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Background: In the global phase III IMpassion031 study, neoadjuvant atezolizumab plus nab-paclitaxel/anthracycline-based chemotherapy improved pathological complete response in patients with early stage triple-negative breast cancer. Here, we report primary analysis results from a subgroup of Japanese patients., Methods: Patients with histologically documented, previously untreated, stage cT2-cT4, cN0-cN3, cM0 triple-negative breast cancer were randomized 1:1 to receive intravenous atezolizumab 840 mg or placebo every 2 weeks in combination with chemotherapy consisting of nab-paclitaxel intravenous 125 mg/m2 once a week, followed by doxorubicin intravenous 60 mg/m2 and cyclophosphamide intravenous 600 mg/m2 every 2 weeks. Patients then underwent surgery. Pathological complete response (ypT0/is ypN0) in the intention-to-treat and PD-L1-positive (≥1% PD-L1-expressing tumor-infiltrating immune cells) populations were co-primary endpoints., Results: This subanalysis (data cutoff: 3 April 2020) included 36 patients from Japan (intention-to-treat; atezolizumab arm, n = 17; placebo arm, n = 19). Pathological complete response occurred in 41% (n = 7; 95% confidence interval, 18-67) of patients in the atezolizumab arm and 37% (n = 7; 95% confidence interval, 16-62) in the placebo arm. In the PD-L1-positive population, pathological complete response occurred in 50% (n = 5; 95% confidence interval, 19-81) of patients in the atezolizumab arm and 45% (n = 5; 95% confidence interval, 17-77) in the placebo arm. Treatment-related grade 3-4 adverse events occurred in 71% and 68% of patients in the respective arms., Conclusion: Atezolizumab added to neoadjuvant chemotherapy numerically improved pathological complete response versus placebo in this small exploratory analysis of Japanese patients with early stage triple-negative breast cancer, a trend directionally consistent with the global study results. No new safety signals were identified., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Skeletal muscle atrophy is characterized by decreases in protein content, myofiber diameter, and contractile force generation. As muscle atrophy worsens the quality of life, the development of anti-atrophic substances is desirable. In this study, we aimed to demonstrate a screening process for anti-atrophic peptides using photo-cleavable peptide array technology and human contractile atrophic muscle models. We developed a 96-well system and established a screening process with less variability. Dexamethasone-induced human atrophic tissue was constructed in the system. Eight peptides were selected from the literature and used for the screening of peptides for preventing the decrease of the contractile forces of tissues. The peptide QIGFIW, which showed preventive activity, was selected as the seed sequence. As a result of amino acid substitution, we obtained QIGFIQ as a peptide with higher anti-atrophic activity. These results indicate that the combinatorial use of the photo-cleavable peptide array technology and 96-well screening system could comprise a powerful approach to obtaining anti-atrophic peptides, and suggest that the 96-well screening system and atrophic model represent a practical and powerful tool for the development of drugs/functional food ingredients., (© 2022 Wiley Periodicals LLC.)

Background: This retrospective observational study validated nuclear grading criteria developed to identify a high-risk group with recurrence rate ≥20-30% and local pathology diagnosis used in a previous multi-institutional randomized N·SAS-BC 01 trial, where the efficacy of adjuvant chemotherapy regimens was evaluated in 733 high-risk node-negative invasive breast cancer patients., Methods: Of 545 patients with long-term follow-up data (median 12.1 years), pathology slides, and local pathology diagnosis, 530 eligible patients were subjected to central pathology review (CPR) for histological type and nuclear grade (NG). Concordance in NGs was compared with local diagnosis. The 10/15-year recurrence-free survival (RFS) and overall survival (OS) rates stratified by NG and histological type were calculated., Results: Local diagnoses were invasive ductal carcinoma (IDC)-NG2, IDC-NG3, invasive lobular carcinoma (ILC), and metaplastic carcinoma (MC) in 158/327/38/7 patients, respectively. The 10/15-year RFS rates were 87.2/82.6% for IDC-NG2 and 81.8/75.0% for IDC-NG3 (p = 0.061), and OS rates were 95.0/92.8% for IDC-NG2 and 90.8/85.7% for IDC-NG3 (p = 0.042). CPR graded 485 locally diagnosed IDCs as IDC-NG1/NG2/NG3/unknown in 98/116/267/4 patients, respectively. No significant difference was found among survival curves for the three NG groups. Although the agreement level between local and CPR diagnoses was low (κ = 0.311), both diagnoses identified a patient group with a 15-year recurrence rate ≥ 20%. The 10/15-year RFS rates were 79.4/63.5% for ILC and 68.6%/unknown for MC., Conclusions: The N·SAS grading system identified a patient group with high-risk node-negative invasive breast cancer, suggesting that local diagnosis was performed efficiently in the N·SAS-BC 01 trial., Trial Registration Number: UMIN000022571. Date of registration: June 1, 2016., (© 2022. The Author(s).)

Cases of breast cancer metastasis after achieving a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) are sometimes encountered in clinical practice. We investigated the prognostic factors for pCR in patients with breast cancer after NAC. This retrospective cohort study included patients with localized breast cancer who underwent NAC followed by surgery between 2004 and 2020 and achieved a pCR. The associations between clinical factors and distant metastasis-free survival rate were statistically analyzed. We analyzed data for 127 patients. Twelve patients (9.4%) had distant metastases, and seven (5.5%) died. For estrogen receptor (ER)-positive patients, the distant metastasis-free survival rate was 94.6% for both 5 and 8 years. In contrast, ER-negative patients had a distant metastasis-free survival rate of 87.6% and 85.4% for 5 and 8 years (p=0.094), respectively. In cT0-2 patients, the distant metastasis-free survival rate was 92.4% for 5 years and 90.5% for 8 years, whereas in cT3-4 patients, the distant metastasis-free survival rate was 83.5% for 5 years and 83.5% for 8 years (p=0.301). This study suggested that patients with ER-negative, pre-NAC cT3 or T4 breast cancer who had achieved a pCR after NAC tended to have a worse prognosis., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy., Methods: Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites)., Results: Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25-87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2., Conclusion: We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC., Study Registration: NCT03078036., (© 2021. The Author(s).)

Chemotherapy is often difficult to treat human epidermal growth factor receptor 2 (HER2)-positive metastatic recurrent breast cancer in the elderly, and no standard treatment has been established at this point. We experienced a case in which trastuzumab (Tmab) + anastrozole (ANA) was ineffective (progressive disease; PD) in elderly HER2-positive breast cancer with postoperative multiple liver metastases, but T-DM1 was significantly effective (complete response; CR), and treatment could be continued safely. An 82-year-old woman was referred to our department with a right breast mass. A close examination revealed right breast cancer cT1bN0M0 cStage I, and total mastectomy and sentinel lymph node biopsy were performed. The postoperative pathological result was pT1bN0M0 pStage I (luminal HER2 type). The patient was elderly and had no adjuvant treatment after the operation. Approximately 2 years after the operation, multiple liver metastases were observed, and treatment with ANA and Tmab was started. Four months later, MRI showed that the number of multiple liver metastases increased. The patient was diagnosed with PD, and the anti-HER2 drug was changed from trastuzumab to trastuzumab emtansine (T-DM1). The dose was reduced due to vomiting (grade 3). Two months later, MRI showed that the multiple liver metastases shrank and became obscure after 5 months. After that, T-DM1 was continued, and the disease did not worsen. In elderly people with difficulty in administering chemotherapy, T-DM1 may have a safe and sufficient therapeutic effect by adjusting the dose and managing side effects appropriately., Competing Interests: Shozo Ohsumi received lecture fee from AstraZeneca K.K. The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background: Hereditary breast and ovarian cancer (HBOC) syndrome is a susceptibility syndrome for cancers, such as breast and ovarian cancer, and BRCA1/2 are its causative genes. Annual breast-enhanced magnetic resonance imaging (MRI) is recommended for BRCA1/2 mutation carriers aged over 25 years as a secondary prevention of breast cancer. However, breast MRI surveillance is rarely performed in Japan, and only four cases of breast cancer diagnosis triggered by MRI surveillance have been reported., Case Presentation: At our hospital, MRI triggered the diagnosis of breast cancer in four cancer-free BRCA1/2 mutation carriers. In one of our four cases, although MRI showed only a 3-mm focus, we could diagnose breast cancer by shortening the surveillance interval considering the patient's high-risk for developing breast cancer., Conclusions: Image-guided biopsy, including MRI-guided biopsy, depending on the size of the lesion, and shorter surveillance intervals are useful when there are potentially malignant findings on breast MRI surveillance for cancer-free patients with HBOC., (© 2021. The Author(s).)

Background: The benefits of postoperative chemotherapy in patients with estrogen receptor (ER)-positive breast cancer remain unclear. The use of tumor grade, Ki-67, or ER expression failed to provide an accurate prognosis of the risk of relapse after surgery in patients. This study aimed to evaluate whether a multigene assay Curebest™ 95GC Breast (95GC) can identify the risk of recurrence and provide more insights into the requirements for chemotherapy in patients., Methods: This single-arm retrospective multicenter joint study included patients with ER-positive, node-negative breast cancer who were treated at five facilities in Japan and had received endocrine therapy alone as adjuvant therapy. The primary lesion specimens obtained during surgery were analyzed using the 95GC breast cancer multigene assay. Based on the 95GC results, patients were classified into low-risk (95GC-L) and high-risk (95GC-H) groups., Results: The 10-year relapse-free survival rates were 88.4 and 59.6% for the 95GC-L and 95GC-H groups, respectively. Histologic grade, Ki-67, and PAM50 exhibited a significant relationship with the 95GC results. The segregation into 95GC-L and 95GC-H groups within established clinical factors can identify subgroups of patients using histologic grade or PAM50 classification with good prognosis without receiving chemotherapy., Conclusions: Based on the results of our retrospective study, 95GC could be used to evaluate the long-term prognosis of ER-positive, node-negative breast cancer. Even though further prospective validation is necessary, the inclusion of 95GC in clinical practice could help to select optimal treatments for breast cancer patients and identify those who do not benefit from the addition of chemotherapy, thus avoiding unnecessary treatment., (© 2021. The Author(s).)

Introduction: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure., Conclusion: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Scalp cooling during chemotherapy infusion to mitigate alopecia for breast cancer patients is becoming widespread; however, studies regarding hair recovery after chemotherapy with scalp cooling are limited. We conducted a prospective study of hair recovery after chemotherapy with scalp cooling., Patients and Methods: One hundred and seventeen Japanese female breast cancer patients who completed planned (neo)adjuvant chemotherapy using the Paxman Scalp Cooling System for alopecia prevention were evaluated for alopecia prevention in our prospective study. We evaluated their hair recovery 1, 4, 7, 10, and 13 months after chemotherapy. Primary outcomes were grades of alopecia judged by two investigators (objective grades) and patients' answers to the questionnaire regarding the use of a wig or hat (subjective grades)., Results: Of 117 patients, 75 completed scalp cooling during the planned chemotherapy cycles (Group A), but 42 discontinued it mostly after the first cycle (Group B). Objective and subjective grades were significantly better in Group A than in Group B throughout 1 year, and at 4 and 7 months after chemotherapy. When we restricted patients to those with objective Grade 3 (hair loss of > 50%) at 1 month, Group A exhibited slightly faster hair recovery based on the objective grades than Group B. There was less persistent alopecia in Group A than in Group B., Conclusions: Scalp cooling during chemotherapy infusion for Japanese breast cancer patients increased the rate of hair recovery and had preventive effects against persistent alopecia., (© 2021. The Author(s).)

Background: The purpose of this study was to investigate the factors related to patient's participation in leisure activity in breast cancer patients with axillary lymph node dissection at 3 months after surgery., Methods: In total, 160 women who were employed before their surgery were evaluated. Age, body mass index (BMI), employment, level of lymph node dissection, marital status, children, coresident household members, preoperative chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, shoulder range of motion test, upper limb function, quality of life, and patient's participation in leisure activity were evaluated., Results: Patients who undertook leisure activities constituted the leisure activity group, and patients who did not constituted the non-leisure activity group. Global health status, emotional function, social function, and dyspnea were significantly different between the leisure activity group and the non-leisure activity group at 3 months after surgery ( p < 0.05). Regarding factors that affected participation in leisure activities, logistic regression analysis showed that only participation in leisure activities before surgery was significantly associated with participation in leisure activities at 3 months after surgery ( p < 0.05)., Conclusion: Patients who did not participate in leisure activities prior to surgery were unlikely to participate 3 months after surgery and thus require intervention to encourage their involvement.

The abilities to invade surrounding tissues and metastasize to distant organs are the most outstanding features that distinguish malignant from benign tumors. However, the mechanisms preventing the invasion and metastasis of benign tumor cells remain unclear. By using our own rat distant metastasis model, gene expression of cells in primary tumors was compared with that in metastasized tumors. Among many distinct gene expressions, we have focused on chloride intracellular channel protein 2 (CLIC2), an ion channel protein of as-yet unknown function, which was predominantly expressed in the primary tumors. We created CLIC2 overexpressing rat glioma cell line and utilized benign human meningioma cells with naturally high CLIC2 expression. CLIC2 was expressed at higher levels in benign human brain tumors than in their malignant counterparts. Moreover, its high expression was associated with prolonged survival in the rat metastasis and brain tumor models as well as with progression-free survival in patients with brain tumors. CLIC2 was also correlated with the decreased blood vessel permeability likely by increased contents of cell adhesion molecules. We found that CLIC2 was secreted extracellularly, and bound to matrix metalloproteinase (MMP) 14. Furthermore, CLIC2 prevented the localization of MMP14 in the plasma membrane, and inhibited its enzymatic activity. Indeed, overexpressing CLIC2 and recombinant CLIC2 protein effectively suppressed malignant cell invasion, whereas CLIC2 knockdown reversed these effects. Thus, CLIC2 suppress invasion and metastasis of benign tumors at least partly by inhibiting MMP14 activity., (Copyright © 2021. Published by Elsevier Inc.)

Perioperative dose-dense chemotherapy (DDCT) with pegfilgrastim (Peg) prophylaxis is a standard treatment for high-risk breast cancer. We explored the optimal timing of administration of 3.6 mg Peg, the dose approved in Japan. In the phase II feasibility study of DDCT (adriamycin+cyclophosphamide or epirubicin+cyclophosphamide followed by paclitaxel) for breast cancer, we investigated the feasibility, safety, neutrophil transition, and optimal timing of Peg treatment by administering Peg at days 2, 3, and 4 post-chemotherapy (P2, P3, and P4 groups, respectively). Among the 52 women enrolled, 13 were aged > 60 years. The anthracycline sequence was administered to P2 (n=33), P3 (n=5), and P4 (n=14) patients, and the taxane sequence to P2 (n=38) and P3 (n=6) patients. Both sequences showed no interaction between Peg administration timing and treatment discontinuation, treatment delay, or dose reduction. However, the relative dose intensity (RDI) was significantly different among the groups. The neutrophil count transition differed significantly among the groups receiving the anthracycline sequence. However, the neutrophil count remained in the appropriate range for both sequences in the P2 group. The timing of Peg administration did not substantially affect the feasibility or safety of DDCT. Postoperative day 2 might be the optimal timing for DDCT., Competing Interests: No potential conflict of interest relevant to this article was reported.

Objective: The purpose of this study was to investigate factors related to early quality of life (QOL) three months after surgery in breast cancer patients with axillary lymph node dissection., Methods: The subjects of this study were 195 consecutive patients who underwent axillary lymph node dissection for breast cancer. Age, body mass index, level of lymph node dissection, marriage, children, co-resident household members, neoadjuvant chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, upper limb function (disabilities of the arm, shoulder, and hand (DASH)), and QOL (European Organization for the Treatment and Research of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)) were evaluated. For each item of the EORTC QLQ-C30, compared with preoperative status and three months after surgery, those who improved or remained unchanged in the three months after surgery were classified as the maintenance and improved groups, and those with worsening status were classified as the worsened group., Results: Age, level of lymph node dissection, DASH, neoadjuvant chemotherapy, postoperative chemotherapy, and postoperative radiotherapy were significantly associated with QOL ( p < 0.05)., Conclusions: The early QOL of postoperative patients with breast cancer is affected by multiple factors, such as upper limb function and postoperative chemotherapy, and thus comprehensive intervention is required.

Objectives: Postoperative shoulder joint dysfunction has been observed at a certain rate after breast cancer surgery with axillary lymph node dissection. The purposes of this study were to verify the feasibility and effects of home-based exercise using a DVD and clarify the target of intensive intervention with physiotherapy by identifying the factors that cause postoperative shoulder dysfunction., Methods: The study comprised 237 female patients who underwent breast cancer surgery with axillary lymph node dissection, whose data were acquired until 3 months postoperatively. All patients were instructed to exercise at home using a DVD. Range of motion (ROM) of shoulder flexion and abduction and the disability of the arm, shoulder, and hand (DASH) score were measured before surgery, 1 week and 1, 2, and 3 months after surgery. As factors influencing the recovery of shoulder ROM at 3 months after surgery, the presence or absence of radiation and factors up to 1 month after surgery (age, body mass index, the relationship between operated side and dominant side of the hand, treatment modalities, and complications)., Results: Shoulder ROM and DASH scores had gradually recovered from 1 week to 3 months postoperatively. As the results of the multivariate analysis, the factors that were associated with the recovery of ROM of shoulder flexion at 3 months were the side of surgery corresponding to the dominant hand (negative factor) and the presence of paresthesia at 1 week postoperatively (positive factor) (p < 0.05). Radiation therapy and the side of surgery corresponding to the dominant hand were negative factors for the recovery of shoulder abduction (p < 0.01). Regarding the feasibility of the home exercise, 214/229 (93.4%), 172/210 (81.9%), and 139/206 (67.5%) of patients performed exercise at least once a day at 1, 2, and 3 months after surgery, respectively., Conclusion: Our result indicated that the side of surgery corresponding to the dominant hand was the inhibiting factor for recovery for both shoulder flexion and abduction at 3 months after surgery. Home-based exercise with DVD was considered feasible. For the verification of this effectiveness, a randomized control study should be planned in the future.

Purpose: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes., Methods: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status., Results: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02)., Conclusions: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

In this study, we examined whether axillary web syndrome (AWS) in patients with breast cancer following axil-lary lymph node dissection affects range of motion (ROM), upper extremity function, and quality of life (QOL). The risk factors for AWS were also evaluated in a total of 238 consecutive breast cancer patients follow-ing axillary lymph node dissection. At 1, 2, and 3 months after surgery, there were no significant differences between the AWS group and the non-AWS group in upper-limb function or QOL. At 2 months after surgery, shoulder flexion and abduction ROM were significantly higher in the AWS group than in the non-AWS group (p < 0.05). Self-training time at home was not significantly different between the groups at 1, 2, or 3 months. Only age was a significant predictor of AWS at 1 month after surgery (p < 0.05). The AWS group in the present study did not have worse results for shoulder joint ROM, upper-limb function, and QOL than the non-AWS group. Younger age should be useful for predicting the development of AWS in the early postoperative period., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background: The identification of factors that are related to return to work after surgery for breast cancer could help healthcare professionals accurately identify patients at risk of return to work-related difficulties in order to provide them with appropriate support during breast cancer management., Objective: The aim of this study was to identify factors related to return to work in breast cancer patients three months after axillary lymph node dissection., Methods: Seventy-three women who were working before the surgery were evaluated. Age, body mass index, level of lymph node dissection, marital status, children, co-resident household members, preoperative chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, shoulder range of motion, upper limb function (Disabilities of the Arm, Shoulder and Hand; DASH), and work were evaluated. Patients who had returned to work constituted the return to work group, and those who had not returned to work constituted the no return to work group., Results: Of the patients, 36 returned to work at three months. Logistic regression analysis including the five variables showed that shoulder flexion range of motion and DASH were significantly associated with return to work (p < 0.05)., Conclusions: The observation that the symptoms and limitations of upper limb function and shoulder flexion range of motion affect return to work may indicate the importance of postoperative rehabilitation in breast cancer patients following axillary lymph node dissection.

Purpose: Scalp cooling during chemotherapy infusion has been recently reported to have moderate efficacy in the mitigation of chemotherapy-induced alopecia; however, there are few reports on Asian patients. We aimed to clarify the effects of scalp cooling in Japanese women., Patients and Methods: Female Japanese breast cancer patients who planned to receive (neo)adjuvant chemotherapy participated in this prospective study on the efficacy of scalp cooling using the Paxman Scalp Cooling System for alopecia prevention. The primary outcomes were the rates of patients with Grade 3 alopecia (defined as hair loss of > 50%) and the rates of patients who used a wig or hat to conceal hair loss 1 month after the last infusion of chemotherapy. The subjects were given a brief questionnaire regarding headaches, bad mood, fatigue, and chills shortly after each cooling., Results: One hundred and forty-three patients participated in the study and used the cooling cap at least once. The mean and median ages of the subjects were 50.6 and 50, respectively (age range 28-76). One hundred and twenty-nine patients completed the planned chemotherapy of 4 to 8 cycles. Among them (7 patients were not evaluable), 74 patients (60.7%) had Grade 3 alopecia 1 month after chemotherapy. Of 80 patients who used the scalp cooling system throughout the planned chemotherapy (1 patient was not evaluable), 36 patients (45.6%) experienced Grade 3 alopecia., Conclusion: The efficacy of scalp cooling during chemotherapy infusion for hair loss mitigation in Asian women is similar to that in Caucasian women.

In the development process for drugs used to treat skeletal muscle, cell-based contractile force assays have been considered as a useful in vitro test. Immortalized human myogenic cells are promising as cell sources for reproducible and well-characterized in vitro models. In this study, it is investigated whether immortalized human myogenic cells, Hu5/KD3, have suitable contractile ability and the potential to be used as cell sources for contractile force assays. Muscle tissues are fabricated using Hu5/KD3 cells on the microfabricated devices used to measure contractile force. The tissues generate a tetanic force of ≈30 µN in response to the electrical pulse stimulation (EPS). Gene expression analysis of the myosin heavy chain (MYH) isoform indicates that the tissues mostly consisted of muscle fibers expressing MYH7 or/and MYH8. The addition of dexamethasone or lovastatin decreases the contractile force of the tissues, indicating that the tissues have the potential to evaluate drug candidates designed to treat muscle atrophy or statin-induced myopathy. It is also demonstrated that the contractile force of tissues increased when EPS is applied as an artificial exercise. These results indicate that the Hu5/KD3 tissues can be employed for contractile force assays and would be useful for in vitro human skeletal muscle models., (© 2020 Wiley-VCH GmbH.)

Background: The global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC)., Methods: Eligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected., Results: Between March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25-89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype., Conclusions: Patient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy., Trial Registration: NCT03078036 .

Background: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients., Patients and Methods: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed., Results: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756)., Conclusions: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although various types of artificial skeletal muscle tissue have been reported, the contractile forces generated by tissue-engineered artificial skeletal muscles remain to be improved for biological model and clinical applications. In this study, we investigated the effects of extracellular matrix (ECM) and supplementation of a small molecule, which has been reported to enhance α7β1 integrin expression (SU9516), on cell migration speed, cell fusion rate, myoblast (mouse C2C12 cells) differentiation and contractile force generation of tissue-engineered artificial skeletal muscles. When cells were cultured on varying ECM coated-surfaces, we observed significant enhancement in the migration speed, while the myotube formation (differentiation ratio) decreased in all except for cells cultured on Matrigel coated-surfaces. In contrast, SU9516 supplementation resulted in an increase in both the myotube width and differentiation ratio. Following combined culture with a Matrigel-coated surface and SU9516 supplementation, myotube width was further increased. Additionally, contractile forces produced by the tissue-engineered artificial skeletal muscles was augmented following combined culture. These findings indicate that regulation of the cell-ECM interaction is a promising approach to improve the function of tissue-engineered artificial skeletal muscles., (Copyright © 2020 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2 -wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2 , BARD1 , and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Background: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated., Methods: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate., Results: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025)., Conclusions: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer., Clinical Trial Registration: Clinical Trial Registration: UMIN-CTR as UMIN000007074.

Transplantation of stem cell-derived myoblasts is a promising approach for the treatment of skeletal muscle function loss. Myoblasts directly converted from somatic cells that bypass any stem cell intermediary stages can avoid the problem of tumor formation after transplantation. Previously, we reported that co-transduction with the myogenic differentiation 1 (MYOD1) gene and the v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog (MYCL) gene efficiently converted human fibroblasts into myoblasts. Although the directly converted myoblasts efficiently fused into multinucleated myotubes in vitro and in vivo, it is not clear whether they have the contractile ability, which is the most significant phenotype of the muscle. In the present study, we aimed to examine the in vitro contractile ability of the myotubes differentiated from the directly converted myoblasts by the overexpression of MYOD1 and MYCL. We fabricated three-dimensional (3D) tissues on a microdevice for force measurement. The 3D culture enhanced the differentiation of the myoblasts into myotubes, which were confirmed by gene expression analysis of skeletal muscle-related genes. The tissues started to generate contractile force in response to electrical stimulation after 4 days of culture, which reached approximately 12 μN after 10 days. The addition of IGF-I decreased the contractile force of the 3D tissues, while the use of cryopreserved cells increased it. We confirmed that the tissues fabricated from the cells derived from three different donors generated forces of similar magnitude. Thus, directly converted myoblasts by the overexpression of MYOD1 and MYCL could be a promising cell source for cell therapy., (Copyright © 2019 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to investigate the factors related to early postoperative psychological conditions in breast cancer patients with axillary lymph node dissection 3 months after the surgery., Methods: The subjects of this study were 200 consecutive patients who underwent axillary lymph node dissection for breast cancer at our hospital. Age, body mass index, surgical side, work, marriage, presence of children, presence of co-resident household members, resection of the pectoralis minor muscle, preoperative chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, shoulder range of motion, upper limb function (Disabilities of the Arm, Shoulder and Hand; DASH), and psychological conditions were evaluated. In this study, a Distress and Impact Thermometer was used to classify patients with adjustment disorders, depression, or major depression and suicidal ideation into a group with psychological problems and the remaining patients into a group with no psychological problems., Results: Logistic regression analysis showed that only DASH was statistically significantly associated with psychological conditions (p < 0.05). Using receiver operating characteristic curve analysis, a DASH score of 18 or greater was found to be very specific for predicting psychological conditions., Conclusions: The observation that somatic symptoms and disability of upper limb function are related to psychological conditions may indicate the importance of postoperative rehabilitation in breast cancer patients with axillary lymph node dissection.

Objective: The aim of the current study was to assess the risk factors for developing lymphedema following breast cancer treatment., Methods: The subjects of this study were 238 consecutive patients who underwent axillary lymph node dissection for breast cancer at Shikoku Cancer Center. The study variables were the occurrence of lymphedema, the body mass index, the follow-up period, the drain removal time, the level of lymph node dissection, the presence or absence of co-resident household members, radiation therapy, neoadjuvant chemotherapy, and adjuvant chemotherapy., Results: We observed lymphedema in 23.9% of patients after axillary lymph node dissection for breast cancer. Neoadjuvant chemotherapy and adjuvant chemotherapy using docetaxel and cyclophosphamide increased the risk of developing lymphedema (P <0.05)., Conclusions: Those patients treated with neoadjuvant chemotherapy and adjuvant chemotherapy using docetaxel and cyclophosphamide should be observed closely after axillary lymph node dissection, and appropriate intervention should be considered from an early stage., Competing Interests: CONFLICT OF INTEREST: The authors declare that they have no conflict of interests., (©2019 The Japanese Association of Rehabilitation Medicine.)

Background: In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2., Methods: In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n = 46) was conducted to compare results with those of the overall population., Results: At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6‒not estimable) with palbociclib-letrozole vs 13.8 months (5.6‒22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26-1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians., Conclusions: These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2‒ ABC. ClinicalTrials.gov: NCT01740427.

Background: Perioperative dose-dense chemotherapy (DDCT) with granulocyte-colony stimulating factor (G-CSF) prophylaxis is a standard treatment for patients with high-risk breast cancer. The approval of this approach in Japan led to the widespread adoption of DDCT, despite limited efficacy and safety data among Japanese patients. We evaluated the efficacy and safety of neoadjuvant DDCT for Japanese patients with breast cancer., Methods: This prospective, multicenter, phase II study evaluated 52 women with operable human epidermal growth factor receptor 2-negative breast cancer and axillary lymph node metastasis. Neoadjuvant DDCT (adriamycin plus cyclophosphamide or epirubicin plus cyclophosphamide followed by paclitaxel) was administrated every 2 weeks with G-CSF support. The study endpoints were the rates of pathological complete response (pCR), febrile neutropenia, treatment completion, toxicities, and the relative dose intensity (RDI)., Results: The pCR rate was 21.9% (9/41) and the triple-negative (TN) subtype was significantly associated with a high pCR rate (triple-negative: 53.3% vs. luminal A: 7.7% and luminal B: 0%; p = 0.003). The treatment completion rate was 80.8% (42/52) and the average RDI was 98.9%. Most adverse events were manageable and tolerable. Six patients (11.5%) developed febrile neutropenia. Grade 3-4 adverse events were slightly more common among older patients (57%) with a low protocol completion rate (≥ 65 years: 42.9% vs. <65 years: 86.7%, p = 0.0062)., Conclusion: The pCR rate for DDCT was similar to that of standard chemotherapy, although it was remarkably effective for the TN subtype. DDCT may be feasible for Japanese patients with breast cancer although caution is needed for older patients.

Background: Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast-conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT., Methods: Individual patient data sets from 9 studies were pooled. The outcomes of interest were the occurrence of LR and/or LRR. A 1-stage meta-analytic approach was used. Cox proportional hazards regression models were applied to identify factors that were predictive of LR and LRR, respectively., Results: A total of 9 studies (4125 patients) provided their data sets. The 10-year LR rate was 6.5%, whereas the 10-year LRR rate was 10.3%. Four factors were found to be associated with a higher risk of LR: 1) estrogen receptor-negative disease; 2) cN + disease; 3) a lack of pathologic complete response in axilla (pN0); and 4) pN2 to pN3 disease. The predictive score for LR determined 3 risk groups: a low-risk, intermediate-risk, and high-risk group with 10-year LR rates of 4.0%, 7.9%, and 20.4%, respectively. Two additional factors were found to be associated with an increased risk of LRR: cT3 to cT4 disease and a lack of pathologic complete response in the breast. The predictive score for LRR determined 3 risk groups; a low-risk, intermediate-risk, and high-risk group with 10-year LRR rates of 3.2%, 10.1%, and 24.1%, respectively., Conclusions: BCT after NCT appears to be an oncologically safe procedure for a large percentage of patients with breast cancer. Two easy-to-use clinical scores were developed that can help clinicians to identify patients at higher risk of LR and LRR after NCT and BCT and individualize the postoperative treatment plan and follow-up. Cancer 2018;124:2923-30. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer., Case Presentation: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome., Conclusions: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

CD200 mediates immunosuppression in immune cells that express its receptor, CD200R. There are two CD200 variants; truncated CD200 that lacks the part of N-terminal sequence necessary for CD200R binding (CD200S) and full-length CD200 (CD200L). We established a novel lung metastasis model by subcutaneously transplanting C6 glioma cells into the backs of neonatal Wistar rats. All transplanted rats developed large back tumors, nearly 90% of which bore lung metastases. To compare the effects of CD200S and CD200L on tumor immunity, CD200L (C6-L)- or CD200S (C6-S)-expressing C6 cells were similarly transplanted. The results showed that 100% of rats with C6-L tumors developed lung metastases, while metastases were found in only 44% of rats with C6-S tumors (n = 25). Tumors disappeared in approximately 20% of the C6-S-bearing rats, and these animals evaded death 180 d after transplantation, while all C6-L tumor-bearing rats died after 45 d. Next generation sequencing revealed that C6-S tumors expressed chemokines and granzyme B at much higher levels than C6-L tumors. Flow cytometry revealed that C6-S tumors contained more dead cells and more CD45 + cells, including natural killer cells and CD8 + lymphocytes. In particular, multiple subsets of dendritic cells expressing CD11c, MHC class II, CD8, and/or CD103 were more abundant in C6-S than in C6-L tumors. These results suggested that CD200S induced the accumulation of multiple dendritic cell subsets that activated cytotoxic T lymphocytes, leading to the elimination of metastasizing tumor cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background This large-scale study was conducted to evaluate the safety and effectiveness of eribulin for the treatment of inoperable or recurrent breast cancer in real-world settings in Japan. Methods Between July and December 2011, eligible patients with inoperable or recurrent breast cancer receiving eribulin for the first time were centrally registered and observed for 1 year. Eribulin was administered intravenously (1.4 mg/m 2 ) on days 1 and 8 of every 3-week cycle. The primary endpoint was the frequency and intensity of adverse drug reactions (ADRs). Secondary endpoints included overall response rate (ORR) and time to treatment failure (TTF). Results Of 968 patients registered at 325 institutions, 951 and 671 were included in the safety and effectiveness analyses, respectively. In the safety population, ADRs were observed in 841 patients (88.4%). The most common (≥15% incidence) were neutropenia (66.6%), leukopenia (62.4%), lymphopenia (18.4%), and peripheral neuropathy (16.8%). The most common grade ≥ 3 ADRs (>5% incidence) were neutropenia (59.8%), leukopenia (50.5%), lymphopenia (16.1%), and febrile neutropenia (7.7%). In the effectiveness population, ORR was 16.5% (95% confidence interval: 13.7, 19.4). The median TTF was 127 days (95% confidence interval: 120, 134). Conclusions The safety and effectiveness profile of eribulin was consistent with prior studies. Eribulin had a favorable risk-benefit balance when used in real-world clinical settings.

Background: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment., Methods: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers., Results: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%., Conclusions: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective., Trial Registration: UMIN CTR C000000416 . Registered on May 10, 2006.

Objectives: The mortality of patients with locally advanced triple-negative breast cancer (TNBC) is high, and pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This retrospective study was designed and powered to investigate the ability of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) to predict pathological response to NAC and prognosis after NAC., Methods: The data of 32 consecutive women with clinical stage II or III TNBC from January 2006 to December 2013 in our institution who underwent FDG-PET/CT at baseline and after NAC were retrospectively analyzed. The maximum standardized uptake value (SUV max ) in the primary tumor at each examination and the change in SUV max (ΔSUV max ) between the two scans were measured. Correlations between PET parameters and pathological response, and correlations between PET parameters and disease-free survival (DFS) were examined., Results: At the completion of NAC, surgery showed pCR in 7 patients, while 25 had residual tumor, so-called non-pCR. Median follow-up was 39.0 months. Of the non-pCR patients, 9 relapsed at 3 years. Of all assessed clinical, biological, and PET parameters, N-stage, clinical stage, and ΔSUV max were predictors of pathological response ( p value of 0.0288, 0.0068, 0.0068 respectively; Fischer's exact test). The cut-off value of ΔSUV max to differentiate pCR evaluated by the receiver operating characteristic (ROC) curve analysis was 81.3%. Three-year disease-free survival (DFS) was lower in patients with non-pCR than in patients with pCR ( p =0.328, log-rank test). The cut-off value of ΔSUV max to differentiate 3-year DFS evaluated by the ROC analysis was 15.9%. In all cases, 3-year DFS was lower in patients with ΔSUV max <15.9% than in patients with ΔSUV max ≥15.9% ( P =0.0078, log-rank test). In non-pCR patients, 3-year DFS was lower in patients with ΔSUV max <15.9% than in patients with ΔSUV max ≥15.9% ( P =0.0238, log-rank test)., Conclusion: FDG-PET/CT at baseline and after NAC could predict pathological response to NAC before surgery and the clinical outcome after surgery in locally advanced TNBC patients.

Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50-100 mg/m 2 ; n = 16). At a dose level of 100 mg/m 2 , predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients. None of the three patients given 80 mg/m 2 had a dose reduction, while a dose delay occurred in two. NK105 exhibited linear pharmacokinetics at doses of 50-100 mg/m 2 , and approximately 5 % of total paclitaxel was released from micelles. Thus, the recommended dose was set at 80 mg/m 2 , and an additional 10 advanced breast cancer (ABC) patients were given this dose in the dose-expansion phase. DLT manifested in two patients, and grade ≥ 3 neutropenia was found in eight patients. Among the nine patients who completed the first cycle, four had a dose reduction, mostly because of neutropenia. Of the 10 patients, six achieved partial response (PR), and four achieved stable disease (SD) status. Overall, weekly NK105 was well tolerated and had a desirable antitumor activity profile. Further investigations of NK105 in ABC patients are currently underway., Competing Interests: Compliance with ethical standards Funding The study was designed and funded by Nippon Kayaku Co., Ltd. NK105 was provided by Nippon Kayaku. Nippon Kayaku collected and analyzed the data and contributed to the interpretation of the results. Disclosure of Potential Conflict of Interest Yasuhiro Matsumura received consigned research funding from Nippon Kayaku. Rika Goda, Takayuki Hirai, and Yoshihiro Nambu are employees of Nippon Kayaku. The other authors have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee as well as with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was conducted in compliance with the International Conference on Harmonization of Good Clinical Practice Guidelines. Before the initiation of the study, the protocol had been reviewed and approved by the institutional review board of each institution. Informed consent Informed consent was obtained from all individual participants included in the study.

Background: We assembled needed data on the prevalence and characteristics of BRCA1/2 in Japan., Materials and Methods: Our study of BRCA1/2 collected data at eight institutions in Japan on 320 individuals with a strong family history of breast cancer, according to the NCCN guidelines, by the end of March 2012., Results: Among 260 proband cases, 46 (17.7 %) were positive for BRCA1, and 35 (13.5 %) were BRCA2-positive. Therefore, the total pathological mutation rate was 30.7 %. Pathology data after breast surgery were obtained from 37 cases of BRCA1 mutation, 23 (62.2 %) of which were triple negative (TN). On the other hand, 29 cases (82.9 %) of BRCA2 mutations were Luminal type. The most prevalent BRCA1 mutation site was L63X, found in 10 families. L63X was reported previously by studies in Japan, and it may be a founder mutation. We found two cases of large deletion detected by multiplex ligation-dependent probe amplification. One was an entire deletion of exon 20 and the lacked exons 1-9. TN with a family history of ovarian cancer was 11/20 (55 %). TN under 40-year-old (y.o.) 15/23 (65.2 %) and TN with one or more breast cancers in family history 17/32 (53.1 %) showed higher incidences of BRCA1 mutation., Conclusion: Hereditary breast and ovarian cancer (HBOC) may have nearly the same prevalence in Japan as in the US or Europe. If TN cases are taken into account, the ratio of BRCA1 is higher. L63X may be one of the founder mutations in Japan. A nationwide database of HBOC is important to develop risk models for BRCA1/2 carriers in Japan.

The primary purpose of this large cohort study is to investigate the effects on breast cancer outcomes of modifiable lifestyle factors after breast cancer diagnosis. These factors include physical activity, smoking, alcohol consumption, obesity and weight gain after diagnosis, alternative medicine and dietary factors. Women diagnosed with Stage 0 to III breast cancer are eligible for participation to this study. Lifestyle, use of alternative medicine, psychosocial factors, reproductive factors and health-related quality of life will be assessed using a questionnaire at the time of breast cancer diagnosis (baseline), and 1, 2, 3 and 5 years after diagnosis. Clinical information and breast cancer outcomes will be obtained from a breast cancer database. The primary endpoint will be disease-free survival. Secondary endpoints are overall survival, health-related quality of life, breast cancer-related symptoms and adverse events. Patient recruitment commenced in February 2013. Enrollment of 2000 breast cancer patients is planned during the 5-year recruitment period. The concept of the study is described in this article., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is currently approved in Japan for treatment of breast cancer. However, apart from phase I clinical trials, data regarding Japanese patients are scant. In the present study, the efficacy and safety of nab-paclitaxel therapy were retrospectively analyzed in 22 patients with advanced or metastatic breast cancer who were treated at the National Hospital Organization Shikoku Cancer Center between November 2010 and June 2012. The nab-paclitaxel was administered once every three weeks. The median age of the patients was 59 years. The tumors were estrogen-receptor positive and/or progesterone-receptor positive in 63.6% patients. None of the patients had HER2-positive breast cancer. The median number of treatment cycles was six (range, two to 12). Six patients exhibited a partial response; the response rate was 27.3% and the clinical benefit rate was 31.8%. The response rate and clinical benefit rate were higher in patients who received nab-paclitaxel as first- or second-line treatment. The median time to treatment failure was 127 days (range, 27-257). Major adverse events were peripheral neuropathy (59%; Grade 3, 9%), myalgia (59%), rash (45%), and nausea and vomiting (50%). The results suggest that nab-paclitaxel is a well-tolerated and clinically useful anticancer preparation.

The structure and functions of placentas were examined in 3 species of rorqual whales, common minke (Balaenoptera acutorostrata), Bryde's (B. brydei) and sei (B. borealis) whales, with the aim of confirming the structural characteristics of the chorion, including the presence of the areolar part, and clarifying steroidogenic activities and fetomaternal interactions in the placentas of these whales. Placentas were collected from the second phase of the Japanese Whale Research Program under Special Permit in the North Pacific (JARPN II). Histological and ultrastructural examinations revealed that these whale placentas were epitheliochorial placentas with the interdigitation of chorionic villi lined by monolayer uninucleate cells (trophoblast cells) and endometrial crypts as well as folded placentation by fold-like chorionic villi. Moreover, well-developed pouch-like areolae were observed in the placentas, and active absorption was suggested in the chorionic epithelial cells of the areolar part (areolar trophoblast cells). Berlin blue staining showed the presence of ferric ions (Fe(3+)) in the uterine glandular epithelial cells and within the stroma of chorionic villi in the areolar part. An immunohistochemical examination revealed tartrate-resistant acid phosphatase (TRAP; known as uteroferrin in uteri) in the cytoplasm of glandular cells and areolar trophoblast cells. This result suggested that, in cetaceans, uteroferrin is used to supply iron to the fetus. Furthermore, immunoreactivity for P450scc and P450arom was detected in trophoblast cells, but not in areolar trophoblast cells, suggesting that trophoblast cells synthesize estrogen in whale placentas. Therefore, we herein immunohistochemically revealed the localization of aromatase and uteroferrin in cetacean placentas during pregnancy for the first time.