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Purpose The impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR. Methods We retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan–Meier method. Results During a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS. Conclusion Our prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR.

Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer. The frequency of DCIS is increasing because of routine mammography; however, the biological features and intratumoral heterogeneity of DCIS remain obscure. To address this deficiency, we performed single-cell transcriptomic profiling of DCIS and invasive ductal carcinoma (IDC). DCIS was found to be composed of several transcriptionally distinct subpopulations of cancer cells with specific functions. Several transcripts, including long noncoding RNAs, were highly expressed in IDC compared with DCIS and might be related to the invasive phenotype. Closeness centrality analysis revealed extensive heterogeneity in DCIS, and the prediction model for cell-to-cell interactions implied that the interaction network among luminal cells and immune cells in DCIS was comparable with that in IDC. In addition, transcriptomic profiling of HER2+ luminal DCIS indicated HER2 genomic amplification at the DCIS stage. These data provide novel insight into the intratumoral heterogeneity and molecular features of DCIS, which exhibit properties similar to IDC. Significance: Investigation of the molecular features of ductal carcinoma in situ at single cell resolution provides new insights into breast cancer biology and identifies candidate therapeutic targets and diagnostic biomarkers.

Supplementary Data from Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features of Ductal Carcinoma In Situ

Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer. The frequency of DCIS is increasing because of routine mammography; however, the biological features and intratumoral heterogeneity of DCIS remain obscure. To address this deficiency, we performed single-cell transcriptomic profiling of DCIS and invasive ductal carcinoma (IDC). DCIS was found to be composed of several transcriptionally distinct subpopulations of cancer cells with specific functions. Several transcripts, including long noncoding RNAs, were highly expressed in IDC compared with DCIS and might be related to the invasive phenotype. Closeness centrality analysis revealed extensive heterogeneity in DCIS, and the prediction model for cell-to-cell interactions implied that the interaction network among luminal cells and immune cells in DCIS was comparable with that in IDC. In addition, transcriptomic profiling of HER2+ luminal DCIS indicated HER2 genomic amplification at the DCIS stage. These data provide novel insight into the intratumoral heterogeneity and molecular features of DCIS, which exhibit properties similar to IDC.Significance:Investigation of the molecular features of ductal carcinoma in situ at single cell resolution provides new insights into breast cancer biology and identifies candidate therapeutic targets and diagnostic biomarkers.

Purpose:Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set.Results:An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set.Conclusions:Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.

Table S1. Definition criteria of categorical variables for logistic-LASSO regression analysis Table S2. Clinicopathological characteristics of patients with benign breast diseases Table S3. Clinicopathological characteristics of patients stratified into the training set and test set Table S4. Comparison of T staging between pre- and post-operative diagnosis Table S5. Comparison of lymphovascular invasion (LVI) between pre- and post-operative diagnosis Table S6. Clinicopathological characteristics of N-positive patients misdiagnosed as N-negative in the test set Table S7. Sensitivity and specificity analysis for the diagnostic index in the test set Table S8. Biomarker candidate miRNAs for N positivity Table S9. Comparison of post-operative lymphovascular invasion (LVI) between original and re-evaluated diagnosis in the training set Table S10. Characteristics of ultrasound findings of axillary lymph node status Table S11. Utility of ultrasonography for the detection of axillary lymph node metastasis Figure S1. Ultrasound findings of suspicious metastatic and negative axillary lymph nodes. Figure S2. Serum levels of miR-629-3p and miR-4710 in the training set. P-values were calculated by one-way ANOVA with Tukey's post-hoc analysis. Figure S3. ROC curves for histological grade and Ki-67 labeling index in the test set (postoperative pathology). Numbers in parentheses are 95% confidence intervals. Text. Materials and Methods

Supplementary Figure from Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features of Ductal Carcinoma In Situ

Purpose This meta-analysis aimed to investigate whether receptor (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) discordances between primary and recurrent breast cancers affect patients’ survival. Methods Search terms contained ER, PR, and HER2 status details in both primary and recurrent tumors (local recurrence or distant metastasis) in addition to survival outcome data (overall survival [OS] or post-recurrence survival [PRS]). Results Loss of ER or PR in recurrent tumors was significantly associated with shorter OS as compared with receptor-positive concordance (hazard ratio [HR], 1.67; 95% confidence interval [% CI] 1.37–2.04; p p p = 0.03). Gain of PR was not a significant predictor of longer survival compared with receptor-negative concordance, but it could be related to better OS at distant metastasis. Both HER2 of loss and gain could be related to poor outcomes. Conclusion This meta-analysis showed that receptor conversion in recurrent tumors may affect patient survival as compared with receptor concordance.

Background Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. Methods A serum miRNA profile (miRNomes)–based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. Results Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type–specific serum miRNomes. Conclusions This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.

Purpose Stromal tumor-infiltrating lymphocytes (TILs) are independent prognostic factors in systemically untreated early-stage triple-negative breast cancer (TNBC). Other immune biomarkers including CD8, CD20, programmed cell death-ligand 1 (PD-L1), and tertiary lymphoid structures (TLS) are also reported to be associated with prognosis. However, whether combining other immune biomarkers with TILs would allow for further prognostic stratification is unknown. Methods We retrospectively analyzed 125 patients with early-stage TNBC not receiving perioperative chemotherapy. Stromal TILs and TLS were evaluated on hematoxylin–eosin slides. PD-L1 expression was evaluated using the SP142 assay. CD8 and CD20 were assessed by immunohistochemistry and counted by digital pathology. Results Immune biomarker levels were positively correlated (p 2 = 9.24, p = 0.01). In Cox regression analysis, high CD8 was significantly associated with better prognosis [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48–0.98, p = 0.04], and PD-L1 positivity was significantly associated with worse prognosis (HR 4.33, 95%CI 1.57–11.99, p = 0.005). Patients with high CD8/PD–L1 (–) tumors had the most favorable prognosis [5 year invasive disease-free survival (iDFS), 100%], while patients with low CD8/PD-L1( +) tumors had the worst prognosis (5 year iDFS, 33.3%). Conclusion CD8 and PD-L1 levels add prognostic information beyond TILs for early-stage TNBC not receiving perioperative chemotherapy. CD8–positive T cells and PD-L1 may be useful for prognostic stratification and in designing future clinical trials of TNBC.

Background Chemotherapy and radiotherapy were postulated to induce an inflamed tumour microenvironment. We aimed to evaluate the effects of adjuvant chemotherapy/radiotherapy on tumour-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression in metastatic breast cancer. Methods We identified paired primary and metastatic tumours in 85 patients with breast cancer. Stromal TILs were assessed according to international guidelines. PD-L1 expression was evaluated using the VENTANA SP142 assay. Results TILs were significantly lower in metastatic tumours than in primary tumours (12.2 vs. 8.3%, p = 0.049). PD-L1 positivity was similar between primary and metastatic tumours (21.2 vs. 14.1%, p = 0.23). TILs were significantly lower in patients who received adjuvant chemotherapy than in those who did not (−9.07 vs. 1.19%, p = 0.01). However, radiotherapy had no significant effect on TILs (p = 0.44). Decreased TILs predicted worse post-recurrence survival (hazard ratio, 2.94; 95% confidence interval [CI]: 1.41–6.13, p = 0.003), while increased TILs was associated with a better prognosis (HR, 0.12; 95% CI: 0.02–0.08, p = 0.04). Conclusions TILs decreased in metastatic tumours, particularly in patients who relapsed after adjuvant chemotherapy. Changes in TILs from primary to metastatic sites could be a prognostic factor after recurrence.

Background Lymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC. Methods The prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan–Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated. Results High mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival. Conclusion This study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.

During the last decade, a dramatic rise in the development and application of artificial intelligence (AI) tools for use in pathology services has occurred. This trend is often expected to continue and reshape the field of pathology in the coming years. The deployment of computational pathology and applications of AI tools can be considered as a paradigm shift that will change pathology services, making them more efficient and capable of meeting the needs of this era of precision medicine. Despite the success of AI models, the translational process from discovery to clinical applications has been slow. The gap between self-contained research and clinical environment may be too wide and has been largely neglected. In this review, we cover the current and prospective applications of AI in pathology. We examine its applications in diagnosis and prognosis, and we offer insights for considerations that could improve clinical applicability of these tools. Then, we discuss its potential to improve workflow efficiency, and its benefits in pathologist education. Finally, we review the factors that could influence adoption in clinical practices and the associated regulatory processes.

Highlights • Breast cancer arising in association with a fibroadenoma (FA) is rare and usually early-stage. • We report a rare case of an advanced triple negative breast cancer, with lymph node metastases, within a long-standing FA. • Pathological complete response was achieved after neoadjuvant chemotherapy, as proven on mastectomy with axillary clearance., Introduction Breast cancer arising from benign fibroadenoma (FA) is rare. The histological type of the former was either carcinoma in situ or early-stage invasive breast carcinoma with hormone receptor positive/HER2 (human epidermal growth factor receptor-2)-negative phenotype. Meanwhile, advanced breast cancer of triple negative (TN) phenotype such as our case is extremely uncommon and clinically challenging. Presentation of case We experienced a case of a 53-year-old woman that had invasive ductal carcinoma of TN phenotype in FA with multiple lymph node metastases. After receiving neoadjuvant chemotherapy (NAC), she underwent breast mastectomy and axillary dissection. The pathological examination on postoperative specimens revealed the dense fibrous stroma in the FA without any residual viable tumor cells and was considered as pathological complete response (pCR). Discussion This is the first report presenting a case of NAC treatment for invasive ductal carcinoma (IDC) in FA. Furthermore, the patient achieved pCR even if IDC was located within FA. Diagnosing breast cancer in FA may be challenging as the carcinoma component may be hidden by the FA component. If imaging of FA became larger or abnormal changes during follow-up examinations, needle biopsy should be recommended for assessment of the lesion positively. Conclusion This is the first report presenting a case of advanced breast cancer in FA of TN phenotype with multiple lymph node metastases who achieved pCR even if IDC was located within FA.

/Objective: To evaluate the usefulness of combining radioisotopes (RI) and indocyanine green (ICG) and investigate discordances in sentinel lymph node (SN) reactivity using each tracer in cN0 breast cancer patients.In total, 338 cN0 primary breast cancer patients who underwent SN biopsy with RI and ICG and axillary lymph node (ALN) dissection were included. SN positivity with RI, ICG, and a combination of RI and ICG was denoted as SN(RI), SN(ICG), and SN(RI+ICG), respectively. We retrospectively estimated metastatic SN detection rates, each method's discordance rate, and the correlation of discordances in SN reactivity with postoperative N staging.The combination of RI and ICG had higher metastatic SN detection rates (99.7%) than RI or ICG alone (91.7% and 96.4%, respectively; p 0.01). The discordance rate between SN(RI) and SN(ICG) in detecting metastatic SNs was 11.3% (38/337 cases). The absence of SN(RI), cT stage (cT2-3), higher histological grade (G3), and histological type (special type) were identified as risk factors of pN2-3 disease (odds ratios: 8.64, 2.56, 1.92, and 3.28, respectively; p 0.01).Discordances in SN reactivity between RI and ICG helps in identifying SN metastasis. Although the absence of SN(RI) is rare, it is a significant sign of advanced ALN metastases. The findings of our study indicate that ALN dissection should be considered for accurate nodal staging in such cases.

Background: To evaluate the usefulness of combining radioisotopes and indocyanine green (ICG) and investigate discordances in sentinel lymph node (SN) reactivity using each tracer in cN0 breast cancer patients.Methods: 338 cN0 primary breast cancer patients who underwent SN biopsy with radioisotopes and ICG and axillary lymph node (ALN) dissection were included. SN positivities with radioisotopes, ICG, and both were denoted as SN(RI), SN(ICG), and SN(RI+ICG), respectively. We retrospectively estimated metastatic SN detection rates, each method’s discordance rate, and correlation of discordances in SN reactivity with postoperative N staging.Results: The combination of radioisotopes and ICG had higher metastatic SN detection rates (99.7%) than radioisotopes or ICG alone (91.7% and 96.4%, respectively; ppConclusions: Discordances in SN reactivity between radioisotopes and ICG helps identify SN metastasis. Although the absence of SN(RI) is rare, it is a significant sign of advanced ALN metastases; ALN dissection should be considered for accurate nodal staging.

Highlights • This case showed spontaneous regression of both the primary and metastasis lesions. • Histopathological findings suggested spontaneous regression of the tumor. • The presence of CD8-positive lymphocytes suggests involvement of the immune response. • Poor prognostic factors of malignant tumors might induce spontaneous regression., Introduction Spontaneous regression of a malignant tumor is defined as “the partial or complete disappearance of a malignant tumor in the absence of any treatment.” Herein, we report a case of occult breast cancer with axillary lymph node metastasis that showed spontaneous tumor regression based on the histopathological findings. Presentation of the case A 67-year-old woman presented with left armpit pain and a lump. Previous examination by another doctor revealed swelling of the left axillary lymph node, but it was difficult to identify the primary lesion. Needle biopsy of the left axillary lymph node revealed malignant tumor tissue with extensive necrosis on histological examination. On initial examination at our hospital, the left axillary lymph node was observed to have shrunk compared to previous observations. Moreover, findings indicated a suspected concentrated cyst in the left breast, with slight contrast enhancement on magnetic resonance imaging. Considering a diagnosis of occult breast cancer with axillary lymph node metastasis, excisional biopsy was performed for the left breast mass and axillary lymph node dissection for left axillary lymph node metastasis. Histological examination revealed a micro adenocarcinoma with lymphocyte infiltration in the left breast, and the viable tumor in the left axillary lymph node had disappeared. The histopathological findings of the primary tumor and dissected lymph nodes suggested the possibility of spontaneous regression of both the primary and metastatic lesions, because effective preoperative therapy was not performed.

Purpose: Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker. Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. Results: An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. Conclusions: Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.

Background Discordance in biomarker expression between primary and metastatic tumor sites has been reported in several studies; yet, few have examined this feature in bone lesions. Methods We retrospectively enrolled patients with breast cancer metastasis to the bone or bone marrow, excluding cases where samples from both the primary and metastatic lesions were not available. Expression patterns of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 were compared in primary tumors and bone or bone marrow lesions. Results Forty-six patients with a median age of 52 years (range, 34-72 years) were included in the study. Discordant rates of ER, PgR and HER2 were 20%, 46% and 0%, respectively. Physicians usually determined treatment options considering the results of biomarker re-evaluation. It is unlikely that biomarker discordance was related to prior treatment. Conclusions Biomarker discordance in bone or bone marrow lesions is common in patients with breast cancer. An accurate and thorough analysis of biomarkers and metastatic tumor properties is important for clinical decision-making.

Simple Summary In this review, we present the latest information on the pathophysiology, diagnosis, and local and systemic treatment of brain metastases from breast cancer, with a focus on recent publications. Improving the local treatment and subtype-specific systemic therapies through advancements in basic and translational research will contribute to better clinical outcomes for patients with breast cancer brain metastasis. Abstract Breast cancer is the second most common origin of brain metastasis after lung cancer. Brain metastasis in breast cancer is commonly found in patients with advanced course disease and has a poor prognosis because the blood–brain barrier is thought to be a major obstacle to the delivery of many drugs in the central nervous system. Therefore, local treatments including surgery, stereotactic radiation therapy, and whole-brain radiation therapy are currently considered the gold standard treatments. Meanwhile, new targeted therapies based on subtype have recently been developed. Some drugs can exceed the blood–brain barrier and enter the central nervous system. New technology for early detection and personalized medicine for metastasis are warranted. In this review, we summarize the historical overview of treatment with a focus on local treatment, the latest drug treatment strategies, and future perspectives using novel therapeutic agents for breast cancer patients with brain metastasis, including ongoing clinical trials.

L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16–7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35–8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

We report a case of total mastectomy and contralateral axillary lymph node dissection (ALND) in a patient with ipsilateral breast tumor recurrence (IBTR) and contralateral axillary lymph node metastasis (ALNM), with lymphoscintigraphy, confirming that the primary lymphatic flow was directed to the contralateral ALNM. The patient in the present case study is a 63-year-old woman. At the age of 46 years, the patient underwent lumpectomy and sentinel lymph node biopsy (SLNB) for left breast cancer. After surgery, she underwent whole-breast irradiation and hormone therapy (tamoxifen) for 5 years. On follow-up, she did not have recurrence. When she underwent breast ultrasound examination at the 17-year checkup after the initial surgery, she was diagnosed with tumor recurrence in the left conserved breast and with contralateral ALNM, without distant metastasis to any other organ. When re-SLNB is performed in patients with IBTR, the primary lymphatic flow is directed toward a lymph node other than the ipsilateral axillary lymph node (ALN). Therefore, it is necessary to discuss whether or not the contralateral ALNM in our case should be treated as stage IV. Therefore, we performed ALND after confirming that the primary lymphatic flow was directed toward the contralateral ALN as observed on lymphoscintigraphy and considering the contralateral ALNM as a localized lesion. Lymphoscintigraphy and intraoperative fluorescence imaging aid in the identification of the primary lymphatic flow. Lymph node metastases beyond the altered primary lymphatic flow are treated as localized lesions, and aggressive surgery is expected to be effective. There is a need to formulate guidelines on the treatment of IBTR considering changes in primary lymphatic flow.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Background It has been determined that axillary lymph node dissection after the detection of limited axillary lymph node metastasis does not improve the prognosis of patients with breast cancer. Thus, a need exists for less-invasive axillary surgery. However, it remains unclear whether a predictive model based on preoperative data would be sufficient to accurately predict the probability of pN2-N3 (> 3 lymph node metastases). We sought to develop an easy-to-use scoring system to distinguish between pN0-N1 (0-3 lymph node metastases) and pN2-N3 using only preoperative data and validate its predictive performance. Patients and Methods We retrospectively identified 2687 patients diagnosed with cT1-3cN0-N1 who had undergone surgery in our hospital from 2013 to 2019. We evaluated the risk factors associated with pN2-N3 by logistic regression analysis and developed a scoring system. Predictive performance was assessed by calculating the receiver operating characteristic area under the curve (AUC) and was validated using K-fold cross-validation. Results We identified 1987 patients with stage pN0, 522 with pN1, and 178 with pN2-N3. Multivariate analysis revealed tumor size, number of suspicious lymph nodes on axillary ultrasound examination, histologic type, histologic grade, and receptor status were significant risk factors for pN2-N3. The AUC value was 0.87, and the mean AUC of the 10-fold cross-validation was 0.88. When the cutoff score was set at 6, the negative predictive value for excluding patients with pN2-N3 was 98.4%. Conclusion Our easy-to-use scoring system could be useful to preoperatively identify patients at lower risk of pN2-N3 and avoid unnecessary axillary lymph node dissection.

Background Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision. Methods In total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate. Results ER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence). Conclusion The strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Objectives To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. Methods We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. Results Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. Conclusions Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

Background ALN dissection (ALND) is the only way to obtain information on ALN metastasis status accurately when sentinel lymph node (SLN) metastasis is present. In this study, we established a model for intraoperatively predicting non-SLN metastasis and the presence of four or more ALNs (pN2), based on the combined use of one-step nucleic acid amplification (OSNA) and histological examination following SLN biopsy. Materials and methods Subjects comprised 318 consecutive breast cancer patients (cTis-3, N0) who underwent SLN biopsy with a combination of OSNA and histological examination, and who were found to have SLN metastasis and were treated by ALND. We allotted points to each patient according to their SLN metastasis status as defined by both OSNA and histology, then defined the “National Cancer Center sentinel lymph node metastatic score” (NCS score) based on the total points. Correlations between the NCS score and both non-SLN metastasis and pN2 status were analyzed by logistic regression analysis. The accuracy of this score was evaluated using receiver operating characteristic (ROC) analysis. Results The NCS score was significantly correlated with both non-SLN metastasis and pN2 status (adjusted odds ratio: 1.26 for non-SLN metastasis, 1.56 for pN2 status). The area under the ROC curve (AUC) of the NCS score demonstrated 0.74 for non-SLN metastasis, 0.91 for pN2 status. Conclusions The NCS score was a strong independent predictor of non-SLN metastasis and pN2 status. Use of this score will facilitate the selection of optimal adjuvant therapies without requiring unnecessary ALND.

Recent retrospective studies have reported discordance rate of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses between primary and recurrent tumors and prognostic values of discordance. However, the results of these reports may possibly include analytical error.We analyzed 153 patients from whom pathological specimens of tumor tissues were available from both primary and recurrent sites. For all specimens, immunohistochemistry was performed for these statuses with a standardized method. Two experienced pathologists evaluated these specimens in a blinded fashion.The discordance rates for estrogen receptor, progesterone receptor, and HER2 were 18%, 26%, and 7%, respectively. Subtype changes based on HR and HER2 status occurred in 21% of patients. Clinical outcome was significantly worse in the patients with the tumors that were primarily HR-positive (HR(+)) converted to HR-negative (HR(-)) at recurrent sites than in the patients with the tumors in which HR status did not change or converted from HR(-) to HR(+) (P = .001). Clinical outcome was also significantly worse in the patients with the primarily HR(+) tumor that converted to triple negative in the recurrence sites than in the patients with a constantly HR(+) tumor (P .001). By the Cox multivariate analyses, loss of HR expression and conversion to triple negative at the recurrence sites were independent indicators of worse clinical outcome.Discordance in HR and HER2 status often occurred between primary and recurrent breast cancer and had independent prognostic impact in the patients with recurrent breast cancer.

MicroRNA (miRNA), which are stably present in serum, have been reported to be potentially useful for detecting cancer. In the present study, we examined the expression profiles of serum miRNA in several large cohorts to identify novel miRNA that can be used to detect early stage breast cancer. We comprehensively evaluated the serum miRNA expression profiles using highly sensitive microarray analysis. A total of 1280 serum samples of breast cancer patients stored in the National Cancer Center Biobank were used. In addition, 2836 serum samples were obtained from non‐cancer controls, 451 from patients with other types of cancers, and 63 from patients with non‐breast benign diseases. The samples were divided into a training cohort including non‐cancer controls, other cancers and breast cancer, and a test cohort including non‐cancer controls and breast cancer. The training cohort was used to identify a combination of miRNA that could detect breast cancer, and the test cohort was used to validate that combination. miRNA expressions were compared between patients with breast cancer and non‐breast cancer, and a combination of five miRNA (miR‐1246, miR‐1307‐3p, miR‐4634, miR‐6861‐5p and miR‐6875‐5p) was found to be able to detect breast cancer. This combination had a sensitivity of 97.3%, specificity of 82.9% and accuracy of 89.7% for breast cancer in the test cohort. In addition, this combination could detect early stage breast cancer (sensitivity of 98.0% for Tis).

Metaplastic carcinoma (MC) is a highly malignant tumor that is mainly classified as a triple-negative subtype exhibiting basal markers on immunohistochemical testing. Immunohistochemical findings of S-100 and SOX10 are useful and valuable in the differential diagnosis of Schwannian, melanocytic, and myoepithelial/basal cell epithelial neoplasms, particularly of unknown differentiation or origin. We report an extremely rare case of MC with a basal-HER2 phenotype (HER2 phenotype breast carcinoma with basal marker expression) that exhibited unusual S-100 and SOX10 immunoreactivity. A 54-year-old Japanese woman presented with a 2-month history of a painful, growing mass in her left breast. Core needle biopsy was performed and immunohistochemical results suggested poorly differentiated carcinoma or melanocytic neoplasm. Because the tumor was located in the breast, the immunohistochemical panel included the St. Gallen consensus markers, which showed focal expression of HER2 (score: 2+, equivocal) and a Ki-67 labeling index of 87.0%, but no expression of estrogen receptors or progesterone receptors. Fluorescence in situ hybridization identified HER2 gene amplification based on the 2013 ASCO–CAP HER2 Test Guidelines (HER2/CEP17 ratio: 3:3; HER2 copy number: 14.7 per cell). The histopathological results suggested that this was a primary breast carcinoma of a “basal-HER2” phenotype. After histological examination of the resected specimen, the tumor was ultimately diagnosed as metaplastic carcinoma. Tumors like this could potentially be mis-diagnosed as other S-100-positive and SOX10-positive malignant neoplasms based on limited sampling, such as that occurring with core needle biopsies. This case highlighted the importance of performing careful histological examinations of HER2 status to correctly diagnose a primary breast neoplasm.

Benign inclusions, such as endosalpingiosis, in an axillary sentinel lymph node (SLN) can be misdiagnosed as metastatic breast carcinoma. However, endosalpingiosis is rare in lymph nodes above the diaphragm. Among 792 patients with breast carcinoma who underwent sentinel lymph node biopsy at our center, 2 patients have experienced benign glandular inclusions in 3 SLNs, and all of these glandular inclusions were lined with columnar and ciliated epithelial cells. Immunohistochemistry revealed that the epithelial cells were positive for Mullerian markers (e.g., PAX8 and WT-1) and negative for mammary markers (e.g., mammaglobin, GCDFP-15, and GATA3), which confirm the diagnosis of endosalpingiosis. The epithelial cells were positive for CK19 but the one-step nucleic acid amplification assay revealed negative results for the axillary SLNs. Although endosalpingiosis is rare in axillary SLNs, care is needed to identify these rare cases and avoid unnecessary axillary lymph node dissection, overstaging, and overtreatment.

To identify social–cognitive factors predicting lymphoedema risk-reduction behaviours (hereafter, self-care) after discharge among patients in Japan with breast or gynaecological cancers, using the extended model of the theory of planned behaviour. A cross-sectional questionnaire study was conducted in an oncology hospital. Items measured were (1) knowledge about self-care; (2) the Cancer Fatigue Scale; (3) social–cognitive factors in the theory of planned behaviour (attitudes, subjective norms, and perceived behavioural control); (4) self-care (limb hygiene, observation, articular movement, recommended risk-reduction behaviours in daily life, and diet and weight control); and (5) demographics. Of 202 respondents, 147 who had not been diagnosed with lymphoedema were eligible for statistical analysis (65.3% with gynaecological cancer, 34.7% with breast cancer). Structural equation modelling was used to examine a hypothesised model based on the theory of planned behaviour. The results revealed that a longer time since surgery, higher levels of fatigue, less knowledge, higher expected efficacy of self-care, and lower perceived behavioural control directly and significantly predicted less self-care behaviour. Besides education about self-care behaviour, levels of fatigue and perceived behavioural control should be taken into account to encourage female patients with cancer to perform self-care after discharge. Continuous psycho-educational programmes after discharge may help to facilitate self-care behaviours among long-term female cancer survivors.

Background Positive margin of breast-conserving surgery (BCS) is well known to be a risk factor for ipsilateral breast tumor recurrence (IBTR). SSO/ASTRO guidelines defined ink on invasive cancer or DCIS as positive margin and recommend considering doing re-excision of the site of positive margin. However, whether re-excision can reduce IBTR has not been fully investigated yet. The aim of this study was to retrospectively assess the oncological impact of re-excision for positive margin status after BCS in invasive breast cancer. Methods The subjects were 196 invasive breast cancer patients who underwent BCS, and who were found to have positive margin. Of the 196 patients, 55 underwent re-excision after initial BCS (group A), and 139 did not (group B). We analyzed IBTR free survival in each group and evaluated the predictors for IBTR and overall survival (OS) using Cox proportional hazards modeling. Results Of the 196 patients, 188 (96%) underwent adjuvant radiotherapy and 24 of 55 re-excision (43%) identified residual disease. There was no significant difference in 10-year IBTR free survival between group A and group B (94.4% versus 93.8%; P = 0.58). In a multivariate analysis, re-excision was not associated with IBTR and OS, while younger age, lack of adjuvant radiotherapy, and invasive component of margin status were independent predictors of IBTR. Conclusions In our retrospective study, re-excision for positive margin after initial BCS in invasive breast cancer does not contribute to prevent IBTR and may not translate into improved OS. Further treatment should be considered when patient was younger and margin status was invasive component. Legal entity responsible for the study Kenjiro Jimbo. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Intraductal papillary lesions of the breast constitute a heterogeneous entity, including benign intraductal papilloma (IDP) with or without atypia and malignant papillary carcinoma. Differentiating between these diagnoses can be challenging. We re-evaluated core biopsy specimens that were diagnosed as IDP and the corresponding surgical excision specimens, and assessed the potential risk for the diagnosis to be modified to malignancy based on excision. By sorting the pathology database of the National Cancer Center Hospital, Tokyo, we identified 146 core biopsy cases that were histologically diagnosed as IDP between 1997 and 2013. The re-evaluated diagnosis was IDP without atypia in 79 (54%) patients, IDP with atypia in 66 (45%), and ductal carcinoma in situ (DCIS) in 1 (1%). Among the 34 patients (23%) who underwent surgical excision subsequent to core biopsy, histological diagnosis was upgraded to carcinoma, excluding lobular carcinoma in situ (LCIS), in 14 (41%) cases, including 4 (33%) of 12 IDPs without atypia and 10 (45%) of 22 IDPs with atypia. Complete surgical excision should be kept in mind for all IDPs diagnosed on core biopsy, not only IDPs with atypia but IDPs without atypia, especially when clinical or imaging diagnosis findings cannot rule out the possibility of malignancy, because papillary lesions comprise a variety of morphological appearances.

Since breast cancers in young women are generally aggressive, young patients tend to be intensively treated with anti-cancer drugs. To optimize the strategy for treatment, particularly in young women, prognostic biomarkers are urgently required. The objective of this study was to identify a tissue microRNA (miRNA) signature that predicts prognosis in young breast cancer patients. Total RNA from 45 breast cancer patients aged 0.7. Five of the miRNAs were validated by qRT-PCR, and the expression levels of three of those five (miR-183-5p, miR-194-5p, and miR-1285-5p), both alone and in combination, were associated with OS. In conclusion, we identified three candidate miRNAs that could be used separately or in combination as prognostic biomarkers in young breast cancer patients. This miRNA signature may enable selection of better treatment choices for young women with this disease.