Breast cancer survival among Japanese individuals and US residents of Japanese and other origins: a comparative registry-based study.

BACKGROUND: Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). METHOD: Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. RESULTS: We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ). CONCLUSIONS: In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

Association between variations in the number of hospital beds and inpatient chemo/radiotherapy for breast cancer: a study using a large claim database.

OBJECTIVE: Chemo/radiotherapy for breast cancer patients does not require hospitalisation in most cases. We investigated the relationship between the proportion of hospitalisation for chemo/radiotherapy over total hospitalisation and the number of hospital beds per capita among breast cancer cases. DESIGN: A retrospective observational study. SETTING: Hospitals in Japan. PARTICIPANTS: In total, 561,165 records of hospitalisation of breast cancer cases were extracted from the Japanese Diagnosis Procedure Combination database from April 2012 to March 2016.Intervention(s) and main outcome measure(s): A multivariable beta regression model accounting for the clustering effect within each prefecture was used to examine the relationship between the number of hospital beds per capita in each prefecture and the proportion of hospitalisation for inpatient chemo/radiotherapy treatment or the number of surgical operations for breast cancer patients in each prefecture. RESULTS: The proportion of hospitalisation for inpatient chemo/radiotherapy treatment varied from 2.6% to 61.8% in 2016. The logit proportion of hospitalisation for inpatient chemo/radiotherapy treatment was significantly higher for every additional hospital bed per capita (0.0027, 95% confidence interval (95% CI) 0.0014-0.0040). In contrast, no significant relationship was observed between the number of surgical operations for breast cancer per capita and the number of hospital beds per capita. CONCLUSIONS: We found that a higher number of regional hospital beds were associated with a higher proportion of hospitalisation for chemo/radiotherapy treatment, suggesting that inpatient chemo/radiotherapy may be a provider-induced practice.

Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis.

PURPOSE: Though advanced and metastatic epidermal growth factor receptor 2 (HER2)-positive disease is not curable, a small proportion of patients with HER2-positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab. METHODS: We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated. RESULTS: The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression-free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor's recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9-9.3 years). CONCLUSION: We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial.

Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients.

The presence of tumor-infiltrating lymphocytes (TILs) is associated with favorable long-term outcome in breast cancer. However, little is known about changes in TILs during metastatic progression. To confirm our hypothesis that malignant tumors escape from the host immune system during metastasis, we evaluated the percentage of TILs in paired samples of primary and metastatic breast tumors. We retrospectively identified 25 patients with human epidermal growth factor receptor-2 (HER2+ , n = 14) and triple negative (TN, n = 11) early breast cancer diagnosed between 1990 and 2009 at Tokai University Hospital (Isehara, Japan) and who subsequently experienced regional or distant recurrence confirmed by tumor biopsy/resection. Hematoxylin-eosin-stained slides of these paired samples were evaluated for stromal TILs. Immunohistochemical staining was carried out using primary antibodies against CD4, CD8, Foxp3, programmed cell death ligand 1 (PD-L1), PD-L2, and HLA class I for characterizing the TILs and breast tumors. The percentage of TILs in the primary tumors was significantly higher (average 34.6%) than that in metastatic tumors (average 15.7%) (paired t-test, P = 0.004) and that of CD8+ and CD4+ T cells significantly decreased from primary to metastatic tumors (paired t-test, P = 0.008 and P = 0.026, respectively). The PD-L1, PD-L2, and HLA class I antibody expression changed from positive to negative and vice versa from the primary to the metastatic tumors. Tumors at first metastatic recurrence in HER2+ and TN breast cancers have a lower percentage of TILs and CD8+ and CD4+ T cells compared to primary tumors, which indicates that immune escape plays a role in tumor progression.

Feasibility and pharmacokinetics of combined therapy with S-1 and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic or recurrent breast cancer.

BACKGROUND: To clarify the tolerance and pharmacokinetics of combined therapy with S-1 and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic or recurrent breast cancer. METHODS: From January 2008 through to September 2009, combined therapy with S-1 and trastuzumab was given to 7 patients with HER2-positive metastatic or recurrent breast cancer. The incidence of adverse events and the pharmacokinetics of tegafur, 5-fluorouracil, and gimeracil in plasma were studied. RESULTS: One patient had grade 3 leukopenia, and another had a grade 3 elevation of alanine aminotransferase. All other adverse events were grade 2 or lower. The combination of S-1 and trastuzumab did not cause any new adverse events. The incidence of adverse events was similar to those associated with S-1 alone. The median number of treatment cycles was 11. The pharmacokinetics of tegafur, 5-fluorouracil, and gimeracil after treatment with S-1 plus trastuzumab did not markedly differ from those after S-1 alone. CONCLUSIONS: Combined therapy with S-1 and trastuzumab did not cause any new adverse events, administration continuity was good, and the therapy was well tolerated.

Impact of Subtype on Survival of Young Patients With Stage IV Breast Cancer.

BACKGROUND: Although younger age is a negative prognostic factor for patients with early stage breast cancer, data regarding the outcomes of young patients with stage IV disease are limited. We evaluated differences in overall survival (OS) according to age and disease subtype among patients with stage IV breast cancer. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER) data, we identified 6,302 patients aged < 60 years with de novo stage IV breast cancer between 2010 and 2014. We examined age-specific OS among hormone receptor (HR)-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative (HER2-), HR+/HER2-positive (HER2+), HR-negative (HR-)/HER2+, and triple-negative cases using log-rank tests and Cox proportional hazards models, adjusting for relevant clinical and demographic variables. RESULTS: Compared with patients aged 40 to 59 years, patients aged < 40 years (n = 944; 15%) had a higher proportion of HER2+ cancers and a lower proportion of HR+/HER2- disease (P < .001), but a similar proportion of triple-negative disease. Patients aged < 40 years also experienced significantly longer survival, with a median OS of 45 months (vs. 33 months). Further, after stratification by subtype, patients aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. These survival differences persisted in adjusted analyses. CONCLUSIONS: Compared with those aged 40 to 59 years, patients with de novo metastatic breast cancer aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. Distinct treatment-related or biological factors may exist between earlier stage and metastatic breast cancers; further examination of the potential reasons for our findings are warranted.

Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.

Comparison of Ki-67 labeling index measurements using digital image analysis and scoring by pathologists.

BACKGROUND: Routine analysis of Ki-67 is not widely recommended for clinical decision-making because of poor reproducibility. Furthermore, counting numerous cells can be laborious for pathologists. Digital image analysis for immunohistochemical analysis was recently developed; however, the clinical efficacy of the Ki-67 index obtained using image analysis is unknown. METHODS: We retrospectively identified female patients with breast cancer with immunohistochemical Ki-67 and survival data using the pathology database at the Tokai University, Japan. Ki-67 expression was scored by three pathologists. Slides were scanned and converted to virtual slides; Ki-67-positive cells were counted using image analysis. Ki-67 indices obtained by the pathologist's scoring and image analysis were evaluated by 2 × 2 analysis. Relationships between Ki-67 index and survival outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Based on the 2 × 2 analysis, Ki-67 index obtained using image analysis was moderately correlated with the pathologist's scoring for all patients (κ 0.41; sensitivity, 0.573; specificity, 0.878). Poorer relapse-free survival was associated with high Ki-67 index than with low Ki-67 index for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and stage I or II patients scored by pathologists (p < 0.001) and obtained using image analysis (p = 0.031). CONCLUSIONS: The Ki-67 indices obtained using image analysis were moderately correlated with those scored by pathologists. Digital image analysis can be effective for measuring Ki-67 values, because they are associated with relapse-free survival in estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and patients at stage I or II.

B-cell populations are expanded in breast cancer patients compared with healthy controls.

BACKGROUND: Historically, humoral immunity was considered unimportant in anti-tumor immunity, and the differentiation and anti-tumor activity of B cells in breast cancer are poorly understood. However, it was recently discovered that B cells participate in tumor immunity through both antibody production and immunosuppressive mechanisms. We analyzed the expression of B-cell differentiation markers in detail using fluorescence-activated cell sorting to investigate the relationship between B-cell subsets and breast cancer etiology. METHODS: Blood samples were taken from breast cancer patients and healthy donors, and peripheral blood mononuclear cells were collected. B cells at various stages of differentiation were identified by the expression of combinations of the cell surface markers CD5, CD19, CD21, CD24, CD27, CD38, CD45, and IgD. Statistical analysis of the proportions of each B-cell subtype in the different patient groups was then performed. RESULTS: Twenty-seven breast cancer patients and 12 controls were considered. The proportion of total B cells was significantly higher in cancer patients than in controls (11.51 ± 2.059 vs 8.905 ± 0.379%, respectively; p = 0.001). Breast cancer patients were then classified as High-B or Low-B for further analysis. A significantly higher proportion of memory B cells was found in the High-B group than in the Low-B or control groups (p = 0.003 and p = 0.043, respectively). CONCLUSIONS: Breast cancer patients generally have a higher proportion of B cells than healthy controls, but this is highly variable. Analysis of the major B-cell surface markers indicates that memory B cells in particular are significantly expanded, or more robust, in breast cancer patients.

Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer.

BACKGROUND: Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. RESULTS: The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1-70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04). MATERIALS AND METHODS: We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed. CONCLUSIONS: There are significantly fewer TILs in brain metastases than in primary breast tumors.

Diagnostic performance of (18)F-fluorodeoxyglucose PET/CT and bone scintigraphy in breast cancer patients with suspected bone metastasis.

BACKGROUND: We prospectively compared the diagnostic accuracies of PET/CT and BS in patients with suspected bone metastases from breast cancer. METHODS: This single-institution prospective study included consecutive patients with suspected bone metastases from biopsy-proven breast cancer seen at Tokai University Hospital between September 2011 and March 2014. Inclusion criteria included suspicions for bone metastases (bone pain, elevated alkaline phosphatase, elevated tumor markers, or suspected bone metastases by BS). Two nuclear medicine physicians evaluated PET/CT and BS images. RESULTS: Thirty patients were initially enrolled in this study. Two were excluded from the analyses because they declined to undergo imaging during follow-up. PET/CT successfully detected bone metastases in all 10 patients finally diagnosed with the condition, whereas BS identified 2. The two methods were not highly concordant in detecting osseous metastases. In 19 of 28 paired studies (68 %), 2 (10 %) were positive for metastasis, and 17 (90 %) were negative. Nine occurrences (32 %) were discordant; of these, 2 were PET/CT positive and BS negative; 5 were PET/CT positive and BS equivocal; one was PET/CT negative and BS equivocal, and one was PET/CT equivocal and BS negative. CONCLUSIONS: Our results indicated that PET/CT was superior to BS for the diagnosis of bone metastases. On the basis of the results of previous studies as well as ours, PET/CT could replace BS as the initial modality to detect bone metastases in patients suspected for the condition.

A Case of Giant Borderline Phyllodes Tumor of the Breast Associated with Hypoglycemia.

We report a patient with a giant phyllodes tumor of the right breast associated with a hypoglycemic attack. A 48-year-old woman experienced a loss of consciousness and was transferred via ambulance to our hospital emergency department. Upon arrival, her blood glucose level was 26 mg/dl, and a giant tumor (>20 cm in diameter) with skin ulceration was observed on the right breast. Core needle biopsy led to a histological diagnosis of a phyllodes tumor of the breast. Ultrasonography and computed tomography detected neither distant metastasis nor a pancreatic endocrine tumor. Her preoperative serum insulin-like growth factor (IGF)-II and insulin levels were 1,330 ng/ml (normal range, 519-1067 ng/ml) and <1.0 µU/ml, respectively. Following a simple mastectomy, the 24-h postoperative serum IGF-II and insulin levels were 496 ng/ml and 10.0 µU/ml, respectively. The IGF-II levels detected in the phyllodes tumor and normal breast tissue were 10,600 ng/Wg (wet weight in grams) and 855 ng/Wg. We conclude from these findings that the hypoglycemic attack was related to the elevated IGF-II level in the giant phyllodes tumor of the breast.

Platypnea-orthodeoxia syndrome caused by a latent atrial septal defect.

A 79-year-old woman presented with unexplained hypoxia that became exacerbated by an upright posture (platypnea-orthodeoxia syndrome). A (99m)Tc-macroaggregated albumin pulmonary perfusion scan revealed a right to left shunt of 25.5% in the supine position and 32.3% in the sitting position. A dynamic CT scan and a transoesophageal echocardiogram confirmed the presence of a shunt across an atrial septal defect (ASD). A percutaneous transcatheter closure of the defect significantly improved the patient's blood oxygenation levels when she was in the upright position. An ASD should therefore be included in the differential diagnosis of platypnea-orthodeoxia syndrome, regardless of the patient's age.