 vs. 1.9 ± 1.33; p = 0.26) and the time to detection of the first SLN (8.7 ± 4.98 vs. 8.3 ± 4.31 min; p = 0.30). In the DM group, transcutaneous lymphatic drainage was visualized by fluorescence imaging for 65.5% (38 of 58) of the patients. The SLN identification rate was 94.7% using ICG-F and 93% using RI (p = 0.79). During and after the operation, no complications, including allergic reactions or skin necrosis, occurred. This study is the first randomized trial to use ICG-F for SLNB in breast cancer patients after NAC. The DM including ICG-F could be a feasible and safe method for SLNB in initially node-positive breast cancer patients with NAC.

Primary malignant melanoma of the breast (PMMB) is a rare tumor with only a few case reports available in the literature. We report two cases of PMMB, one derived from the breast parenchyma and the other from the breast skin. The first case consisted of atypical epithelioid cells without overt melanocytic differentiation like melanin pigments. The tumor cells showed diffuse positivity for S100 protein, tyrosinase, and BRAF V600E. However, the tumor cells were negative for cytokeratin, epithelial membrane antigen, and HMB-45. The second case showed atypical melanocytic proliferation with heavy melanin pigmentation. The tumor cells were positive for S100 protein, HMB-45, tyrosinase, and BRAF V600E. These two cases represent two distinct presentations of PMMB in terms of skin involvement, melanin pigmentation, and HMB-45 positivity. Although PMMB is very rare, the possibility of this entity should be considered in malignant epithelioid neoplasms in the breast parenchyma.

Purpose: Conditional relative survival (CRS) could provide more relevant information on the current prognosis of cancer survivors than standard 5-year relative survival (RS). This study aimed to estimate the 5-year CRS of Korean breast cancer patients. Patients and Methods: We identified 145,083 breast cancer cases with diagnosis between 2002 and 2013 in the Korea Central Cancer Registry. The CRS was estimated for every year after diagnosis, according to sex, age, histologic types, stage, and year of diagnosis. Results: The 5-year RS at diagnosis was 90.8% and 10-year RS was 85.7%. Five-year CRS was 91.0% and 94.3% at 1-year and 5-year after diagnosis. Women had better 5-year CRS than men after 5 years of survival (94.3% vs. 79.5%), and very young and very old patients had worse 5-year CRS after 5 years of survival than other age groups (92.2% in Conclusion: This study showed that CRS of breast cancer survivors in Korea has been improved, which varied by sex, age, stage, and histologic types. These CRS analysis could provide a more detailed information for survival to breast cancer survivors and clinicians. Citation Format: Jung S-Y, Jung K-W, Won Y-J, Kwon Y, Ha J, Kim YA, Kong S-Y, Lee ES. Conditional survival of breast cancer patients: Korean nationwide registry [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-24.

Although Ki67 labeling index is a potential predictive marker for chemotherapy benefit, its clinical utility has been limited by the lack of a standard scoring method resulting in poor interobserver reproducibility. Especially, there is no consensus on the use of average versus hotspot score for reporting. In order to determine the best method for Ki67 scoring and validate manual scoring method proposed by the International Ki67 Working Group (IKWG), we systematically compared average versus hotspot score in 240 cases with a public domain image analysis program QuPath. We used OncotypeDx Recurrence Score (RS) as a benchmark to compare the potential clinical utility of each scoring methods. Both average and hotspot scores showed statistically significant but only modest correlation with OncotypeDx RS. Only hotspot score could meaningfully distinguish RS low-risk versus high-risk patients. However, hotspot score was less reproducible limiting its clinical utility. In summary, our data demonstrate that utility of the Ki67 labeling index is influenced by the choice of scoring method.

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Additional file of Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study

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Metastasis of a phyllodes tumor to the stomach is an extremely rare condition with important clinical implications. A 44-year-old woman was initially diagnosed with a phyllodes tumor in her right breast in 2008, and subsequently presented to an outpatient clinic with dizziness on December 16, 2013. We found that she had severe anemia (hemoglobin levels, 6.7 g/dL), and we quickly performed esophagogastroduodenoscopy to identify the cause. This procedure revealed large ulcerofungating masses with active bleeding in the stomach. Histopathological examination revealed that the masses were consistent with phyllodes tumor metastases. In patients with a metastatic phyllodes tumor presenting as anemia, gastric metastasis should be considered as one of the differential diagnoses because overlooking the possibility might have dire consequences if cytotoxic chemotherapy were administered.

// In Hae Park 1, 2 , Han Na Yang 2 , Kyoung Joo Lee 3 , Tae-Sik Kim 4 , Eun Sook Lee 1 , So-Youn Jung 1, 2 , Youngmee Kwon 1, 2 , Sun-Young Kong 3, 4, 5 1 Center for Breast Cancer, National Cancer Center, Korea 2 Breast and Endocrine Cancer Branch of Research Institute, National Cancer Center, Korea 3 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Korea 4 Translational Epidemiology Research Branch, Research Institute, National Cancer Center, Korea 5 Department of Laboratory Medicine, Hospital, National Cancer Center, Korea Correspondence to: Sun-Young Kong, email: ksy@ncc.re.kr Keywords: IL-18, NK cells, breast cancer, hormone receptor, PD-1 Received: September 30, 2016 Accepted: March 09, 2017 Published: March 16, 2017 ABSTRACT Purpose: While the inflammatory cytokine interleukin-18 (IL-18) is known to activate natural killer (NK) cells, its precise role in cancer is controversial. In this study, we investigated the role of tumor-derived IL-18 on peripheral blood NK cells in breast cancer patients. Results: In breast cancer cell lines, IL-18 was expressed and secreted in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC-70 but not in MCF-7 cells. The immature and non-cytotoxic CD56 dim CD16 dim/- NK cell fraction was increased following co-culture with MDA-MB-231 cells, and this increase was not observed with tumor cells transfected with siRNA for IL-18 or in MCF-7 cells. In addition, tumor-derived IL-18 increased PD-1 expression on CD56 dim CD16 dim/- NK cells, although no effect on PD-L1 expression in tumor cells was observed. Among EBC patients, serum IL-18 levels were significantly increased in those with a TNBC subtype compared to levels from patients with other subtypes, and the IL-18 levels were strongly associated with poor survival. Similarly, serum IL-18 and CD56 dim CD16 dim/- NK cells were also increased in patients with metastatic TNBC who had progressive disease following cytotoxic chemotherapy. Experimental Design: We performed in vitro experiments in breast cancer cell lines, measured cytokine levels by RT-qPCR, western blot, and ELISA, and analyzed NK cell subsets by flow cytometry. For clinical validation, we collected and analyzed blood sample from patients with early breast cancer (EBC, N = 545) and metastatic breast cancer (MBC, N = 42). Conclusions: Our data revealed that tumor-derived IL-18 is associated with bad prognosis in patients with TNBC. Tumor-derived IL-18 increased the immunosuppressive CD56 dim CD16 dim/- NK cell fraction and induced PD-1 expression on these NK cells.

Background: Obesity is one of the well-known cause and prognostic factor of breast cancer. Body mass index (BMI) is often used to estimate the magnitude of obesity. Currently, muscle weight itself, instead of higher BMI, is more closely related to poor outcomes in chronic metabolic disease. However, this question was not thoroughly questioned in breast cancer survivors. We aim to find out whether the prognosis of breast cancer survivors is affected by muscle mass and fat volume. We also present that the higher muscle mass and muscle fat ratio do have a good influence on the prognosis. Methods and Materials: Between January, 2001, and December, 2009, all consecutive patients diagnosed the breast cancer in National cancer center, Republic of Korea were 3909. Of all populations, the patients who had available chest Computed Tomography (CT) images within two years after the time of diagnosis were extracted. CT images were analyzed for total skeletal muscle and adipose tissue in cross-sectional area of 10mm thickness at level 3 of the lumbar vertebrae. Results: Of all consecutive 3909 patients, final eligible cases were 1493. The median age was 46.0 (range 25∼77). Median follow up period was 96.8 months and the 5 year survival rate was 96.5%. Recurrence free survival rate was 92.1%, and local recurrence free survival was 98.6% in 5 years. Median skeletal muscle volume of all patients was 93.3cc (range 39.6∼236.9). Median fat volume of the same sections was 419.7cc (range 19.5∼1392.3) and the median muscle-fat ratio was 0.22 (0.08∼3.18). There is no known standard value of muscle mass in Korean women, the median volume was used as an indicator for comparison of two groups in terms of overall survival and recurrence free survival. The group with muscle volume greater than median value appeared better outcomes in overall survival and recurrence free survival than those of the other group (p=0.007, p=0.019). There were several factors related to overall survival and recurrence free survival such as age, operation types, clinical stage, pathologic stage, and tumor size in univariate cox regression analysis. In multivariate analysis by adjusting those factors, the muscle volume showed a remarkable correlation with survival, especially in recurrence free survival (Hazard ratio 0.61, p=0.029). As the indicator using with median muscle-fat ratio, the analysis revealed that overall survival had no significant difference (p=0.177) between two groups. However, the group with higher muscle-fat ratio showed better recurrence free survival and local recurrence free survival (p-value Conclusions: Our study showed that the actual amount of skeletal muscle rather than fat volume has higher effect on the prognosis of breast cancer survivors. In our knowledge, this is the largest study to analyze the prognosis of breast cancer with skeletal muscle volume. In view of the different magnitude of obesity among multiple ethnics, the actual muscle mass could be the most important parameter to assess the amount of exercise and patient's health status. Citation Format: Song EJ, Park SJ, Lee MH, Kwon Y, Ko KL, Lee KS, Ro J, Jung SY, Lee SY, Kang HS, Lee ES. The role of skeletal muscle volume on prognosis of breast cancer survivors using with cross-sectional image. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-30.

Background: Ki-67 has been increasingly used as a prognostic marker in spite of debates on the evaluation methods and inconsistent results on its clinical values. CKAP2 is a microtubule-associated protein which plays key roles in microtubule assembly and disassembly. In the present study, the clinical significance of CKAP2-positive cells was evaluated and compared with the results of Ki-67 positive cells. Methods: A total of 579 early breast cancer patients who underwent surgery at the National Cancer Center Hospital between 2001 and 2005 were accrued. The proliferation activity was measured by CKAP2-positive cell count (CPCC) and Ki-67 labeling index (Ki-67 LI) using CKAP2 and Ki-67 antibodies, respectively, by immunohistochemcial staining on FFPE tumor tissue. The correlation of CPCC or Ki-67 LI with recurrence free survival (RFS) was analyzed. The immunofluorescent staining was performed on HeLa cells after synchronization by double thymidine block to compare the patterns between CKAP2 and Ki-67. Results: The CPCC (median, 8 with the range of 0- 170) and Ki-67 LI (median, 10.2 with the range of 0%- 91.7%) were highly correlated (R = 0.754, P < 0.001). While CPCC was marginally significant in multivariate analysis for RFS in all cases, it was a significant variable for RFS in the subset analysis with HER2-negative luminal breast cancer patients (HR, 3.154; 95% CI, 1.154-10.693; P = 0.027). On the contrary, Ki-67 LI failed to show any correlation with RFS in all or any subgroups. In the analysis on HeLa cells, CKAP2 staining was more specific to cells in metaphase than Ki-67 staining. Conclusions: CPCC can be an independent prognostic factor specifically in a HER2-negative luminal type of breast cancer. In addition, CPCC appears to be superior to Ki-67 LI as a survival indicator which may be related to the restricted expression pattern of CKAP2 in metaphase cells. Further study is warranted. Citation Format: Sim SH, Bae C-D, Kwon Y, Park IH, Lee KS, Jung S-Y, Lee S, Kang H-S, Lee ES, Kim H-S, Hong K-M, Ro J. CKAP2 (cytoskeleton associated protein 2) is a new prognostic marker in HER2-negative luminal breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-25.

We assessed the use of chemotherapy in breast cancer patients to investigate the factors that changed trends in chemotherapy following the adoption of the 21-gene expression assay in tumor genomic profiling. Our study used 2033 patients from the National Cancer Center in Korea diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (tumor size of 0.5 cm or larger and 0–3 node metastases) from 2010 to 2015. We analyzed use of the 21-gene expression assay, changes in frequency of adjuvant chemotherapy use, and clinicopathological factors related to adjuvant chemotherapy to assess the impact of the 21-gene expression assay. Adjuvant chemotherapy use declined from 33.33% (2011) to 13.59% (2015) [relative risk (RR), 0.71; 95% CI 0.56–0.89; ptrend = 0.004] in patients with 21-gene expression assay data. Among patients without assay data, adjuvant chemotherapy use decreased from 76.79 to 40.17% between 2010 and 2015 (RR 0.87; 95% CI 0.84–0.91; ptrend

Background This retrospective study was performed to investigate the need for management modification in MBC according to evaluation of characteristics and failure patterns compared with IDC. Patients and Methods We performed this multicenter study taking MBC and randomly assigned IDC cases matched for age (± 3 years), pathologic stage (T and N), locoregional treatment methods (surgery with or without radiation therapy), and period of treatment (± 6 months) that occurred from January 1999 to November 2011 in the 6 institutions of the Korean Radiation Oncology Group. Results A total of 144 female MBC patients were enrolled. The median follow-up was 51 months (range, 1-186 months). The rates of positivity for estrogen receptor ( P P P = .007) were significantly lower in MBC patients. During follow-up, recurrence developed in 22 (15.3%) MBC and 6 (4.2%) IDC patients ( P = .002). The median time to recurrence of MBC and IDC was 15 months and 24 months, respectively. Most instances of recurrence in MBC developed in the triple-negative (TN) subgroup (TN-MBC). In particular, locoregional recurrence developed exclusively in the TN-MBC subgroup. In the TN-MBC subgroup, the number of risk factors (pT2-3, N1-3) was related to significant differences in overall survival ( P = .001) and recurrence-free survival ( P Conclusion The MBC patients had a higher rate of TN, poorer differentiation, and a higher recurrence rate than did the IDC patients. Considering the unique characteristics and failure patterns, it is necessary to modify the current management guidelines for MBC.

Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity. In addition, we investigated the mutational status of PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR. Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks along with everolimus 5 mg daily. Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy. Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5). Stomatitis and hematologic toxicities were observed most frequently in the GPE arm. PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment. Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients. Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.

Immunohistochemistry (IHC) plays an important role in biomarker-driven cancer therapy. Although there has been a high demand for standardized and quality assured IHC, it has rarely been achieved due to the complexity of IHC testing and the subjective validation-based process flow of IHC quality control. We present here a microfluidic immunostaining system for the standardization of IHC by creating a microfluidic linearly graded antibody (Ab)-staining device and a reference cell microarray. Unlike conventional efforts, our system deals primarily with the screening of biomarker staining conditions for quantitative quality assurance testing in IHC. We characterized the microfluidic matching of Ab staining intensity using three HER2 Abs produced by different manufacturers. The quality of HER2 Ab was also validated using tissues of breast cancer patients, demonstrating that our system is an efficient and powerful tool for the standardization and quality assurance of IHC.

We evaluated whether the sequence or regimen of systemic chemotherapy could be a risk factor for breast cancer-related lymphedema (LE). We retrospectively analyzed 848 patients with stage II/III breast cancer who underwent curative surgery with adequate systemic therapy from 2004 to 2009. Adjuvant chemotherapy (ACT) was performed in 552 patients (65.1 %) and neoadjuvant chemotherapy (NAC) in 296 (34.9 %). We evaluated the incidence of LE based on clinicopathological factors and treatments. At a median follow-up of 5.1 years, 358 patients (42.2 %) had experienced LE and 243 (28.7 %) had retained (persistent LE) [120/552 (21.7 %) with ACT vs. 123/296 (41.6 %) with NAC; P 0.001]. The incidence of LE in patients with taxane was greater than in those without taxane [233/704 (33.1 %) vs. 10/144 (6.9 %); P 0.001]. Multivariate analysis showed that NAC [hazard ratio (HR), 1.63 in LE event; P 0.001; HR, 1.39 in persistent LE; P = 0.02] and RT including supraclavicular area (SCRT) (HR 1.55; P = 0.02; HR 1.93; P = 0.006), number of dissected axillary lymph nodes (N-ALNs)10 (HR, 1.37; P = 0.01; HR, 1.71; P = 0.001), advanced stage (HR, 1.31; P = 0.03; HR, 1.60; P = 0.002), and taxane (HR, 1.69; P = 0.03; HR, 2.07; P = 0.04) were independent risk factors for the LE occurrence. In addition to advanced stage, N-ALNs and SCRT, NAC, and taxane were shown to increase the risk of LE, which could help clinicians identify patients at risk for LE.

Objective: The heterogeneity of triple negative breast cancer (TNBC) confers the difficulties in chemotherapy and induces poor outcome. Subtype classification of TNBC using gene expression profile could achieve to identify molecular markers to suggest therapeutic guidance. Methods: In this study, we collected gene expression profiles of 957 TNBC patients from GEO and integrated into one meta-data using meta analysis. We identified subtypes using nonnegative matrix factorization (NMF) and explored for comprehensive characteristics of consensus molecular subtype (CMS) by investigating key pathway activity, tumor microenvironment, stemness and so on. In addition, we computed the drug response score (DRscore) from MSigDB chemical perturbation signature gene set and examined drug associations with key pathways of CMS. Drug candidates were validated from independent two data sets; our patients’ expression profile (n = 38) and biobank TNBC organoids (n=64). Results: We classified four different TNBC subtypes displaying gene expression patterns including mesenchymal-like (MSL), luminal-AR (LAR), immunomodulatory (IM), and stem-like (SL). MSL were activated pathways with epithelial-to-mesenchymal (EMT) and TGF-beta signaling whereas SL was up-regulation of cell cycle and WNT signaling pathway. The LAR subtype was activated of androgen and estrogen receptor pathway. Although metastatic TNBC generally shared equal activity of key pathways with primary, coagulation, toll-like receptors, TNF, and Jak-STAT signaling pathways were dysregulated in metastasis. Especially, SPP1 gene expression to induce metastasis was associated with poor prognosis. DRscores were discriminative in CMS of meta-data and biobank expression profile. We found subtype-specific 18 drugs as therapeutic candidates and these drugs were also correlated with key pathways. In a case of cisplatin, DRscores appear resistant in MSL while response in SL. Our patients’ expression profiles were shown to consistent result as well as biobank. Conclusion: These finding might facilitate understanding heterogeneity of TNBC. Our novel approach to explore drug response suggested functional intervention landscape of drug response without in-vivo experiment. Taken together, we propose biomarkers for diagnosis and also suggest therapeutic strategy depending on CMS. Citation Format: Jihyun Kim, Doyeong Yu, Jiyoon Noh, Wooyeong Jang, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, In Hae Park, Charny Park. Consensus molecular subtype of triple negative breast cancer to implicate in chemotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3424.

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers were identified by gene expression analysis of PDX samples using Nanostring nCount cancer panels. Validation of predictive biomarkers for treatment response was conducted in established PDX models by in vivo drug testing. Twenty breast cancer PDX models were generated from different molecular subtypes (overall success rate, 17.5%, 3.6% for HR+/HER2&minus, 21.4% for HR+/HER2+, 21.9% for HR&minus, /HER2+ and 22.5% for triple-negative breast cancer (TNBC)). The histopathologic features of original tumors were retained in the PDX models. We detected upregulated HIF1A, RAF1, AKT2 and VEGFA in TNBC cases and demonstrated the efficacy of combined treatment with sorafenib and everolimus or docetaxel and bevacizumab in each TNBC model. Additionally, we identified upregulated HIF1A in two cases of trastuzumab-exposed HR&minus, /HER2+ PDX models and validated the efficacy of the HIF1A inhibitor, PX-478, alone or in combination with neratinib. Our results demonstrate that PDX models can be used as effective tools for predicting therapeutic markers and evaluating personalized treatment strategies in breast cancer patients with resistance to standard chemotherapy regimens.

This abstract was not presented at the conference. Citation Format: Jung S-Y, Han JH, Park SJ, Lee E-G, Lee MH, Lee ES, Kang H-S, Lee KS, Park IH, Sim SH, Jeong HJ, Kwon Y, Lee D-E, Joo J, Kim S-K, Lee S. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-05.

Background: The breast cancer-related lymphedema (LE) has been known to be closely related to axillary lymph nodes dissection (ALND), chemotherapy, and radiation therapy. In this study, we evaluated whether the sequence of systemic chemotherapy and surgery could be a predictive factor in stage II/III breast cancer. Methods and Materials: A total of 867 patients with stage II/III breast cancer, who underwent curative surgery with adequate systemic therapy from 2004 to 2009, were retrospectively analyzed. Adjuvant chemotherapy (ACT) was performed in 571 patients (65.9%) and preoperative systemic chemotherapy (PSC) in 296 (34.1%). We evaluated the incidence of LE by clinicopathologic factors and treatments. Results: At a median follow-up of 5.1 years (range, 3.0-8.3 years), 360 patients (41.5%) had experienced LE, 244 patients have retained LE (permanent LE), and 116 patents were normalized. The overall 5-year cumulative incidence of LE was 17%. LE occurred in 188 patients (32.9%) in patients with ACT, 172 patients (58.1%) with PSC (P Conclusions: The risk factors associated with LE were advanced stage, ALND and radiotherapy. PSC was one of predictors for transients LE. However, further evaluation should be done whether it is a risk factor for permanent LE. This research was supported by National Cancer Center Grant NCC-1210181-2 by the National Cancer Center, Republic of Korea. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-14.

Solid pseudopapillary neoplasm of the pancreas (SPN) is relatively rare and it occurs almost exclusively in women. We recently experienced three cases of SPN diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). These three cases were two male and one female patient whose age was 29, 37, and 44 years old. Radiological diagnosis was pancreatic endocrine tumor (PEN) showing solid with a heterogenous echogenicity. EUS-FNA cytology specimens consisted of single cells and aggregates of uniform cells, forming microadenoid structures, branching, papillary clusters with delicate fibrovascular cores. In conclusion, a single diagnosis of SPN based on clinical and radiological findings would be risky because there is a possibility of it being misdiagnosed as PEN or other malignancies. An EUS-FNA is therefore essential for establishing the diagnosis. In addition, the pathologists should recognize the characteristic cytologic findings with immunoprofiles of SPN to prevent misdiagnosis of SPN.

The prognosis of metaplastic breast cancer (MBC) is reportedly worse than that of triple-negative invasive ductal carcinoma (TN-IDC), but the determinants of poor prognosis are not yet known.Patients from two Korean cancer centres were included in this study (67 MBC and 520 TN-IDC). Characteristics of the two disease groups, including clinical parameters, histological features, chemoresponsiveness, disease recurrence and survival estimates, were evaluated.MBC presented with larger tumours, more frequent distant metastasis and higher histological grade compared with TN-IDC (p0.001). All but nine patients with MBC had triple-negative disease. Disease-free survival and overall survival (OS) of MBC were worse than TN-IDC (p0.001). Multivariable analysis of disease-free survival revealed MBC type as an independent prognostic factor (HR 2.53; 95% CI 1.32 to 4.84) along with lymph node metastasis and implementation of breast conserving surgery. For OS, MBC type remained a significant prognostic factor (HR 2.56; 95% CI 1.18 to 5.54). Chemoresponsiveness of MBC and TN-IDC were similar in both neoadjuvant (p=1.000) and advanced disease settings (p=0.508). For a given MBC type, risk factors for disease recurrence included the presence of a squamous component (HR 4.0; 95% CI 1.46 to 10.99) and lymph node metastasis (HR 4.76; 95% CI 1.67 to 13.60); the risk factor for OS was initial distant metastasis (HR 10.77; 95% CI 2.59 to 44.76).MBC had worse survival outcomes compared with TN-IDC. Poor prognosis for MBC was likely caused by frequent recurrence with high initial stage and the unique biology of MBC itself.

Background This study evaluated the prognostic impact of p53 accumulation by immunohistochemistry (IHC) in lymph node-negative breast cancer (LNN-BC), and in subgroups of St Gallen consensus and intrinsic subtypes. Methods A total 845 with a pathologic diagnosis of LNN-BC patients that underwent surgery at the National Cancer Center, Korea between 2001 and 2005 were retrospectively reviewed. Results The median age was 48 years (range: 25–85) and median follow-up period was 66.0 months (range: 9–101). Univariate analysis determined that tumor size, estrogen receptor (ER), progesterone receptor (PgR), p53, and Ki-67 were significant for disease free survival (DFS). Of these factors, PgR negativity (HR 3.57; 95% CI 1.26–10.09; P = 0.01) and p53 positivity (HR 3.17; 95% CI 1.51–6.65; P = 0.002) were independent prognostic factors in multivariate analysis. In the subanalysis for 4 intrinsic subtypes (luminal A, luminal B, HER2-overexpression, and triple-negative subtypes) and risk groups by St Gallen consensus, there were significant differences of DFS rates by p53 (5-year DFS rate, luminal A; 97.2% for p53 (−) vs 93.8% for p53 (+); P = 0.03, triple-negative subgroups; 94.1% vs 78.7%; P = 0.002, intermediate-risk group; 96.5% vs 90.7%; P = 0.003). Conclusions P53 has prognostic power in LNN-BC, and gives the additional prognostic information for intrinsic subtypes and St Gallen consensus. J. Surg. Oncol. 2011; 103:207–211. © 2010 Wiley-Liss, Inc.

The purpose of the study was to evaluate the methylation status of the interleukin-10 (IL-10) gene in breast cancer tissues compared with normal and benign breast disease tissues. Between 2000 and 2001, we used paraffin-embedded specimens of 30 normal, 31 benign and 72 breast cancer tissues from the National Cancer Center, Korea. The methylation patterns of the IL-10 gene were evaluated using bisulfite DNA sequencing and the expression levels of IL-10 mRNA were evaluated using real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) and reverse transcriptase-polymerase chain reaction (RT-PCR). The methylation rates of the IL-10 gene were significantly lower in malignant tumors than in benign and normal tissues (normal; 63.3%, benign; 74.2%, cancer; 45.8%, p = 0.02). The methylation density rates of the IL-10 gene were also significantly lower in malignant tumors (normal; 59.68 ± 7.12%, benign; 48.89 ± 7.45%, cancer; 30.56 ± 4.18%, p = 0.001). Tissues with aberrant methylation of the IL-10 gene showed significantly lower rates of mRNA expression compared with unmethylated cases (12.5% vs. 68.0%, p = 0.012). The mRNA expression of tissues with unmethylated IL-10 was upregulated approximately ten thousand-fold compared to those with IL-10 methylation in the real-time RT-PCR experiment. IL-10 methylation demonstrated a significant association with lower expression of Ki-67 (9.36 ± 2.43 vs. 19.68 ± 3.42, p = 0.02). IL-10 methylation in cancer tissues is lower than that in normal and benign breast tissues, and DNA hypomethylation in the gene influences gene activation. Our data suggest that hypomethylation of the IL-10 gene can be involved in the process of breast carcinogenesis.

We consider jump processes which has only downward jumps with size axed fraction of the current process. The jumps of the pro- cesses are interpreted as crashes and we assume that the jump intensity is a nondecreasing function of the current process say ( X) ( X = X( t): process). For the case of ( X) = X ; > 0, we show that the process X should explode innite time, say te, conditional on no crash. For the case of ( X) = (ln X) , we show that = 1 is the borderline of two different classes of processes. We generalize the model by adding a Brownian noise and examine the blow up properties of the sample paths.

Background This study aimed to define predictive factors of pathologic complete response (pCR) and disease progression in stage II and III breast cancer patients. Patients and Methods Three hundred thirty-eight patients were included in the study. Patients had received preoperative chemotherapy as follows: 101 had doxorubicin plus cyclophosphamide (AC); 91 had doxorubicin plus docetaxel; 103 had docetaxel plus capecitabine; and 43 had paclitaxel plus gemcitabine. A pCR was defined as the absence of residual invasive carcinoma in the breast. Results The majority of patients (73%) were premenopausal with a median age of 44 (range, 21–76) years. Fifty-four patients (16%) achieved pCR and were distributed among the 4 breast cancer subtypes as follows: 10% of patients with –ER or PR+/HER2−, 13% with ER or PR+/HER2+, 33% with ER-/PR-/HER2+, and 19% with ER-/PR-/HER2−(p = 0.001). Taxane-containing regimen (p = 0.042) and Breast cancer subtype (p = 0.005) were significant predictive variables for pCR. On the other hand, significantly more patients who received non-taxane-containing regimen (AC) experienced no response (p = 0.001) or progression (p = 0.006). Conclusions Patients with ER-/PR-/HER2+ tumors and those who received taxane-containing regimen achieved a higher pCR rate, while significantly more patients developed tumor progression by preoperative non-taxane-containing regimen (AC) compared to those who received taxane-containing chemotherapy.

Objective: The molecular profile of primary breast cancer has been studied associated with drug responses. Metastatic triple-negative breast cancer (mTNBC) is heterogeneous disease and there is no effective therapeutic target. We investigated the genomic profiles of mTNBC to find potential drug targets. Methods: Metastatic breast cancer samples were collected for genomic analysis (fresh tissue, n=17; FFPE, n=28). We conducted both whole-exome sequencing and RNA-seq for these samples and validated genomic variants by Sanger sequencing. We built up pipelines for somatic mutation, copy number alteration, mRNA expression, and fusion gene analysis. Precise somatic mutations were additionally filtered out for FFPE without matched normal. In addition, we investigated the differences of genomic profiles of mTNBC with those of primary breast cancer from TCGA data. Results: Most of somatic mutation profiles of mTNBC were similar with those of primary cancer. However, there were some specific alterations that were not found in primary tumor. TP53 (>40 %) was concordantly discovered with primary TNBC, but KDM6A (>20 %) was highly recurrent than other breast datasets. We ascertained the diversity of immune cell activity from mRNA expression analysis, and additional pathways also represented the variance within our mTNBC population, which was differentiated from those of primary breast cancer. In addition, we found two novel FGFR1/2 fusion in two cases and validated it by RT-PCR and Western blot. Conclusion: We found specific genomic profiles of mTNBC that were distinct from those of primary tumor. Novel structural variants discovered in our dataset could be potential therapeutic targets for mTNBC patients. Citation Format: Wooyeong Jang, Jihyun Kim, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, Kyounghee An, In Hae Park, Charny Park. The genomic profile investigation of metastatic triple-negative breast cancer for precision medicine achievement [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4279.

The biological mechanisms underlying resistance to tamoxifen are of considerable clinical significance. However, little is known about the correlation between tamoxifen resistance and methylation of genes related to drug-metabolizing enzymes. To address this issue, we examined the methylation pattern and expression of the selected genes coding for drug-metabolizing enzymes, including COMT, CYP1A1, CYP2D6, NAT1, and SULT1A1 in tamoxifen-resistant and control breast cancers. Bisulfite genomic sequencing and methylation-specific PCR were carried out to evaluate the methylation patterns of the five genes from control (n = 74) and tamoxifen-resistant tissues (n = 37) chosen by an age-matched sampling method. Also, end-point reverse transcriptase polymerase chain reaction (RT-PCR) and real-time RT-PCR were performed to determine RNA expression of the genes. Bisulfite genomic sequencing revealed methylation of the NAT1 gene in 25 of the control cancers (33.8%) and 23 of the resistant tumors (62.2%). Of the five genes, only NAT1 showed a significant lower methylation rate in the control group than in the resistant group (p = 0.004). No significant difference of the methylation rate was found in the other four genes including COMT, CYP1A1, CYP2D6, and SULT1A1 (p > 0.05). Furthermore, the expression rate of NAT1 mRNA was lower in the tumors from the resistant group than in control tumors (28.6% vs. 65.2%, p = 0.031). Real-time RT-PCR analysis demonstrated that the NAT1 gene was more down-regulated in resistant tissues than in control group (p = 0.023). Moreover, malignant cells from the resistant cases demonstrated a higher percentage of positive staining for Ki67 (p = 0.001) and cyclin D1 (p = 0.043) than those from the control group. Taken together, the higher methylation rate of the NAT1 gene is related to tamoxifen resistance, and this fact supports the hypothesis that hypermethylation of the NAT1 gene might affect the initiation of tamoxifen resistance.

Purpose Goserelin and letrozole in premenopausal patients can result in clinical outcomes comparable to those obtained by letrozole alone in postmenopausal patients with metastatic breast cancer (MBC). Patients and Methods A total of 73 patients with hormone-responsive MBC were included. Of those, 35 premenopausal patients received goserelin (3.6 mg subcutaneously every 28 days) plus letrozole (2.5 mg orally daily), and 38 postmenopausal patients received letrozole alone as their first-line endocrine therapy in a metastatic setting. Results Baseline characteristics were similar in the two groups, except for a younger age (median, 41 v 53.5 years; P < .001) and a shorter disease-free interval (median, 1.8 v 3.3 years; P = .03) in the premenopausal group. Clinical benefit rates were comparable between the two groups (77% v 74%; P = .77). With the median follow-up of 27.4 months, there was no statistical difference in the median time to progression between the two groups (9.5 months [95% CI, 6.4 to 12.1 months] v 8.9 months [95% CI, 6.4 to 13.3 months]). In patients who did not receive bisphosphonate, letrozole ± goserelin caused a greater loss of bone mineral density at 6 months compared with that of patients receiving bisphosphonate treatment (premenopausal group, −16.7% v 53.9%; P = .002 and postmenopausal group, −13.3% v 17.4%; P = .04 at the lumbar spine). Conclusion Clinical efficacies in premenopausal MBC patients with combined letrozole and goserelin therapy were comparable to those in postmenopausal patients treated with letrozole alone. Although letrozole ± goserelin resulted in a modest increase in bone resorption, concurrent treatment with bisphosphonate could prevent bone loss at 6 months.

It is not known whether the HER2 status of malignant CSF cells coincides with that of the original breast carcinoma cells. We investigated whether CSF cytology specimens were suitable to evaluate HER2 status by fluorescence in situ hybridization (FISH) in patient with leptomeningeal metastasis (LM). Both formalin-fixed paraffin-embedded (FFPE) breast cancer tissue and liquid based CSF cytology specimens were evaluated for HER2 status in 16 patients with LM. We evaluated HER2 gene amplification using FISH on destained CSF cytology slides containing a minimum of 20 malignant cells per slide, and compared these with the HER2 status by immunohistochemistry (IHC) or FISH in FFPE tissues. HER2 was considered positive when the HER2:CEP17 ratio wasor=2.0 or IHC 3+. Of 16 cases, four were HER2 positive and 12 were HER2 negative by FISH analysis in CSF cytology. All CSF-positive cases were HER2 positive by IHC in FFPE tissue. Of 12 HER2 FISH-negative cases in CSF cytology, 10 were HER2 negative (IHC 0 or 1+) and two were IHC 2+ in FFPE tissue. Two IHC 2+ cases had HER2:CEP17 ratios of 1.27 and 2.1, respectively, by FISH in FFPE tissue. As a result, the HER2 status concordance rate between metastatic breast cancer cells in CSF and FFPE primary tissue by IHC and FISH was very high. When CSF cytology specimens were appropriately prepared and had adequate cellularity without dry artifacts, the CSF cytology was suitable to evaluate HER2 status by FISH analysis in patients with LM.

The purpose of this study was to evaluate pathologic complete response (pCR) rates and adverse events with primary systemic therapy (PST) of intermittent weekly paclitaxel and gemcitabine in patients with stage II and III breast cancer. Node-positive patients with stage II and III breast cancer received paclitaxel 80 mg/m(2) followed by gemcitabine 1,200 mg/m(2) on day 1 and day 8, every 3 weeks for four cycles. Postoperatively, four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks were given. Of 44 enrolled patients, 73% had stage III breast cancer with 68% hormone-receptor positive and 41% HER2 positive tumors. Eight patients achieved pCR in primary tumors (18%), 11 in axillary nodes (25%), and five in both tumor and axillary nodes (11%). Breast conservation was possible in 28 patients (64%). Grade III/IV toxicities were neutropenia (57%), leukopenia (14%), febrile neutropenia (2%), and headache (2%). In conclusion, PST with intermittent weekly paclitaxel and gemcitabine in patients with stage II/III breast cancer is both well tolerated and effective, showing 18% pCR rate in the breast.

The examination of lymph nodes in colorectal cancer is a critical procedure for determining the stage, which determines prognosis and need for adjuvant therapy. The current recommendation is to harvest at least 12 lymph nodes by conventional manual node dissection (MND). Recent studies have suggested that all lymph nodes in mesenteric tissue should be retrieved using a special method such as the entire submission of residual mesenteric tissue (ESMT) after MND. We investigated the efficacy of ESMT with its potential impact on the pN stage. After an MND in 48 consecutive colorectal cancer resection specimens, the residual mesenteric tissues were entirely submitted for routine histologic examination by ESMT. After initial MND, 933 (mean, 19.4) lymph nodes were found, and there were 29 pN0, 10 pN1, and 9 pN2 cases. By ESMT after MND, 1132 (mean, 23.6) additional lymph nodes were found. Most (88.6%) of them were 2.0 mm or less in maximum dimension, and of the 1132 additional lymph nodes, 14 (1.2%) lymph nodes revealed tumor metastases. Although there was no additional nodal metastasis in any of the initial 29 pN0 cases, additional nodal metastases were found in 10 of the original 19 node-positive cases. Two of the 10 cases with additional positive nodes identified would be upstaged from pN1 to pN2. Both of these cases had fewer than 12 nodes identified by MND but had 1 and 2 additional nodes identified by ESMT. Our study demonstrated that MND seems to be accurate and efficient in evaluating tumors with pN stage of pN0. Although ESMT may be useful to assess the correct pN stage in pN1 cases with fewer than 12 lymph nodes in MND, it may not add any additional information in pN0 cases or in node-positive cases with 12 or more lymph nodes found by MND.

Primary angiosarcoma of the bone (PAB) is a rare and fatal high-grade malignant vascular bone tumor. We report a rare case of multicentric PAB mimicking bone metastasis in a 59-year-old female patient with a history of sigmoid colon cancer. This patient complained of lower back and pelvic pain and presented with multiple osteolytic bone lesions on plain radiography and pelvic computed tomography. First, bone metastasis of sigmoid colon cancer was suspected. However, on the (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) scan, the patient presented unusual multiple hypermetabolic osteolytic bone lesions involving contiguous bones of the lower half of the body. After bone biopsy, these lesions were confirmed to be multicentric PAB. To the best of our knowledge, this is the first case report of an (18)F-FDG PET/CT scan in a patient with multicentric primary bone angiosarcoma.

The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes.We investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS).The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P.001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P.001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P.001), and PD-L1 expression was more frequent in HR-positive BC (P.001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations.Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.