Publications by authors named "Minoru Miyashita"

77 Publications

Trends in adjuvant therapy after breast-conserving surgery for ductal carcinoma in situ of breast: a retrospective cohort study using the National Breast Cancer Registry of Japan.

Breast Cancer 2021 Oct 19. Epub 2021 Oct 19.

Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Purpose: Radiotherapy (RT) and endocrine therapy (ET) are standard treatment options after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). We investigated the national patterns of adjuvant therapy use after BCS for DCIS in Japan.

Methods: We obtained relevant data of patients diagnosed with DCIS undergoing surgery and treated with BCS between 2014 and 2016 from the Japanese Breast Cancer Registry database. The relationship between the clinicopathologic, institutional, and regional factors, and adjuvant treatment was examined using multivariable analyses.

Results: We identified 9516 patients who underwent BCS for DCIS. Overall, 23% received no adjuvant treatment, 71% received RT, 32% received ET, and 26% received combination therapy. The percentages of patients who received ET and combination therapy in 2016 were significantly lower [odds ratio (OR): 0.71, 0.77, respectively] than in 2014. The proportion of RT was low among young or elderly patients (OR: 0.75, 0.44, respectively) and in non-certified facilities (OR: 0.56). The proportion of ET was high in non-certified facilities (OR: 1.58) and among patients with positive margins (OR: 1.62). Combination therapy was higher among patients with positive margins (OR: 1.53).

Conclusions: Our study found a distinct adjuvant treatment pattern after BCS for DCIS depending on clinicopathologic factors, year, age, which indicate that physicians provide individualized treatment according to the background of the patients and the biology of DCIS. The facilities and regions remain significant factors of influencing adjuvant treatment pattern.
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http://dx.doi.org/10.1007/s12282-021-01307-zDOI Listing
October 2021

Forkhead Box I1 in Breast Carcinoma as a Potent Prognostic Factor.

Acta Histochem Cytochem 2021 Aug 31;54(4):123-130. Epub 2021 Jul 31.

Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Forkhead box (FOX) proteins are family of transcriptional factors and regulate cell growth and differentiation as well as embryogenesis and longevity. Previous studies have demonstrated that several FOX members regulate growth or metastasis of breast carcinoma, but clinical significance of total FOX members remains unclear. We first examined associations between expression of 40 FOX genes and TNM status of 19 breast carcinoma using microarray data. Subsequently, we immunolocalized FOXI1 in 140 breast carcinomas and evaluated its clinicopathological significance. In the microarray analysis, we newly identified that gene expression of FOXI1 was most pronouncedly linked to metastasis of the breast carcinoma among the FOX members examined. However, clinicopathological significance of FOXI1 has not been examined in the breast carcinoma. FOXI1 immunoreactivity was positive in 44 out of 140 (31%) of breast carcinomas, and it was significantly associated with stage, lymph node metastasis and distant metastasis. The FOXI1 status was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both distant disease-free survival and breast cancer-specific survival. These findings suggest that FOXI1 plays important roles in the metastasis of breast carcinoma and immunohistochemical FOXI1 status is a potent prognostic factor.
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http://dx.doi.org/10.1267/ahc.21-00034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424250PMC
August 2021

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer.

Cancers (Basel) 2021 Aug 30;13(17). Epub 2021 Aug 30.

Department of Pathology Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan.

The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.
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http://dx.doi.org/10.3390/cancers13174375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431153PMC
August 2021

Welfare receipt and the risk of vitamin D deficiency in Japanese patients on maintenance hemodialysis: a cross-sectional, retrospective study.

Ren Replace Ther 2021 26;7(1):45. Epub 2021 Aug 26.

Division of Nephrology and Hypertension, Kawasaki Municipal Tama Hospital, 1-30-37, Shukugawara, Tama-ku, Kawasaki, Kanagawa 214-8525 Japan.

Background: Vitamin D deficiency is often observed in patients undergoing maintenance hemodialysis and is associated with significantly increased risk of overall mortality. Despite reports of poor nutrition/intake, vitamin D status among patients on maintenance hemodialysis receiving welfare remains unknown. This study investigated the vitamin D status in welfare recipients undergoing maintenance hemodialysis.

Methods: This cross-sectional study investigated vitamin D status among 106 outpatients undergoing maintenance hemodialysis at two medical facilities in Japan. Patients were divided into welfare and non-welfare groups based on their status as of September 2018. Patients were divided into two categories: serum vitamin D deficiency, defined as serum 25(OH)D concentrations < 12 ng/mL, or non-deficiency. Vitamin D deficiency was used as a dependent variable, while welfare receipt was used as the main predictor variable.

Results: Mean [± standard deviation] patient age, median [interquartile range] body mass index, and hemodialysis duration were 66.9 [± 10.8] years, 21.5 [19.6, 24.3] kg/m, and 7.9 [2.9, 12.3] years, respectively. Among 106 patients, 45 were women (42.5%) and 16 (15.1%) were receiving welfare. The welfare group had a higher diabetes prevalence ( = 0.003) and significantly lower median serum 25-hydroxyvitamin D concentrations (11.5 [8.7, 14.0] vs. 14.8 [11.2, 19.9] ng/mL,  = 0.005). Multiple logistic regression analysis revealed that welfare receipt was a significant risk factor for vitamin D deficiency (odds ratio [95% confidence interval], 4.41 [1.08, 18.07]).

Conclusions: Welfare recipients undergoing maintenance hemodialysis are at significantly increased risks of vitamin D deficiency compared with patients not receiving welfare.
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http://dx.doi.org/10.1186/s41100-021-00364-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390068PMC
August 2021

D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation.

Histol Histopathol 2021 Jul 23:18362. Epub 2021 Jul 23.

Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: D-2-hydroxyglutarate dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the regulation of cellular energy and biosynthetic intermediates. Previously, D2HGDH was reported to decrease 2-hydroxyglutarate level in breast carcinoma cells, but no other report has examined D2HGDH in breast carcinoma, and its significance remains unknown.

Methods: We first immunolocalized D2HGDH in 224 invasive breast carcinomas and evaluated its clinicopathological significance. We next examined associations between gene expression of D2HGDH and α-ketoglutarate-dependent dioxygenases in 23 breast carcinoma tissues using the gene expression profile data. Finally, we examined the effects of D2HGDH on the proliferation in three breast carcinoma cells.

Results: D2HGDH immunoreactivity was detected in 49% of invasive breast carcinomas, and the immunohistochemical D2HGDH status was positively associated with histological grade, HER2 and Ki-67, while it was inversely associated with estrogen receptor. Moreover, it was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both the disease-free and breast cancer-specific survival in these patients. Gene expression profile data revealed that D2HGDH expression was positively associated with the expression of 6 α-ketoglutarate-dependent dioxygenases (KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and ALKBH7). Consequent in vitro experiments demonstrated that D2HGDH overexpression significantly increased the cell proliferation activity of MCF-7, T47D and MDA-MB-231 cells.

Conclusion: These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of α-ketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.
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http://dx.doi.org/10.14670/HH-18-362DOI Listing
July 2021

Androgens enhance the ability of intratumoral macrophages to promote breast cancer progression.

Oncol Rep 2021 Sep 19;46(3). Epub 2021 Jul 19.

Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi‑ken 980‑8575, Japan.

Androgens are produced locally in breast carcinoma tissues by androgen‑producing enzymes such as 5α‑reductase type 1 (5αRed1) and affect not only breast cancer cells but the tumor microenvironment as well. Tumor‑associated macrophages (TAMs) are primary components of the tumor microenvironment and contribute to tumor progression. Although previous studies suggest that androgen/androgen receptor (AR) signaling in macrophages has important roles in human diseases, androgen action on TAMs has remained largely unknown. We immunolocalized macrophage marker CD163 as well as AR and 5αRed1 in 116 breast carcinomas and correlated them with clinicopathological parameters and clinical outcomes. Moreover, we examined the roles of androgens on macrophages in breast cancer progression using cell lines 4T1 (mouse breast cancer) and RAW264.7 (macrophage) in a tumor‑bearing female BALB/c mouse model. Double immunohistochemistry revealed that AR was sporadically expressed in the macrophages in breast carcinoma tissues. Macrophage infiltration was significantly correlated with an aggressive phenotype of breast carcinomas and worse prognosis, especially in the 5αRed1‑positive group. In a sphere‑forming assay using 4T1 and RAW‑AR cells, which stably express AR, the sphere size was significantly increased due to androgens when 4T1 cells were cocultured with RAW‑AR cells. Furthermore, experiments revealed that tumor growth and Ki67, a cell proliferation marker, were increased when androgens were stably produced in breast cancer cells and AR was expressed in macrophages. In conclusion, AR is expressed in intratumoral macrophages and is associated with an aggressive phenotype of breast carcinomas, especially when breast cancer cells actively produce androgens. Thus, androgens may enhance the ability of macrophages to promote breast cancer progression.
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http://dx.doi.org/10.3892/or.2021.8139DOI Listing
September 2021

Breast Cancer, Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor Toward Exploring Their Possible Associations.

Breast Cancer Res Treat 2021 Aug 2;189(1):39-48. Epub 2021 Jul 2.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Purpose: Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology.

Methods: We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues.

Results: GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070).

Conclusion: These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.
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http://dx.doi.org/10.1007/s10549-021-06288-3DOI Listing
August 2021

Discriminating low-grade ductal carcinoma in situ (DCIS) from non-low-grade DCIS or DCIS upgraded to invasive carcinoma: effective texture features on ultrafast dynamic contrast-enhanced magnetic resonance imaging.

Breast Cancer 2021 Sep 26;28(5):1141-1153. Epub 2021 Apr 26.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, Seiryo 1-1, Sendai, 980-8574, Japan.

Purpose: To investigate effective model composed of features from ultrafast dynamic contrast-enhanced magnetic resonance imaging (UF-MRI) for distinguishing low- from non-low-grade ductal carcinoma in situ (DCIS) lesions or DCIS lesions upgraded to invasive carcinoma (upgrade DCIS lesions) among lesions diagnosed as DCIS on pre-operative biopsy.

Materials And Methods: Eighty-six consecutive women with 86 DCIS lesions diagnosed by biopsy underwent UF-MRI including pre- and 18 post-contrast ultrafast scans (temporal resolution of 3 s/phase). The last phase of UF-MRI was used to perform 3D segmentation. The time point at 6 s after the aorta started to enhance was used to obtain subtracted images. From the 3D segmentation and subtracted images, enhancement, shape, and texture features were calculated and compared between low- and non-low-grade or upgrade DCIS lesions using univariate analysis. Feature selection by least absolute shrinkage and selection operator (LASSO) algorithm and k-fold cross-validation were performed to evaluate the diagnostic performance.

Results: Surgical specimens revealed 16 low-grade DCIS lesions, 37 non-low-grade lesions and 33 upgrade DCIS lesions. In univariate analysis, five shape and seven texture features were significantly different between low- and non-low-grade lesions or upgrade DCIS lesions, whereas enhancement features were not. The six features including surface/volume ratio, irregularity, diff variance, uniformity, sum average, and variance were selected using LASSO algorism and the mean area under the receiver operating characteristic curve for training and validation folds were 0.88 and 0.88, respectively.

Conclusion: The model with shape and texture features of UF-MRI could effectively distinguish low- from non-low-grade or upgrade DCIS lesions.
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http://dx.doi.org/10.1007/s12282-021-01257-6DOI Listing
September 2021

Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases.

Breast Cancer 2021 Jul 12;28(4):915-926. Epub 2021 Mar 12.

Department of Pathology and Histotechnology, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Background: Isocitrate dehydrogenase (IDH) is an important enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, and three isoforms (IDH1-3) have been identified. Overexpression and/or downregulation of IDH isoforms was reported in several human malignancies, suggesting importance of IDH in oncogenesis. However, significance of IDH isoforms remains largely unclear in the breast carcinoma.

Methods: We immunolocalized IDH1, IDH2 and IDH3α in 226 breast carcinomas and evaluated their clinical significance. Subsequently, we examined effects of IDH2 on proliferation in breast carcinoma cells.

Results: Immunoreactivity of IDH1-3α was detected in 53%, 38% and 41% of breast carcinomas, and the non-neoplastic epithelium was IDH1-positive, IDH2-negative and IDH3α-positive. IDH1 immunoreactivity was inversely associated with pathological T factor (pT) and Ki-67 in the breast carcinoma, while IDH3α immunoreactivity was not significantly associated with clinicopathological factors. IDH2 status was positively correlated with stage, pT, histological grade, HER2, Ki-67 and microvessel density. Moreover, IDH2 status was significantly associated with worse prognosis of the patients, and it turned out an independent prognostic factor for estrogen-receptor (ER) positive patients. These findings were more evident in the IDH1-negative / IDH2-positive/IDH3α-negative subgroup which is the opposite immunohistochemical IDH phenotype of normal mammary epithelium. In vitro studies demonstrated that RNA interference of IDH2 significantly decreased proliferation activity of T47D and SKBR-3 cells.

Conclusion: These results suggest that IDH2 is associated with an aggressive phenotype of breast carcinoma through increasing cell proliferation, different from IDH1 and IDH3α, and immunohistochemical IDH2 status is a potent prognostic factor especially in ER-positive breast cancer patients.
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http://dx.doi.org/10.1007/s12282-021-01228-xDOI Listing
July 2021

Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Pathology and Histotechnology, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan.

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.
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http://dx.doi.org/10.3390/ijms22041918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919043PMC
February 2021

L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism.

Sci Rep 2021 01 12;11(1):589. Epub 2021 Jan 12.

Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.
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http://dx.doi.org/10.1038/s41598-020-80668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803739PMC
January 2021

[Analysis of Delayed Diagnosis of a Spontaneous Spinal Epidural Hematoma].

No Shinkei Geka 2020 09;48(9):855-858

Department of Neurosurgery, Higashi-Sumiyoshi Morimoto Hospital.

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http://dx.doi.org/10.11477/mf.1436204283DOI Listing
September 2020

Annual report of the Japanese Breast Cancer Registry for 2017.

Breast Cancer 2020 Sep 24;27(5):803-809. Epub 2020 Jul 24.

Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Background: The Japanese Breast Cancer Society Registry started in 1975; it was transferred to the registry platform of the National Clinical Database in 2012. We provide the annual data and an analysis of the Breast Cancer Registry for 2017.

Methods: Patients' characteristics and pathological data of the 95,203 registered Japanese breast cancer patients from 1,427 institutes in 2017 were obtained. Trends in age at diagnosis and pathological stage were determined during the most recent 6 years (2012-2017).

Results: The mean onset age was 60.2 years with bimodal peaks at 45-49 years and 65-69 years. A short-term trend of the most recent 6 years of data caused the second, older peak. At diagnosis, 32.4% of breast cancer patients were premenopausal. The distribution of stages revealed that the proportion of early stage breast cancer (stage 0-I) increased up to 60%. At the initial diagnosis, 2.2% of patients presented with metastatic disease. Sentinel node biopsy without axillary node dissection was performed without neoadjuvant chemotherapy (NAC) in 68.8%, and with NAC in 31.1%, of patients. For patients without NAC, lymph node metastasis was less than 3% if the tumor size was less than 1 cm. The proportion of node-negativity decreased to 79.5% when tumor size was 2.1-5 cm.

Conclusions: This analysis of the registry provides new information for effective treatment in clinical practice, cancer prevention, and the conduct of clinical trials. Further development of the registry and progress in collecting prognostic data will greatly enhance its scientific value.
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http://dx.doi.org/10.1007/s12282-020-01139-3DOI Listing
September 2020

Multispectral quantitative immunohistochemical analysis of tumor-infiltrating lymphocytes in relation to programmed death-ligand 1 expression in triple-negative breast cancer.

Breast Cancer 2020 Jul 23;27(4):519-526. Epub 2020 May 23.

Department of Pathology, Kawasaki Medical School, Kurashiki, Japan.

Background: Programmed death-ligand 1 (PD-L1) expression on immune cells (ICs) is a predictive marker for PD-L1 checkpoint blockade in patients with triple-negative breast cancer (TNBC). However, the level of PD-L1 expression and the percentage of cells that are PD-L1+ are continuous variables not dichotomous variables for tumor-infiltrating lymphocytes (TILs) and other cells.

Methods: Multiplexed immunohistochemistry was applied to 31 archived surgical specimens from untreated TNBC patients. TIL levels were visually scored, and CD8+ T cells and PD-L1+ ICs were quantified using an automated multispectral imaging system. PD-L1 expression was assessed within a multiplexed context (CD8 combined spectral composite).

Results: The mean value of stromal TILs (i.e., the percentage of the stromal area with a dese mononuclear infiltrate) was 20%. The frequency of patients with PD-L1-positive tumor cells (TC) and ICs was 38.7% and 32.2%, respectively, with a significant association between them. TIL levels were correlated with CD8+ T cell infiltration in the stroma (Spearman r = 0.795, p < 0.0001). PD-L1 expression on IC was significantly associated with TIL levels (Spearman r = 0.790, p < 0.001) and infiltration of CD8+ T cells (Spearman r = 0.683, p < 0.0001).

Conclusions: The level of PD-L1 on IC was correlated with the level of PD-L1 on TC as well as TIL levels and infiltration of CD8+ T cells. These results suggest that high PD-L1 on IC may reflect T cell-inflamed tumors with the amount of TILs present, including the CD8+ T cells required for anti-tumor responses.
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http://dx.doi.org/10.1007/s12282-020-01110-2DOI Listing
July 2020

Annual report of the Japanese Breast Cancer Society registry for 2016.

Breast Cancer 2020 Jul 11;27(4):511-518. Epub 2020 May 11.

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606, Japan.

The Japanese Breast Cancer Society (JBCS) registry began data collection in 1975, and it was integrated into National Clinical Database in 2012. As of 2016, the JBCS registry contains records of 656,896 breast cancer patients from more than 1400 hospitals throughout Japan. In the 2016 registration, the number of institutes involved was 1422, and the total number of patients was 95,870. We herein present the summary of the annual data of the JBCS registry collected in 2016. We analyzed the demographic and clinicopathologic characteristics of registered breast cancer patients from various angles. Especially, we examined the registrations on family history, menstruation, onset age, body mass index according to age, nodal status based on tumor size and subtype, and proportion based on ER, PgR, and HER2 status. This report based on the JBCS registry would support clinical management for breast cancer patients and clinical study in the near future.
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http://dx.doi.org/10.1007/s12282-020-01081-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297705PMC
July 2020

Rac1 activation in human breast carcinoma as a prognostic factor associated with therapeutic resistance.

Breast Cancer 2020 Sep 20;27(5):919-928. Epub 2020 Apr 20.

Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi-ken, 980-8575, Japan.

Background: RAS-related C3 botulinus toxin substrate 1 (Rac1) is a molecular switch fluctuating between GDP-bound inactive form (Rac1-GDP) and GTP-bound active form (Rac1-GTP) and involved in diverse function in both normal and malignant cells such as breast carcinoma cells. Although several studies have demonstrated immunolocalization of Rac1 protein in human breast carcinoma tissues, activation status of Rac1 still remains to be elucidated.

Methods: We immunolocalized active form of Rac1 (Rac1-GTP) as well as total Rac1 using antibody specific for them in 115 invasive breast carcinoma tissues and correlated with clinicopathological parameters and clinical outcomes.

Results: Rac1-GTP was frequently immunolocalized in the cytoplasm or cell membrane of breast carcinoma cells and it was positively correlated with Ki-67 labeling index and total Rac1 while negatively correlated with progesterone receptor. On the other hand, immunohistochemical Rac1-GTP status was significantly correlated with increased risk of recurrence and breast cancer-specific mortality of breast cancer patients and multivariate analyses did demonstrate Rac1-GTP as an independent worse prognostic factor for both disease-free and breast cancer-specific survival. In addition, Rac1-GTP was still correlated with worse prognosis in the patients who had received adjuvant chemotherapy or endocrine therapy.

Conclusion: These findings suggested Rac1 activation played pivotal roles in the progression and therapeutic resistance of breast cancers and Rac1 might be an important therapeutic target for improvement of the therapy for breast cancer patients.
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http://dx.doi.org/10.1007/s12282-020-01091-2DOI Listing
September 2020

Prospect of immunotherapy in neoadjuvant/adjuvant treatment for early breast cancer.

Chin Clin Oncol 2020 06 17;9(3):28. Epub 2020 Apr 17.

Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.

Immunotherapy is revolutionary and changing the cancer therapy of multiple solid tumors. Immunotherapy began with discovering the proteins of immune checkpoints such as programmed death-1 (PD-1), programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4). Breast cancer, unlike cancers with high tumor mutation burden, is generally considered to be of intermediate immunogenicity; therefore, the efficacy of checkpoint monotherapy is limited. Among breast cancer subtypes, triple negative breast cancer (TNBC) is considered to be the most immunogenic and is mainly evaluated in clinical trials. Some trials have demonstrated that checkpoint inhibitors when combined with chemotherapy improve the survival of TNBC patients. When investigating new drugs, a neoadjuvant setting is preferred because drug efficacy can be evaluated earlier using pathological complete response (pCR) as an alternative endpoint for survival. The strategy is based on the accumulated results that pCR after neoadjuvant therapy significantly correlates with both progression free survival (PFS) and overall survival (OS). We aimed to review relevant articles, and discuss the current position of immunotherapy and future prospects of immunotherapy as neoadjuvant/adjuvant therapy in breast cancer based on our conclusions from the findings in the current literature.
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http://dx.doi.org/10.21037/cco.2020.04.01DOI Listing
June 2020

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Breast Cancer 2020 May 2;27(3):322-331. Epub 2020 Apr 2.

Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.

Purpose: We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Methods: The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting.

Results: The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ.

Conclusion: The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.
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http://dx.doi.org/10.1007/s12282-020-01085-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062371PMC
May 2020

Developmental competence of interspecies cloned embryos produced using cells from large Japanese field mice (Apodemus speciosus) and oocytes from laboratory mice (Mus musculus domesticus).

J Reprod Dev 2020 Jun 26;66(3):255-263. Epub 2020 Mar 26.

Graduate School of Biology-Oriented Science and Technology, Kindai University, Wakayama 649-6493, Japan.

The large Japanese field mouse (Apodemus speciosus) is endemic to Japan and may be used as an animal model for studies related to environmental pollution, medical science, and basic biology. However, the large Japanese field mouse has low reproductive ability due to the small number of oocytes ovulated per female. To produce experimental models, we investigated the in vitro developmental potential of interspecies somatic cell nuclear transfer (iSCNT) embryos produced by fusing tail tip cells from the large Japanese field mouse with enucleated oocytes from laboratory mice (Mus musculus domesticus). Only a small number of iSCNT embryos developed to the 4-cell (0-4%) and blastocysts (0-1%) stages under sequential treatment using trichostatin A (TSA) and vitamin C (VC) supplemented with deionized bovine serum albumin (d-BSA). This sequential treatment led to the reduction in H3K9 trimethylation and did not affect H3K4 trimethylation in at least the 2-cell stage of the iSCNT embryos. Moreover, iSCNT embryos that received tail tip cells with exposure treatment to ooplasm from cell fusion to oocyte activation or VC treatment prior to cell fusion did not exhibit significant in vitro development improvement compared to that of each control group. This suggests that large Japanese field mice/laboratory mice iSCNT embryos that received sequential treatment using TSA and VC with d-BSA may have slightly better developmental potential beyond the 4-cell stage. Our results provide insights into the reprogramming barriers impeding the wider implementation of iSCNT technology.
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http://dx.doi.org/10.1262/jrd.2019-167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297636PMC
June 2020

Turbo Spin-echo Diffusion-weighted Imaging Compared with Single-shot Echo-planar Diffusion-weighted Imaging: Image Quality and Diagnostic Performance When Differentiating between Ductal Carcinoma in situ and Invasive Ductal Carcinoma.

Magn Reson Med Sci 2021 Mar 6;20(1):60-68. Epub 2020 Mar 6.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine.

Purpose: To compare the image quality between turbo spin-echo (TSE)-diffusion weighted imaging (DWI) and single-shot echo-planar imaging (EPI)-DWI, and to verify the diagnostic performance of the apparent diffusion coefficient (ADC) parameters of the two techniques by using histogram analysis in terms of differentiation between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) lesions.

Methods: Ninety-four women with 94 lesions diagnosed as breast cancer by surgery underwent IRB-approved preoperative magnetic resonance imaging, including TSE and EPI-DWI with b-values of 50 and 850 s/mm. Twenty lesions were identified as DCIS and 74 as IDC. Image quality [signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and geometric distortion] was evaluated quantitatively and compared between the TSE and EPI-DWI. A histogram analysis of the entire tumor voxel-based ADC data was performed, and the 10th, 25th, 50th, 75th, and 90th percentile values of each technique were compared between DCIS and IDC lesions.

Results: The SNR and CNR of TSE-DWI were significantly higher than those of EPI-DWI (P < 0.0001 and < 0.0001). The geometric distortion of TSE-DWI was significantly lower than that of EPI-DWI (P < 0.0001). In TSE-DWI, the 10th, 25th, 50th, and 75th percentile values were significantly different between the DCIS and IDC lesions (P = 0.0010, 0.0004, 0.0008, and 0.0044, respectively). In EPI-DWI, the 50th and 75th percentile values were significantly different between the two groups (P = 0.0009 and 0.0093). There was no significant difference in the area under the curve of the receiver operating characteristic analysis of the 10th, 25th, 50th, and 75th percentile values of TSE-DWI, and the 50th and 75th percentile values of EPI-DWI (P = 0.29).

Conclusion: The image quality of TSE-DWI was better than that of EPI-DWI. DCIS lesions were distinguished from IDC lesions with a wider range of percentile values in TSE-DWI than in EPI-DWI, although diagnostic performance was not significantly different between the techniques.
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http://dx.doi.org/10.2463/mrms.mp.2019-0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952202PMC
March 2021

Significance of glucocorticoid signaling in triple-negative breast cancer patients: a newly revealed interaction with androgen signaling.

Breast Cancer Res Treat 2020 Feb 27;180(1):97-110. Epub 2020 Jan 27.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Purpose: Chemotherapy is the only current effective systemic treatment for triple-negative breast cancer (TNBC) patients. Therefore, the identification of active biological pathways that could become therapeutic targets is crucial. In this study, considering the well-reported biological roles of glucocorticoid and androgen receptors (GR, AR) in TNBC, we attempted to explore the effects of glucocorticoids (GCs) on cell kinetics as well as the potential interaction between GR and AR in TNBC.

Methods: We first explored the association between the status of GR, AR, and/or GCs-metabolizing enzymes such as 11β-hydroxysteroid dehydrogenase (11βHSD) 1 and 2 and the clinicopathological variables of the TNBC patients. Thereafter, we also studied the effects of dexamethasone (DEX) with/without dihydrotestosterone (DHT) on TNBC cell lines by assessing the cell proliferation, migration and GC response genes at the transcriptional level.

Results: GR positivity in carcinoma cells was significantly associated with adverse clinical outcome of the patients and AR positivity was significantly associated with lower histological grade and Ki-67 labeling index of the cases examined. In particular, AR positivity was significantly associated with decreased risks of developing recurrence in GR-positive TNBC patients. The subsequent in vitro studies revealed that DEX-promoted cell migration was inhibited by the co-treatment with DHT in GR/AR double-positive HCC38 cells. In addition, DHT inhibited the DEX-increased serum and glucocorticoid-regulated kinase-1 (SGK1) mRNA expression.

Conclusion: This is the first study to reveal that the interaction of GR and AR did influence the clinical outcome of TNBC patients and GCs induced cell migration in TNBC cells.
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http://dx.doi.org/10.1007/s10549-020-05523-7DOI Listing
February 2020

Risks and benefits of bevacizumab combined with chemotherapy for advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials.

Breast Cancer 2020 May 23;27(3):347-354. Epub 2020 Jan 23.

Department of Breast Oncology, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.

Background: The combination of bevacizumab and chemotherapy has greatly improved progression-free survival (PFS) and objective response rate (ORR) in HER2-negative metastatic breast cancer in many pivotal trials. However, risk-benefit balance related to bevacizumab addition could not be confirmed because of a lack of overall survival (OS) improvement. Therefore, we conducted a meta-analysis to evaluate multiple endpoints pertaining to bevacizumab use in metastatic breast cancer (MBC) treatment.

Methods: We searched PubMed and Cochrane Library databases and included seven studies in our meta-analysis in which bevacizumab combined with chemotherapy was compared with chemotherapy alone in MBC.

Results: Compared to the chemotherapy-alone group, the combination treatment group had significantly improved PFS [hazard ratio (HR): 0.72, 95% CI 0.67-0.77, P < 0.00001]. Furthermore, bevacizumab addition did not significantly improve OS (HR: 0.95, 95% CI 0.87-1.03, P = 0.22). The ORRs in the combination treatment and chemotherapy-alone groups were 42% and 32%, respectively (HR: 1.47, 95% CI 1.26-1.71, P < 0.00001). Bevacizumab addition significantly increased the incidence of therapy discontinuation due to toxicity and toxicity of grade 3 or higher (HR: 1.43, 95% CI 1.06-1.93, P = 0.02, HR: 1.43; 95% CI 1.25-1.64, P < 0.00001, respectively). A qualitative systematic review of two randomized controlled trials indicated no significant differences in quality of life from baseline between the two groups.

Conclusions: Compared to chemotherapy alone, bevacizumab combined with chemotherapy significantly improved PFS in the HER2-negative MBC patients. However, the lack of a significant OS difference remained.
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http://dx.doi.org/10.1007/s12282-020-01052-9DOI Listing
May 2020

Alcohol consumption and survival after breast cancer diagnosis in Japanese women: A prospective patient cohort study.

PLoS One 2019 13;14(11):e0224797. Epub 2019 Nov 13.

Department of Breast Surgery, Miyagi Cancer Center Hospital, Natori, Miyagi, Japan.

Background: It is unclear whether alcohol consumption may impact survival after breast cancer diagnosis. To clarify the association between pretreatment alcohol consumption and survival in breast cancer patients, a prospective patient cohort study was conducted.

Methods: The cohort comprised 1,420 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. Alcohol drinking and other lifestyle factors were assessed by questionnaire survey at the initial admission. The patients were followed until December 31, 2016. The crude associations of pretreatment alcohol intake with survival were evaluated by Kaplan-Meier analysis. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) controlled by confounders.

Results: During a median follow-up period of 8.6 years, 261 all-cause and 193 breast cancer-specific deaths were documented. Survival curves showed that ever-drinkers tended to have better survival than never-drinkers (breast cancer-specific survival, log-rank p = 0.0381). Better survival was also observed for light drinkers with an intake of <5.0 g per day. In the Cox model, ever-drinking was associated with a decreased risk of all-cause (HR: 0.75; 95% CI: 0.54-1.05) and breast cancer-specific death (HR: 0.68; 95% CI: 0.46-0.99). Light drinkers had a lower risk of breast cancer-specific death (frequency of drinking, HR = 0.57 for occasional or 1-2 times per week and 0.72 for 3-7 times per week; amount of alcohol consumed per day, HR = 0.57 for <5.0 g and 0.68 for ≥5.0 g compared with never-drinking). In terms of hormone receptor status, a significantly decreased risk of death associated with ever-drinking was observed among women with receptor-negative cancer (ER-/PR-, HR = 0.41; 95% CI: 0.20-0.84 for breast cancer-specific death).

Conclusions: Pretreatment, i.e., pre-diagnosis alcohol consumption is unlikely to have an adverse effect on survival after breast cancer diagnosis. Light alcohol consumption may have a beneficial effect on patient survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853331PMC
March 2020

A metabolic profile of routine needle biopsies identified tumor type specific metabolic signatures for breast cancer stratification: a pilot study.

Metabolomics 2019 11 4;15(11):147. Epub 2019 Nov 4.

Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Introduction: Metabolomics has recently emerged as a tool for understanding comprehensive tumor-associated metabolic dysregulation. However, only limited application of this technology has been introduced into the clinical setting of breast cancer.

Objectives: The aim of this study was to determine the feasibility of metabolome analysis using routine CNB/VAB samples from breast cancer patients and to elucidate metabolic signatures using metabolic profiling.

Methods: After breast cancer screenings, 20 consecutive patients underwent CNB/VAB, and diagnosed with benign, DCIS and IDC by histology. Metabolome analysis was performed using CE-MS. Differential metabolites were then analyzed and evaluated with MetaboAnalyst 4.0.

Results: We measured 116-targeted metabolites involved in energy metabolism. Principal component analysis and unsupervised hierarchical analysis revealed a distinct metabolic signature unique to namely "pure" IDC samples, whereas that of DCIS was similar to benign samples. Pathway analysis unveiled the most affected pathways of the "pure" IDC metabotype, including "pyrimidine," "alanine, aspartate, and glutamate" and "arginine and proline" pathways.

Conclusions: Our proof-of-concept study demonstrated that CE-MS-based CNB/VAB metabolome analysis is feasible for implementation in routine clinical settings. The most affected pathways in this study may contribute to improved breast cancer stratification and precision medicine.
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http://dx.doi.org/10.1007/s11306-019-1610-6DOI Listing
November 2019

ASO Author Reflections: Impact of Radiotherapy for Breast Cancer is Changing in the Modern Era.

Ann Surg Oncol 2019 12 11;26(Suppl 3):780-781. Epub 2019 Oct 11.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

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http://dx.doi.org/10.1245/s10434-019-07941-4DOI Listing
December 2019

A population-based recurrence risk management study of patients with pT1 node-negative HER2+ breast cancer: a National Clinical Database study.

Breast Cancer Res Treat 2019 Dec 26;178(3):647-656. Epub 2019 Aug 26.

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606, Japan.

Purpose: Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD).

Methods: We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS).

Results: There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p < 0.001) were significantly improved in treated compared with untreated patients. In the Cox proportional hazards model, treated patients had significantly longer OS than untreated patients in pT1b (hazard ratio (HR) 0.20) and pT1c (HR 0.54) groups. Estrogen receptor-negative tumors was also a significant predictor of survival in pT1c (HR 2.01) but not pT1ab patients. Furthermore, HR was greater in patients aged ≤ 35 years (3.18) compared to that in patients aged 50-69 years in the pT1b group.

Conclusions: NCD data revealed that systemic treatment improved OS in pT1bc but not in pT1a node-negative HER2+ breast cancer patients. Future observational research using big-sized data is expected to play an important role in optimizing treatment for patients with early-stage breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05413-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817748PMC
December 2019

Role of Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in Breast Cancer Patients: A Study from the Japanese Breast Cancer Registry.

Ann Surg Oncol 2019 Aug 17;26(8):2475-2485. Epub 2019 May 17.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: The role of postmastectomy radiotherapy (PMRT) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is controversial. We aimed to evaluate the effectiveness of radiotherapy in patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry.

Methods: We enrolled patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer. We evaluated the association between radiotherapy and outcomes, locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) based on ypN status by multivariable analysis.

Results: Of the 145,530 patients, we identified 3226 who met the inclusion criteria. Among ypN1 patients, no differences were found in LRR, DDFS, or OS between groups with and without radiotherapy (p = 0.72, p = 0.29, and p = 0.36, respectively). Radiotherapy was associated with improved LRR-free survival (p < 0.001), DDFS (p = 0.01), and OS (p < 0.001) in patients with ypN2-3. Multivariable analysis demonstrated that use of radiotherapy was independently associated with improved LRR [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.45-0.82, p = 0.001] and OS [HR 0.69, 95% CI 0.53-0.89, p = 0.004) for ypN2-3 patients only. The association between radiotherapy and OS was not statistically significant among ypN0 (p = 0.22) and ypN1 patients (p = 0.51).

Conclusions: The results from this nationwide database study did not show significant associations between PMRT and improved survival among ypN0 and ypN1 patients. Radiotherapy may be beneficial only for ypN2-3 breast cancer patients who receive NAC and mastectomy in the modern era.
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http://dx.doi.org/10.1245/s10434-019-07453-1DOI Listing
August 2019

Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR/HER2 Breast Cancer.

Cancers (Basel) 2019 Apr 12;11(4). Epub 2019 Apr 12.

Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.

In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed "the nearest-neighbor method" to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quantification of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR ( = 0.94) and flow cytometry ( = 0.98). High ERα ENR was significantly associated with poor overall survival ( = 0.048) and disease-free survival (DFS) ( = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4-11.8; = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR/HER2 BC indicates decreased likelihood of benefiting from ET.
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http://dx.doi.org/10.3390/cancers11040526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520781PMC
April 2019
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