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Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the "PS3," "PM2," "PM3," and "PP3" criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a "likely pathogenic" variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Although various diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human tumor cell lines, little information is available regarding the antiproliferative effects of C 20 -diterpenoid alkaloids against MCF-7 cells. Six new diterpenoid alkaloid derivatives (13, 14, 22, 23, 25, 26) were prepared by C-11 and 15 esterification of kobusine (6). The natural parent alkaloid 6 and all synthesized derivatives (7 - 27, 12a, 15a, 15b, 18a, 18b) were evaluated for antiproliferative activity against MCF-7 cells. The structure-based design strategy resulted in an initial lead derivative, 11,15-dibenzoylkobusine (7; IC 50 8.6 µM). Subsequent synthesized 11,15-diacylkobusine derivatives (9, 16, 20, 21, 23, 25, and 26) showed substantially increased suppressive effects against the MCF-7 cell line (IC 50 2.3-4.4 µM). In contrast, parent alkaloid 6, two 11-acylkobusine derivatives (15a, 18a), and two 15-acylkobusine derivatives (15b, 18b) showed no effect. 11,15-Diacylation appears to be critical for producing antiproliferative activity in this alkaloid class and could introduce a new avenue in overcoming breast cancer cell proliferation using natural product derivatives. In a preliminary mechanism of action study, representative derivatives (5, 8, 9, and 17) decreased cyclin D1 mRNA expression., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Background: Persistent post-surgical pain (PPSP) is associated with upper limb dysfunction and decreased quality of life and causes long-term suffering for breast cancer survivors after surgery. However, the predictors of PPSP remain unclear. The purpose of this study was to examine predictors of PPSP intensity and interference at 1 year postoperatively, focusing on treatment-related factors, pre- and postoperative central sensitization (CS), CS-related symptoms (e.g., muscle stiffness, fatigue, sleep disturbances), and psychological factors., Methods: Eighty-eight women with planned unilateral breast cancer surgery were included in this longitudinal study. CS, CS-related symptoms, and psychological factors were assessed preoperatively, 1 month postoperatively, and 1 year postoperatively. Analysis of covariance was used to compare the groups with and without PPSP, accounting for treatment-related factors. Multiple regression analysis was performed to identify predictors of PPSP intensity and interference at 1 year postoperatively., Results: Even after adjusting for covariates, preoperative and 1-month postoperative Central Sensitization Inventory scores in the PPSP group were significantly higher than scores in the group without PPSP. Multiple regression analysis showed that axillary lymph node dissection (ALND) and 1-month postoperative CS-related symptoms were independent predictors of PPSP intensity and interference at 1 year postoperatively (p < 0.01)., Conclusion: We found that ALND and 1-month postoperative CS-related symptoms were predictors of PPSP intensity and interference at 1 year postoperatively., (© 2022. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Background/aim: A subset of patients with estrogen receptor (ER)-positive, HER2-negative, and node-negative breast cancer experience recurrences. Predicting patients who will have recurrences within 5 years of surgery is essential so that patients can be selected to receive adjuvant chemotherapy. The 95-gene classifier (95-GC) has been validated as a method to differentiate patients into high and low-risk groups for early recurrence., Patients and Methods: In this study, we performed 95-GC analysis on 56 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients who underwent surgery for ER-positive, HER2-negative, and node-negative breast cancer and did not receive adjuvant chemotherapy. We associated the obtained high- and low-risk groups with clinicopathological characteristics and recurrence-free survival (RFS)., Results: We classified 12 out of 56 patients into the high-risk recurrence group. We found significantly higher KI67 scores in patients in the high-risk group. Other clinicopathological characteristics were not associated with the 95-GC risk groups. Patients in the 95-GC low-risk group had a significantly better prognosis than those in the high-risk group (p=0.0387). The 5-year RFS rate was 97.6% in the low-risk group and 74.1% in the high-risk group, while the 10-year RFS rates were 90.1% and 74.1%, respectively., Conclusion: The 95-GC score can accurately predict RFS within 5 years of surgery for ER-positive, HER2-negative, and node-negative breast cancer using FFPE tissue samples. These prediction models could help assign patients to the most effective treatment regimen., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence., Methods: The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model., Results: A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years)., Conclusion: The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort., Methods: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing., Results: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations., Conclusion: Our results reveal diversity within each individual during breast cancer progression., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration., Methods: In total, 143 patients with breast cancer who received docetaxel (75 mg/m 2 ) or paclitaxel (175 mg/m 2 )-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated., Results: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences., Conclusion: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Central sensitization (CS)-related symptoms and pain catastrophizing contribute to persistent post-mastectomy pain (PPMP). Pain neuroscience education (PNE) is effective in reducing CS-related symptoms and pain catastrophizing in patients with chronic pain. However, to date, no intervention study of PNE has been conducted to patients with PPMP. This study was aimed to examine whether PNE is more effective than biomedical education (BME) for PPMP., Methods: In this retrospective case-control study, 118 patients were included. We intervened different patients at different times as follows: (1) a BME group (n = 58) of patients who received BME combined with physiotherapy and (2) a PNE group (n = 60) of patients who received PNE combined with physiotherapy. One year after surgery, we assessed pain intensity and interference (brief pain inventory [BPI]), CS-related symptoms (central sensitization inventory [CSI]), and pain catastrophizing (pain catastrophizing scale [PCS]). Propensity score matching was used to reduce or minimize selection bias and confounding biases and to make the number of cases in both groups match 1:1., Results: Propensity score matching generated the BME group (n = 51) and the PNE group (n = 51). The BPI score, CSI score, and PCS score were statistically significantly lower in the PNE group than in the BME group (all, p < 0.05). The effect sizes for the BPI intensity (r = 0.31) were moderate., Conclusions: PNE resulted in a better outcome of pain management with less functional disability and CS-related symptoms compared to BME after breast surgery., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Background: Orbital metastases from cancers of various organs can arise via the hematogenous route, and many originate from breast, prostate, and lung cancers. Such metastatic orbital tumors may be diagnosed before the primary tumor. We have encountered a case of breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and responded to chemotherapy, with improvement in visual function., Case Presentation: A woman in her fifties visited our ophthalmology department with a chief complaint of foreign body sensation and exophthalmos in her right eye. An elastic soft mass was palpated from the lateral orbit to the temporal region. A systemic examination revealed breast cancer and a metastatic orbital tumor. Excisional biopsy of the breast revealed a diagnosis of invasive ductal carcinoma with neuroendocrine differentiation, and immunohistochemical examination was negative for cytokeratin 7, making the case unusual. Chemotherapy was remarkably effective, and the tumor size decreased, resulting in improvement of visual function. Her general condition and quality of life are still good at present. We searched the PubMed English language literature focusing on metastatic orbital tumors from breast cancer in which ocular symptoms had been the initial presenting sign. No previous reports have documented neuroendocrine differentiation or cytokeratin 7 expression in isolated orbital metastases from breast cancer. Although it is not possible to be certain from this case alone, we speculated that some such cases might involve cytokeratin 7-negative invasive breast cancer with neuroendocrine differentiation., Conclusion: We have described our experience of a very rare case of cytokeratin 7 negative breast ductal carcinoma with neuroendocrine differentiation that metastasized to the orbit and formed a solitary giant tumor initially manifesting as ocular symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Togashi, Nishitsuka, Hayashi, Namba, Goto, Takeda, Suzuki, Kato, Yamada, Konno, Yoshioka, Yamakawa, Sonoda, Suzuki and Yamashita.)

Objectives: Our newly developed brief collaborative care intervention program has been suggested to be effective in reducing breast cancer patients' unmet needs and psychological distress; however, there has been no controlled trial to investigate its effectiveness. The purpose of this study was to examine the effectiveness of the program in relation to patients' perceived needs and other relevant outcomes for patients including quality of life, psychological distress and fear of recurrence (Clinical trial register; UMIN-CTR, Clinical registration number; R5172)., Methods: Fifty-nine highly distressed breast cancer patients receiving adjuvant chemotherapy and/or hormonal therapy were randomly assigned either to a treatment as usual group or to a collaborative care intervention, consisting of four sessions that mainly included assessment of the patients' perceived needs, learning skills of problem-solving treatment for coping with unmet needs and psycho-education provided by trained nurses supervised by a psycho-oncologist., Results: Although >80% of the eligible patients agreed to participate, and >90% of participants completed the intervention, there were no significant differences with regard to patients' needs, quality of life, psychological distress and fear of recurrence, both at 1 and 3 months after intervention., Conclusion: Newly developed brief collaborative care intervention program was found to be feasible and acceptable. The trial, however, failed to show the effectiveness of the program on patients' relevant subjective outcomes. Further intervention program having both brevity and sufficient intensity should be developed in future studies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Background: Multimorbidity is associated with a high mortality rate and low health-related quality of life. Previous studies have indicated that multimorbidity tends to be associated with not receiving cancer screening, although this association remains unclear. This study aimed to investigate the associations between multimorbidity and the delivery of breast, cervical, and colorectal cancer screening in Japan, and to identify subgroups that did not receive cancer screening., Methods: This study used cross-sectional data from the 2016 Comprehensive Survey of Living Conditions, which used a stratified random sample of the general Japanese population. Multivariable logistic regression models were used to evaluate the associations between the number of chronic conditions and each cancer's screening proportion. The relevant covariates included age, marital status, education level, occupation, and household income., Results: Relative to subjects with no chronic conditions, subjects with two chronic conditions received more screening for breast, cervical, and colorectal cancers (breast cancer, adjusted odds ratio [aOR]: 5.42, 95% confidence interval [CI]: 2.80-10.5; cervical cancer, aOR: 4.59, 95% CI: 2.03-10.4; male colorectal cancer, aOR: 3.26, 95% CI: 1.29-8.24; female colorectal cancer, aOR: 1.05, 95% CI: 0.39-2.81). Low socioeconomic status was associated with not receiving any type of cancer screening consistently., Conclusion: Multimorbidity and high socioeconomic status were associated with higher proportions of screening for breast, cervical, and colorectal cancers in the Japanese population. More aggressive strategies may be needed to promote screening among Japanese individuals with no chronic conditions and individuals with low socioeconomic status., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely used in patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report a breast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving anti-cancer therapies.

The characteristic adverse events of olaparib, a PARP inhibitor, are nausea, vomiting, and anemia, and interstitial pneumonia is rarely reported. We report a case of interstitial pneumonia following the treatment of a metastatic breast cancer with olaparib. The patient was a 34-year-old woman. In March 2018, she was diagnosed with stage Ⅳ breast cancer(multiple lung metastases). She was treated with epirubicin and cyclophosphamide followed by paclitaxel. In November 2018, brain and spinal cord metastases were detected, and she was treated with radiation. In December 2018, a BRCA1 deleterious mutation was confirmed, and treatment with olaparib was initiated. Six weeks later, olaparib was discontinued due to anemia; it also caused interstitial pneumonia. The interstitial pneumonia resolved following multidisciplinary treatment during hospitalization. Subsequently, she was treated with cyclophosphamide/methotrexate/fluorouracil. It is necessary to consider interstitial pneumonia as an adverse effect of olaparib.

Background: Because primary squamous cell carcinoma (SCC) of the breast is a rare disease, the standard therapy has not been established. We examined the clinical outcomes of postoperative adjuvant radiotherapy for breast SCC., Material and Methods: We conducted a multicenter retrospective cohort study. Patients diagnosed with primary breast SCC who received adjuvant radiotherapy as part of their primary definitive treatment were included. Overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free interval (RFi) were evaluated., Results: Between January 2002 and December 2017, 25 breast SCC patients received adjuvant radiotherapy as a primary treatment were included. Median follow-up time was 43.5 months. Three (12%), fifteen (60%) and seven (28%) patients had clinical stage I, II and III disease, respectively. Fourteen patients underwent breast-conserving surgery and subsequent adjuvant radiotherapy. Eleven patients underwent mastectomy and post-mastectomy radiotherapy. Ten patients received regional lymph node irradiation. Nine (36%) patients had disease recurrence. The first site of recurrence was locoregional in five, but distant metastasis arose in one. Concurrent local and distant metastasis were seen in two. Six cases of local recurrence occurred within the irradiated site. Seven patients died, and six of the deaths were due to breast cancer. Five-year OS, BCSS, and Rfi were 69%, 70%, and 63%, respectively. In multivariate analysis, age and lymphatic invasion were associated with increased risk of recurrence., Conclusion: Breast SCC has a high incidence of locoregional recurrence and poor prognosis. Age and lymphatic invasion are significant risk factors for recurrence., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We report the case of a 44-year-old male who underwent mastectomy plus axillary lymph node dissection after neoadjuvant chemotherapy for left breast cancer. During adjuvant therapy, multiple bone metastases and pericardial effusion were detected. Pericardial drainage was mandated for the patient, although no malignant cells were found. Despite the change in treatment, pericardial effusion worsened. Based on clinical findings, the patient was diagnosed with carcinomatous pericarditis and was switched to bevacizumab plus paclitaxel therapy. CT at 5 months showed improved pericardial effusion; treatment is ongoing.

Background: Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients., Methods: OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study., Results: A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age (< 60 years), longer time from ABC diagnosis to fulvestrant use (≥ 3 years), no prior palliative chemotherapy before fulvestrant use, and progesterone receptor (PgR) negativity (PgR-) were significantly correlated with prolonged OS (median 7.0 years). For cases with histological or nuclear grade data, lower histological or nuclear grades were also correlated with longer OS. In recurrent metastatic cases, long disease-free interval (DFI) was not correlated with longer OS., Conclusions: In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR-, and lower histological or nuclear grade correlated positively with prolonged OS.

Background: In Japan, with the rapid increase of breast cancer patients, there has been increasing demand for breast cancer treatment. As the main workforce for breast cancer treatment, women physicians are thought to be in key positions, since the number of women physicians has recently been increasing., Methods: To clarify the current statuses and issues of physicians and work conditions at the accredited breast cancer care facilities, a survey was conducted by the Japanese Breast Cancer Society (JBCS)., Results: The main workforces engaged in breast cancer care are surgeons, and the number of breast surgeons of all institutions in this survey was 1338 (full time 1124, part time 214). The percentages of women among surgeons, breast specialists accredited by the JBCS, and residents are 22%, 25%, and 38%, respectively. Among breast specialists, more women tended to work at university hospitals and cancer hospitals. Twenty-eight percent of women were married and among those, 76% had at least one child. Many hospitals allow short working hours or exemption from in-house call for women surgeons during pregnancy and child-rearing. In contrast, half of the facilities apply a "single doctor-in-charge system", where the patient's primary physician has to be on-call every day. Many institutions convene conferences for breast cancer treatment planning before or after the scheduled working hours., Conclusions: Current systems for treatment of breast cancer should be improved so that all surgeons specializing in the breast can develop their career while maintaining their personal life.

Background/aim: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse., Materials and Methods: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53., Results: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women., Conclusion: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its differentiation from metastases to the pancreas from other organs remains challenging. We report a case in which immunohistochemical staining for MUC5AC was useful in distinguishing primary pancreatic cancer from breast cancer metastasis. A 51-year-old Japanese woman who underwent curative resection of her breast cancer was referred to our hospital with a pancreatic head tumor. Although we surmised her pancreatic tumor to be metastatic breast cancer based on her past history and imaging studies, she was subsequently diagnosed with PDAC on the basis of immunohistochemical staining for MUC5AC using specimens obtained by endoscopic ultrasound-fine-needle aspiration. Thus, MUC5AC may be a useful diagnostic marker for discriminating PDAC from a secondary malignancy., (© 2019 Wiley Periodicals, Inc.)

Background: We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC., Methods: Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated., Results: Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 ± 110.9 vs. 1022.2 ± 250.0 × 10 - 6  mm 2 /s, p = 0.027, minimum 696.7 ± 128.0 vs. 925.0 ± 257.6 × 10 - 6  mm 2 /s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC., Conclusions: The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV.

Background: Expression of estrogen receptor α in breast cancer is essential for estrogen-dependent growth and partially determines the breast cancer subtype. In premenopausal women, expression of estrogen-regulated genes in estrogen receptor-positive breast cancer tissues are reportedly influenced by the menstrual cycle., Methods: We investigated correlations between serum estradiol (E2; tested on the day of surgery) and expression of estrogen-regulated genes and proliferation genes in strongly estrogen receptor α-positive breast cancer tissues from 91 premenopausal women by quantitative reverse transcription-polymerase chain reaction. We also investigated correlations between serum progesterone levels on the day of surgery and mRNA expression of progesterone-regulated genes and proliferation genes., Results: The serum E2 level affected expression of estrogen-regulated genes, including progesterone receptor (P = 0.016, Rs = 0.07) but showed no correlation with expression of genes associated with proliferation. We also observed strong positive correlations between mRNA expression of ESR1 and that of estrogen-regulated genes (P < 0.0001, Rs = 0.329-0.756) and proliferation genes (P < 0.0001, Rs = 0.753-0.843). The serum progesterone level affected expression of RANKL mRNA. However, we observed no correlations between serum progesterone and expression of Wnt-4 or proliferation genes., Conclusions: The serum E2 level on the day of surgery influences estrogen-regulated gene expression moderately in patients found to be strongly positive for estrogen receptor α by immunohistochemistry. Changes in serum E2 levels might influence the results of molecular profiling tests in premenopausal women with breast cancer.

Background: We conducted an open-label, randomized controlled trial evaluating the appropriate treatment duration of leuprorelin acetate 3-month depot, TAP-144-SR (3M), administered postsurgically every 3 months for 2 years versus 3 or more (up to 5) years, in combination with tamoxifen, for 5 years in premenopausal endocrine-responsive breast cancer patients and reported similar survival benefit in the two treatment groups. We hereby present patient-reported quality of life (QOL) data obtained from this trial., Methods: Three self-administered QOL questionnaires (QOL-ACD, QOL-ACD-B, FACT-ES subscale) were used, and the difference in QOL score changes between the two groups was analyzed using a mixed-effects model for repeated measures., Results: Eligible patients (N = 222) were randomly assigned to a 2-year (2YG, N = 112) or 3-or-more-year treatment group (3YG, N = 110). The time courses of the three QOL scores during the trial period were similar in the two groups. The mean changes in the QOL scores from week 96 were largely stable through week 240 in the 3YG, but showed significantly greater improvement in the score changes from week 96 in the 2YG than the 3YG. Symptoms associated with menopause such as hot flashes and sweating contributed to these results. Menstruation recovery was associated with significantly greater improvement of these symptoms in the 2YG than the 3YG., Conclusions: Patient-reported menopause-associated symptoms and QOL improved after discontinuation of the LH-RH agonist administration and menstruation recovery. QOL information should be a consideration in long-term treatment.

Estrogen receptor(ER)-positive breast cancer accounts for approximately 80%of all breast cancers. The basic concept of endocrine therapy is to deplete estrogen(LH-RH agonist and aromatase inhibitor)and inhibit the action of estrogen against estrogen-dependent growth in ER-positive breast cancer. Recently, new molecular targeting agents, including an mTOR inhibitor and a CDK4/6 inhibitor, have been used in combination with endocrine therapy for the treatment of ER-positive metastatic breast cancer.

Objective: The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2-) cases., Methods: The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p < .001), no prior chemotherapy (p < .001), and F500 treatment line (p < .001) were correlated with prolonged TTF (median = 5.39 months)., Conclusions: In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer., Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed., Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months., Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating full-field digital mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Phantom validations reached an R 2 of 0.993. Intra-patient validations ranged from R 2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R 2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Objective: This study aimed to investigate the feasibility of an intervention program for women with breast cancer undergoing adjuvant anticancer therapy, and determine its preliminary effectiveness in reducing their unmet needs and psychological distress., Methods: The intervention was based on the collaborative care model, and compromised four domains: identification of unmet needs, problem-solving therapy and behavioral activation supervised by a psychiatrist, psychoeducation and referral to relevant departments. Eligible women with breast cancer were provided the collaborative care intervention over four sessions. The feasibility of the program was evaluated by the percentage of women who entered the intervention and by the percentage of adherence to the program. Self-reported outcomes were measured by the Supportive Care Needs Survey-Short Form 34 (SCNS-SF34), the Profile of Mood States (POMS), the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Concern about Recurrence Scale, and pre- and post-intervention satisfaction with medical care., Results: In total, 40 patients participated in this study. The rate of participation in the intervention was 68%, and the rate of adherence was 93%. Participants had significantly improved scores on total perceived needs, physical needs and psychological needs on the SCNS-SF34; vigor and confusion on the POMS and function (physical, emotional and cognitive), nausea and vomiting, dyspnea, appetite loss and financial difficulties on the EORTC QLQ-C30 compared with the baseline assessment., Conclusions: Our findings indicated the intervention program was feasible. Further study is needed to demonstrate the program's effectiveness in reducing unmet needs., (© The Author 2016. Published by Oxford University Press.)

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer., Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than 10 years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age., Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy., Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Background: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown., Methods: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group., Results: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059)., Conclusions: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

Purpose: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer., Methods: The NF-κB/p65 expression and the effects of a NF-κB inhibitor, (-)-DHMEQ, were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed for their expression of NF-κB/p65, Bcl2 and Ki67 by immunohistochemistry in pre- and post-treatment specimens. The factors predicting the response to neoadjuvant chemotherapy and the prognosis were analyzed., Results: NF-κB/p65 was predominantly expressed in the cytoplasm of MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in seven tumors before neoadjuvant chemotherapy, while the expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. The expression levels of NF-κB/p65 were not associated with the response to neoadjuvant chemotherapy, although the cytoplasmic NF-κB/p65 staining intensity was significantly decreased in the post-treatment tumor samples compared with the pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease free., Conclusion: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker for patients with triple-negative breast cancer.

Background: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies., Methods: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated., Results: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms., Conclusions: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Background: Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin., Methods: We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety., Results: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2., Conclusions: Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.

Human chromosome 21 is known to be associated with the high risk of hematological malignancy but with resistance to breast cancer in the study of Down syndrome. In human cancers, we previously observed the significant alterations of the protein expression encoded by the ganp/MCM3AP gene on human chromosome 21q22.3. Here, we investigated GANP protein alterations in human breast cancer samples (416 cases) at various stages by immunohistochemical analysis. This cohort study clearly showed that expression of GANP is significantly decreased in human breast cancer cases with poor prognosis as an independent risk factor (relapse-free survival, hazard ratio = 2.37, 95% confidence interval, 1.27-4.42, P = 0.007 [univariate analysis]; hazard ratio = 2.70, 95% confidence interval, 1.42-5.13, P = 0.002 [multivariate analysis]). To investigate whether the altered GANP expression is associated with mammary tumorigenesis, we created mutant mice that were conditionally deficient in the ganp/MCM3AP gene using wap-cre recombinase transgenic mice. Mammary gland tumors occurred at a very high incidence in female mammary gland-specific GANP-deficient mice after severe impairment of mammary gland development during pregnancy. Moreover, tumor development also occurred in female post parous GANP-heterodeficient mice. GANP has a significant role in the suppression of DNA damage caused by estrogen in human breast cancer cell lines. These results indicated that the GANP protein is associated with breast cancer resistance., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment., Methods: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601)., Results: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14% and 52% of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25% vs 67% for clinical response, p = 0.011, N = 51; 0% vs 41% for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not., Conclusions: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE., Trial Registration: UMIN C000000345 (2006/03/06).

Purpose: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes., Methods: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes., Results: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p=0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p=0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748×10(-6)mm(2)/s; p<0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702×10(-6)mm(2)/s; p<0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors., Conclusion: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study investigates the prevalence of clinical anxiety, the possible impact of patients' anxiety on quality of life and the association between their anxiety levels and patients' perceived needs., Methods: Randomly selected disease-free patients with breast cancer who survived >2 years were invited to participate in the study. The participants were asked to complete the Hospital Anxiety and Depression Scale, the European Organization for Research and Treatment of Cancer QLQ-C 30 and the Short-form Supportive Care Needs Survey questionnaire, which covers five domains of need (health system and information, psychological, physical, care and support and sexuality needs)., Results: Complete data were available for 146 of the patients, and 14% of them suffered from clinical anxiety. Anxiety score had a statistically significant correlation with all domains of quality-of-life measures. The only perceived need that was significantly associated with anxiety was the psychological domain., Conclusions: Not negligible patients may suffer from clinical anxiety >2 years after their initial cancer diagnoses. Anxiety can impact on patients' quality of life, and unmet psychological needs are expected to increase anxiety levels. Management of anxiety could be one of the key components to improving the quality of life for breast cancer survivors and that reducing their unmet psychological needs may contribute to alleviating anxiety., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Employed cancer patients confront some challenges as they attempt to return to work after treatment. We aimed to identify correlates of return to work for cancer survivors in Japan, with an emphasis on employment status. Participants were 260 patients (aged <65 years) who had received a cancer diagnosis ≥ 1 year previously and who were employed at the time of diagnosis. Participants completed questionnaires at consultations at any Regional Cancer Center Hospitals in Yamagata, Japan between 28 November 2011 and 9 December 2011. Logistic regression analysis was used to identify correlates of return to work. Data cross-tabulation was used to evaluate relationships to workplace and income-changes by employment status. A high proportion of patients (75.8%) had returned to work. Non-regularly employed survivors were less likely to return to work (odds ratio = 5.03; 95% confidence interval, 1.18-21.35). Individuals with poor health, advanced-stage tumours, of advanced age and women were significantly less likely to return to work. Only 52.8% of non-regular employees continued to be employed, and their income decreased by as much as 61.1%. Social and financial support policies should be organised based on more intensive study of employment circumstances., (© 2015 John Wiley & Sons Ltd.)

Purposes: We conducted a study to analyze the clinicopathological characteristics of breast cancer in Japan registered to the Japanese Breast Cancer Registry of the Japanese Breast Cancer Society (JBCS). Trends in the management of breast cancer patients in Japan were also analyzed., Patients and Methods: More than 250,000 breast cancer patients were registered to the JBCS registry between 2004 and 2011. Demographic and clinicopathological factors in newly diagnosed primary breast cancer patients were registered to the JBCS through the Web-based system from affiliated institutes nationwide., Results: Two distinct peaks were observed, in patients in their late 40s and early 60s, in the population-adjusted age distribution of breast cancer patients. An increased rate of screen-detected breast cancer may contribute to an earlier detection of breast cancer and increased rate of non-invasive ductal carcinoma. The positive rate of either ER or PgR appears to have increased in recent years. The annual rates of patients treated with breast-conserving surgery increased until 2006, but these increases stopped in 2007 and thereafter plateaued at approximately 60 %. The annual rates of patients treated with sentinel lymph node dissection alone have steadily increased. The annual rates of patients treated with preoperative trastuzumab plus chemotherapy have also increased, as well as those treated with postoperative aromatase inhibitors. The annual rates of patients treated with postoperative anthracycline-containing regimens have decreased, whereas those treated with postoperative taxane-containing regimens have increased. The postoperative use of trastuzumab has markedly increased since 2007., Conclusion: Although this study was based on the registry database, several unique clinicopathological characteristics of breast cancer in Japan have been unveiled. Our results suggest that recent trends in the management of breast cancer patients in Japan were strongly followed by clinical evidence that originated from a number of clinical trials worldwide.

According to the Japanese Breast Cancer Society national breast cancer registration, 71.8%of breast cancer cases reported in 2004 and 79.8% of cases reported in 2010 were estrogen receptor(ER)positive. The frequency of ER-positive breast cancer is increasing annually in Japan. Many clinical trials have proven that adjuvant hormonal treatment affects both progression- free survival and overall survival in ER-positive breast cancer cases. However, some clinical questions remain, including those regarding the definition of preoperative hormonal treatment, appropriate dosage period, and therapeutic drug choice. In January 2013, we conducted a questionnaire survey of 53 medical doctors engaged in breast cancer treatment at 15 Japanese Breast Cancer Society-authorized facilities in Hokkaido. This survey included 6 clinical questions about preoperative hormonal treatment, 5 clinical questions about postoperative hormonal treatment for premenopausal breast cancer, and 4 clinical questions about postoperative hormonal treatment for postmenopausal breast cancer. We obtained replies from 35 medical doctors at 27 facilities. The response rate was 66%. We accumulated and analyzed these data. The discussion of questionnaire results in the medical administration field facilitates the sharing of information regarding differences in the approaches of different facilities to breast cancer patients. As a result, standardization of the breast cancer medical treatment system in this area has been accomplished.

Background: Recent studies have indicated that the response to chemotherapy and the prognostic impact of a pathological complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Predictors of response to chemotherapy and prognostic factors for survival might be different in estrogen receptor (ER)-positive breast cancer., Methods: Women with Stage II to III ER-positive HER2-negative breast cancer treated with anthracycline and taxane-containing neoadjuvant chemotherapy between 2003 and 2011 were retrospectively analyzed. Expression of forkhead box A1 (FOXA1), B cell lymphoma 2 (BCL2) and microtubule-associated protein tau (MAPT) as well as ER, progesterone receptor, HER2 and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Factors predictive of response to neoadjuvant chemotherapy and distant disease-free survival were analyzed., Results: Tumor grade was positively correlated with Ki67 expression. Expression levels of ER were positively correlated with expression levels of HER2, BCL2, FOXA1 and MAPT in pre-treatment tumors. The Ki67 labeling index was the only factor that was significantly associated with clinical response measured by the reduction of tumor volume and pCR. Lymph node status, expression of ER before neoadjuvant chemotherapy and expression of FOXA1 after neoadjuvant chemotherapy were significantly associated with distant disease-free survival, both by univariate and multivariate analyses., Conclusions: Patients with ER-positive HER2-negative breast cancer should be selected for neoadjuvant chemotherapy. FOXA1 expression could be a prognostic marker in ER-positive breast cancer.

Background: Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes., Methods: Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype., Results: Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) <14 %) and 22 as luminal B (Ki67 LI ≥ 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype., Conclusions: It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

We herein report the case of a 93-year-old woman with breast cancer on the left side. Preoperative computed tomography of the chest showed irregularities and narrowing of the mid-trachea. Bronchoscopy was performed, and the results of a biopsy supported a diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma. The patient responded to treatment with prednisone alone, with a reduction in the size of the lesion. MALT lymphoma of the trachea is extremely rare, and there are only a few case reports of double cancer, i.e., MALT lymphoma of the trachea and breast cancer.

Objective: The purpose of this study was to investigate the difference of patients' perceived needs after cancer diagnosis. Differences in quality of life and psychological distress were also examined., Methods: Ambulatory breast cancer patients who were randomly selected participated in this study. The patients were asked to complete the Short-form Supportive Care Needs Survey, which covers five domains of need (health system and information, psychological, physical, care and support and sexuality needs), the European Organization for Research and Treatment of Cancer QLQ-C 30 and the Hospital Anxiety and Depression Scale., Results: A total of 408 patients were enrolled and distributed into four groups [Group 1 (N = 115)], within 1 year of diagnosis; Group 2 [N = 105], 1-3 years since diagnosis; Group 3 [N = 94], >3 years since diagnosis; and Group 4 [N = 94], recurrence). Significant differences were observed in total, psychological, physical and daily living, and patient care and support needs, as well as in quality of life, whereas there were no significant differences in health system and information, sexuality needs and psychological distress. In general, Groups 1 and 4 had a higher need level and lower quality of life., Conclusions: Patients' perceived needs and quality of life may vary according to time since cancer diagnosis and the presence of cancer recurrence. The findings suggest that different care for supporting breast cancer survivors after diagnosis should be recommended, and that the time since diagnosis and/or the presence of recurrence may be relevant indicators for providing optimal and individualized care., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: There are many molecular differences between estrogen receptor α (ERα)-positive and ER-negative breast cancers. Recent analyses have shown that the former can be divided into two subtypes, luminal A and luminal B. These differ in response to endocrine therapy and chemotherapy, and in prognosis. In a previous study, we found that microRNA (miR)-1290 that was significantly down-regulated in luminal A tumors and its potential target arylamine N-acetyltransferase 1 (NAT1). The aim of the present study was to determine whether NAT1 is a bona fide target of miR-1290, and to investigate the impact of NAT1 on breast cancer prognosis., Methods: Luciferase reporter assays were employed to validate NAT1 as a putative miR-1290 target gene. Expression of NAT1, ERα, progesterone receptor (PgR) and HER2 was analyzed in 394 breast cancer samples by immunohistochemistry., Results: NAT1 was confirmed to be a direct target of miR-1290. Levels of expression of NAT1 were positively correlated with those of ERα (P < 0.0001) and PgR (P < 0.0001), but negatively correlated with both tumor grade and size (P < 0.0001). Kaplan-Meier analysis showed that the presence of NAT1 was significantly associated with increased overall survival (OS) (P = 0.0416) in these patients. Similarly, significant associations of NAT1 with disease-free survival (DFS) (P = 0.0048) and OS (P = 0.0055) in those patients who received adjuvant endocrine therapy with tamoxifen (n = 176) were found. Moreover, NAT1 was also significantly associated with increased DFS (P = 0.0025) and OS (P = 0.0007) in the subset of lymph node-positive patients (n = 147). Univariate and multivariate analyses showed significant associations between levels of NAT1 and DFS (P = 0.0005 and 0.019, respectively)., Conclusions: We report that miR-1290 directly targets the NAT1 3'-UTR and that NAT1 protein expression is correlated with improved OS of breast cancer patients. NAT1 is a possible prognostic biomarker for lymph node-positive breast cancer. Thus, miR-1290 and its target NAT1 are associated with important characteristics of breast cancer.

Background: The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer., Methods: Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline., Results: Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) (P = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014-0.721; P = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592-0.846)., Conclusion: Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer.

Objective: Human epidermal growth factor receptor 2 (HER2) gene amplification is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-human epidermal growth factor receptor 2 agents. Human epidermal growth factor receptor 2 somatic mutations have been reported in patients without human epidermal growth factor receptor 2 gene amplification. Since these are activating mutations, these patients may also benefit from human epidermal growth factor receptor 2-targeted drugs., Methods: In this study, we searched for human epidermal growth factor receptor 2 mutations in a group of 286 Japanese breast cancer patients with human epidermal growth factor receptor 2-negative tumors. The activating mutations of human epidermal growth factor receptor 2 identified were analyzed by direct Sanger sequencing of two major areas: the extracellular domain at 309-310 and the kinase domain between 755 and 781., Results: Two tumors were found to have a human epidermal growth factor receptor 2 somatic mutation; one with I767M mutation and another with D769Y. No mutation was observed in the extracellular domain. One of these patients with human epidermal growth factor receptor 2 mutation recurred early with liver metastasis., Conclusions: Better knowledge of human epidermal growth factor receptor 2 mutation status will help us to choose personalized molecular targeted therapy for use in human epidermal growth factor receptor 2-negative Japanese breast cancer patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The neutrophil:lymphocyte ratio (NLR) has been reported to reflect systemic inflammation and to have independent prognostic value for patients with various cancers. In this study, we analyzed the association between NLR and clinicopathological factors and verified the significance of NLR as a prognostic factor for Japanese patients with breast cancer., Patients and Methods: A total of 167 Japanese female patients with stage I-III breast cancer were retrospectively recruited into this study. Associations with clinicopathological factors and NLR were assessed, and disease-free survival and breast cancer-specific survival were estimated., Results: In multivariate analysis, lymph node metastases and NLR were significantly associated with disease-free survival and breast cancer-specific survival. NLR was significantly higher in patients with lower body-mass index., Conclusion: Preoperative NLR may be an independent prognostic factor for survival in Japanese patients with breast cancer. Reduction of body mass index has been implicated in NLR elevation, particularly in postmenopausal women., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)