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PURPOSE Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor–positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was CONCLUSION Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor–positive breast cancer.

We report a rare case of hereditary breast and ovarian cancer syndrome (HBOC) with pathogenic variants in both BRCA1 and BRCA2. The patient was a 78-year-old woman who visited the hospital after noticing a lump in her left breast 6 months before, which gradually increased in size. According to her family history, her maternal aunt developed breast cancer in her 40s. On palpation, a 4-cm large mass was palpated in the upper outer part of the left breast. A needle biopsy revealed invasive ductal carcinoma of the breast, which was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The patient was diagnosed with cT2N0M0 stage IIA, and primary systemic treatment was planned. The patient developed drug-induced interstitial pneumonia after receiving paclitaxel. Although she recovered spontaneously, she did not wish to receive further chemotherapy, and thus surgery was performed. Four months after the surgery, the patient became aware of dyspnea. After a thorough examination, she was diagnosed with postoperative cancer recurrence of the left breast with multiple liver metastases, cancerous peritonitis, multiple bone metastases, and multiple lymph node metastases. Genetic testing was performed, and pathogenic variants were found in both BRAC1 and BRCA2. However, her condition worsened, and she died 8 months after the surgery. BRCA pathogenic variants had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. It is desirable to consider the optimal approach to the treatment of breast cancer in pathogenic variants. In elderly patients with triple-negative breast cancer, HBOC may be suspected, based on biomarkers and family history. It is important to provide information on genetic counseling, genetic testing, and effective treatment plans proactively.

In the absence of clear interstitial invasion, encapsulated papillary carcinoma (EPC) of the breast may be attributed to an extremely good prognosis if handled similarly to ductal carcinoma in situ (DCIS) with suitable local treatment. Here, we report our experience with a case of EPC of the breast that presented with carcinomatous pleuritis and lymphangitis carcinomatosa postoperatively, which rapidly resulted in a poor outcome. A 67-year-old woman was diagnosed with DCIS of the left breast and underwent left partial mastectomy and sentinel lymph node biopsy. EPC was diagnosed because the pathological examination showed no sign of interstitial infiltration. Postoperative radiation therapy was performed. Five years and 9 months postoperatively, the patient began experiencing cough and shortness of breath on exertion. Imaging showed right pleural effusion and consolidation of the lung field, but nothing suggesting local recurrence in the preserved left breast, local lymph nodes, or opposite breast was observed. Postoperative recurrence of breast cancer, carcinomatous pleuritis, and lymphangitis carcinomatosa were diagnosed based on the results of pleural fluid cytology. One month later, multiple brain metastases were found, and the patient died of the primary disease 5 months after recurrence. After surgery for EPC without clear interstitial infiltration, there was a small possibility of a poor outcome from distant metastasis. Therefore, although distant metastasis is uncommon, regular examination and testing should be performed.

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 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.

Luminal B-like breast cancer is sensitive to both chemotherapy and endocrine therapy. We aimed to assess the safety and efficacy of concomitant chemotherapy and endocrine therapy compared with chemotherapy alone in the preoperative setting in luminal B-like breast cancer. This two-arm randomized clinical trial enrolled patients with luminal B-like human epithelial growth factor 2-negative breast cancer, who were randomly assigned at a 1:1 ratio to receive preoperative chemotherapy alone or preoperative endocrine therapy concurrent with chemotherapy for 24 weeks before surgery. The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints included the clinical response rate, toxicity, and health-related quality of life (HRQOL). Overall, 70 patients were randomly assigned to the chemotherapy and chemo-endocrine therapy groups. The pCR rates were 9.7% and 3.0% (P = 0.319), and the clinical complete response rates were 5.9% and 5.6% (P = 0.745) in the chemotherapy and chemo-endocrine therapy groups, respectively. There were no clear differences in treatment-related adverse events or HRQOL between the two groups. In patients with luminal B-like breast cancer, the pCR, clinical response rate, toxicity, and HRQOL with the concomitant administration of endocrine therapy and chemotherapy were not superior to chemotherapy alone in the preoperative setting.

Background: The St.Gallen consensus guideline recommends the sequential administration chemotherapy followed by endocrine therapy as postoperative therapy for the higher risk of ER-positive breast cancer patients based on results of a single study. In metastatic settings, however, several trials conducted in the 1980s' demonstrated that tumor response rates were higher when chemotherapy and tamoxifen was concomitantly administered than when chemotherapy and tamoxifen administered were given sequentially. In the preoperative settings, pathological complete response (pCR) rate can be used as a surrogate marker to predict event-free survival or overall survival in Luminal B-like (HER2-negative) breast cancer. We, therefore, designed a prospective randomized safety and efficacy trial in order to test a hypothesis that the concomitant administration of an aromatase inhibitor and chemotherapy improves pathological complete response (pCR) rate than chemotherapy alone in the preoperative setting. Trial design: This two-arm randomized clinical trial enrolled operable breast cancer patients with Luminal B-like (HER2-negative) subtype. Patients were randomly assigned (1:1) to receive preoperative chemotherapy alone or preoperative chemotherapy concurrent with endocrine therapy for 24 weeks before surgery. Chemotherapy consisted of 12 cycles of weekly paclitaxel followed by 4 cycles of every 3-week AC. Endocrine therapy consisted of anastrozole for postmenopausal patients or anastrozole plus leuprorelin for premenopausal patients. Eligibility criteria: 1)Female patients with operable and histologically confirmed invasive breast cancer; 2)HER2-negative; 3)Either ER-positive or PgR-positive; 4)Either Ki67-LI>=14% and NG>=2 or NG=3 regardless of Ki67-LI. Endpoints: Primary endpoint is the pCR rate. Secondary endpoints are the clinical response rate (RECIST), the breast-conserving surgery rate, the adverse events, and HRQOL. Results: Between March 2012 and August 2017, 70 patients were randomly assigned to chemotherapy group (n=34) or chemo-endocrine therapy group (n=36). pCR rates were 8.8 % and 2.7 % in the chemotherapy and the chemo-endocrine group, respectively (P = 0.319). Similarly, clinical complete response rates were 5.9 % and 5.6 % in the chemotherapy and the chemo-endocrine group, respectively (P = 0.745). There were no clear differences in treatment-related side effects and HRQOL between interventions. Conclusion: The concomitant administration of endocrine therapy and chemotherapy in Luminal B-like breast cancer patients is similar to chemotherapy alone in pCR rate and clinical response in the preoperative setting. Citation Format: Roichi Matsunuma, Toru Watanabe, Yasuo Hozumi, Kei Koizumi, Yasushi Ito, Hirofumi Fujita, Hiroyuki Ogura, Keigo Goto, Hiroki Mori, Noriko Sawai, Norihiko Shiiya. An efficacy and safety trial of preoperative chemo-endocrine therapy in Luminal B-like (HER2-negative) breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-03.

Background: It is critical that a large proportion of eligible patients should participate in clinical trials. However, recruitment into clinical trials requires informed consent and involves some difficult and complex problems. Therefore, it is important to know what factors affect the participation of eligible patients in clinical trials. Patients and Methods: Patients with metastatic breast cancer (MBC) who were eligible to participate in the SELECT BC or SELECT BC-CONFIRM trials were recruited to a prospective study accompanying them named SELECT BCFEEL. The SELECT BC and SELECT BC-CONFIRM trials were randomised controlled trials (RCTs) that compared taxanes or anthracyclines, respectively, with the oral regimen of S-1 in the first line setting for Japanese patients with MBC. The SELECT BC FEEL was conducted to identify factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. The questionnaire included the following items: Physician recommendation, family or friend recommendation, satisfaction with the explanation about the trial, both from the doctor or clinical research coordinator and from printed matter, regimens used, understanding of the concept of the trial, benefit to future patients, relationship with the doctor, attitude toward random assignment, concerns about privacy, burden on the patient, and potential adverse effects. We also asked the patients their age, whether they received prior chemotherapy, and about the time needed to decide whether or not to participate, communication with their doctor or other patients, potential adverse effects they were concerned about, and other people's opinions that affected their decision. The patients were asked to answer most of the questions in 5-point Likert scales. To investigate the associations between patients’ decision regarding whether or not to participate in the RCTs and their responses to each question, the Chi-square test, the Mann-Whitney U test, and the t-test were used. P values of < 0.05 were considered statistically significant. Results: Two hundred and thirty-two patients participated in the present study. Data were missing for 3 patients, and they were excluded from the analyses. One hundred and eighty five participated in the RCT, but 44 did not. The patients who chose to participate in these RCTs were more likely to answer that they decided to participate because "My doctor wanted me to participate in this trial" (69.2% vs. 25.6%; P Conclusions: To enhance the consent rate in randomised trials of Japanese breast cancer patients, the concepts of the trials must be considered important and acceptable by the doctors and families of the patients. Citation Format: Yasuo Hozumi, Shozo Ohsumi, Hirofumi Mukai, Masato Takahashi, Hiromitsu Akabane, Youngjin Park, Eriko Tokunaga, Tsutomu Takashima, Takanori Watanabe, Yoshiaki Sagara, Tetsuji Kaneko, Yasuo Ohashi. Factors affecting enrolment in randomised controlled trials of Japanese patients with metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-01.

Reports of multiple cancer cases are increasing with the improvement of diagnostic techniques and the extension of life expectancy. In addition, the increase in the prevalence of multiple cancers is expected because the increase in the prevalence of juvenile breast cancer has been a concern in recent years. Particularly, in the case of simultaneity, the problem is how much treatment priority and curability should be sought depending on the stage and prognosis of each tumor. We report a case of malignant lymphoma and colon cancer that occurred during breast cancer treatment.

Background We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. Methods We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. Results We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). Conclusions S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Clinical trial registration The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Background: Anthracycline-containing regimens and taxane have been standard as the first-line chemotherapy for metastatic breast cancer (MBC). We conducted SELECT BC (randomized phase 3 study of taxane versus S-1 as first-line treatment for MBC) for evaluating the efficacy of S-1 for patients with HER2-negative MBC from 2006 to 2010 in Japan. This study demonstrated non-inferiority of S-1 in overall survival (OS) (median OS was 37.2 months in taxes group and 35.0 months in S-1 group (HR 1.05, 95% CI 0.86–1.27, p=0.015)), and superiority in health-related quality of life (HRQOL) to taxanes. S-1 was also shown as less toxic than taxane (Lancet Oncol 2016; 17: 90-98). S-1 might provide clinical benefit as first-line treatment for patients with HER2-negative MBC. To confirm this suggestion, we have conducted further study (randomized phase 3 study of anthracycline-containing regimens versus S-1 as first-line treatment for HER2-negative MBC: SELECT BC-CONFIRM) from 2011 to present, and a combined analysis of two randomized studies (SELECT-BC CONFIRM and SELECT-BC). Methods: In SELECT BC-CONFIRM, 230 patients receiving first-line treatment for MBC were randomly assigned to either anthracycline group (n=115) or S-1 group (n=115). Anthracycline group patients received anthracycline-containing regimens (AC, EC, FAC, FEC, q3w) at the discretion of the treating physician. S-1 group patients received S-1 40–60 mg twice daily based on the patient's body surface area for 28 days on, 14-day off. The primary endpoint was OS, and secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), adverse events, HRQOL, and cost-effectiveness. The results were combined with SELECT-BC, to confirm the hypothesis that S-1 treatment is not inferior to the standard therapy (taxanes / anthracycline) for HER2-negative MBC. Results: A combined analysis of the two studies showed that HR was 1.06, 95%CI 0.90-1.253, and p=0.0071 between the standard therapy group and S-1 group. In addition, the Bayesian posterior probability for which HR would be less than 1.333 was about 99.6%. Conclusions: A combined analysis of SELECT BC-CONFIRM and SELECT BC clearly demonstrated that OS with S-1 was not inferior to that with the standard therapy in patients receiving first-line treatment for HER2-negative MBC. S-1 could become a standard therapy for this patient population. Citation Format: Park Y, Akabane H, Watanabe T, Takahashi M, Sagara Y, Nishimura R, Tsurutani J, Takashima T, Fujisawa T, Hozumi Y, Uemura Y, Mukai H. Randomized phase 3 study of anthracycline-containing regimens versus S-1 as first-line treatment for metastatic breast cancer (SELECT BC-CONFIRM)–A combined analysis of two randomized phase 3 studies (SELECT BC-CONFIRM and SELECT BC)– [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-07.

Background: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on the risk of breast cancer recurrence. Methods: This prospective, randomised, multicentre open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients with stage I–IIIA hormone receptor-positive breast cancer who were disease-free after treatment with either 5 years of anastrozole alone or 2–3 years of tamoxifen followed by 2–3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole (1 mg/day orally) for an additional 5 years or stop anastrozole, using the central computer at the Comprehensive Support Project for Oncology Research Data Centre. Randomisation was stratified by type of postoperative endocrine therapy, nodal status, prior adjuvant chemotherapy, and facility. The primary endpoint was disease-free survival, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with UMIN clinical trials registry, number UMIN000000818. Findings: We enrolled 1697 patients from 117 facilities between November 2007 and November 2012. Patients were assigned randomly to the continue group (n=849) or the stop group (n=848). Follow-up information was available for 1593 patients (n=787 in the continue group, n=806 in the stop group) as the full analysis set. After a median follow-up of 5·1 years, there were 172 events involving disease recurrence or the occurrence of contralateral breast cancer (75 in the continue group and 97 in the stop group) and 40 deaths (21 in the continue group and 19 in the stop group). The 5-year disease-free survival rates were 91% (95% confidence interval [CI] 89–93) in the continue group and 86% (95% CI 83–88) in the stop group (hazard ratio [HR] for disease-free survival 0·61, 95% CI 0·46–0·82; p

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.

PURPOSE Most distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified HSD17B4 methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only HSD17B4 methylation was significantly different. The HSD17B4 methylation was at the transcriptional start site of its major variant, and was associated with its silencing. HSD17B4 was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and HSD17B4 methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy, HSD17B4 methylation was the most reliable marker to monitor response to the therapy. These results showed that HSD17B4 methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.

Neoadjuvant systemic therapy (NST) induces tumor shrinkage and boosts the chance of breast-conserving thearpy (BCT) in patients with breast cancer. However, only a few trials have evaluated the effect of NST in conversion from BCT ineligibility to BCT eligibility in HER2-positive breast cancer.We conducted the surgical sub-study of a phase II randomized trial, which compared standard neoadjuvant treatment or an experimental treatment modified according to the interim Ki-67 evaluation in women with stage II or III HER2-positive breast cancer. The treating surgeons assessed eligibility for BCT before and after NST. We evaluated the change in BCT eligibility following NST. We also analyzed the type of surgery performed and the success rate of BCT.Two hundred six patients were included in this study. Of these, 44.0% were considered BCT candidates at baseline, while 69.8% were deemed eligible for BCT after NST (P 0.001). Among non-BCT candidates at baseline, 46% successfully converted to BCT candidates. Of 139 patients deemed eligible for BCT following NST, 84.2% attempted BCT, and successful BCT, defined as tumor-free at all surgical margins, was achieved in 96.8% of patients. Different treatment arms did not affect the rate of post-NST BCT eligibility (70.0% vs 69.7%).This study demonstrated that NST resulted in an absolute increase of 25.8% in the rate of BCT eligibility in HER2-positive breast cancer. About a half of non-BCT candidates converted to BCT candidates. BCT was successful in most patients who attempted BCT. There were still patients who chose mastectomy even though they were deemed eligible for BCT. Patients considered BCT-ineligible due to large tumor size most likely converted to BCT-eligible with NST. On the other hand, NST had less impact on the surgical indication of patients with multicentric disease or probable poor cosmetic outcome.

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.

Bowen’s disease is a type of intraepidermal squamous cell carcinoma that commonly develops in areas of the skin exposed to sunlight, such as the scalp, trunk, and limbs. Although development of Bowen’s disease in other sites, such as the nipple, is extremely rare, we herein report our experience with one such case. A 76-year-old female presented to our hospital with complaints of right nipple pruritus. We diagnosed Bowen’s disease via nipple skin biopsy, and the patient underwent right nipple resection. The deep tissue margin was positive for malignancy; therefore, the patient subsequently underwent right partial mastectomy. Histopathology revealed tumor cells inside the lactiferous ducts, but the resection margin was negative for malignancy. Bowen’s disease of the nipple may progress from the skin to the lactiferous ducts. Clinical findings can be used to evaluate lesion progression and determine the necessary extent of skin and mammary gland resection.

Intramammary metastasis of renal cell carcinoma (RCC) is extremely rare, accounting for only 1.5% of all intramammary metastases. Distinguishing intramammary metastases from benign tumors and breast cancer is clinically problematic. Some patients undergo excessive surgery after a misdiagnosis of breast cancer instead of a mammary tumor. We performed a core needle biopsy (CNB) of a breast mass that developed in a 71-year-old woman after surgeries for bilateral RCC and breast cancer, leading to a diagnosis of intramammary metastasis of RCC. In this case, the CNB and immunohistochemical examination were critical for reaching a definitive diagnosis. We conclude that, when examining patients with mammary tumors, establishing their history of malignant tumors may help diagnose intramammary metastasis and select the best treatment strategy.

Background: After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with advanced/metastatic breast cancer (BC), it is unclear which of the various kinds of endocrine monotherapy is the most appropriate. In a previous report it was found that toremifene 120 mg (TOR 120), a selective estrogen receptor modulator (SREM), was superior to steroidal AI in terms of progression-free survival after ns-AI in the Hi-FAIR ex trial. A phase II randomized trial of TOR 120 versus fulvestrant 500 mg (FUL 500), a selective estrogen receptor down regulator (SERD), was also conducted to select the most promising endocrine monotherapy after ns-AI in advanced/metastatic BC(Study registry number: UMIN000010087). Patients and Methods: Postmenopausal women (n=106) with advanced/metastatic hormone-receptor positive BC from October 2011 to September 2014 were enrolled in this study. Fifty-three of the patients were randomly assigned to the TOR 120 (120 mg daily p.) group and 53 of the patients were randomly assigned to the FUL 500 group. In the FUL 500 group they were administered 500 mg of fulvestrant intramuscularly (im) on day 0, then 500 mg im on days 14 and 28 and every 28 days thereafter). If treatment failure occurred in either of the randomly assigned groups the patients were then removed and treated accordingly. A full analysis set was targeted for all cases that received the protocol treatment even once (TOR 120 (n=53) and FUL 500 (n=52)). The primary end point was the clinical benefit rate (CBR). The secondary end points were the objective response rate (ORR), progression-free survival (PFS), time to chemotherapy (TTCT), overall survival (OS), toxicity, and CBR, ORR and PFS after crossover of non-assigned treatment. Results: A median follow up period of 30 months revealed that the CBR of FUL 500 (57.7%) tended to be superior to the CBR of TOR 120 (45.3%), the odds ratio (OR) was 1.70 (95% CI 0.74–3.62), and the median PFS was 7.8 months in the FUL 500 group and 5.8 months in the TOR 120 group. Moreover the hazard ratio (HR) was 0.79 (95% CI 0.52–1.21). However, there was no difference between the two groups in terms of ORR (17.7% and 15.1%, respectively), TTCT (13.3 months vs. 17.7 months, HR = 0.94 (95%CI 0.57 – 1.53)), and OS (33.4 months vs. not reached HR 1.29; 95% CI 0.80–2.09). At the cross-over phase, 33 and 24 patients after failure of assigned treatment were treated with FUL 500 and TOR 120, respectively. The CBR and PFS of FUL 500 after TOR 120 was better than that of TOR 120 after FUL 500 (CBR; 42.4% vs. 20.8%, OR = 0.33, 95%CI 0.09 – 1.11, median PFS; 6.2 months vs. 3.4 months; HR = 1.95, 95%CI 1.08–3.51). No difference between the two groups was observed in PFS from randomization to the end of the crossover phase. Moreover, there were few severe adverse events in either of the two groups. Conclusions: FUL 500 used as a subsequent endocrine therapy for advanced/metastatic BC patients who failed ns-AI could potentially be more effective than TOR 120. However, the efficacy of SERM after failure of FUL 500 may be limited. Citation Format: Nishimura R, Yamamoto Y, Narui K, Kijima Y, Hozumi Y, Ikeda M, Takao S, Ohtani S, Iwase H. A randomized phase II trial of toremifene (120 mg) versus fulvestrant (500 mg) after prior non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer (Hi-FAIR fx study) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-02.

The static and dynamic characteristics of 13-kV class 4H-SiC junction barrier Schottky (JBS) diodes with a three-zone junction termination extension (JTE) are presented. Using an anisotropy breakdown model, technology computer-aided design simulation of devices with a three-zone JTE agrees well with the obtained experimental results, correctly predicting a sharp drop in blocking voltage at high JTE acceptor concentrations. The forward voltage of the JBS diode at 75°C and a forward current of 500 mA is reduced to approximately one-ninth by that of 13 series-connected 1000-V Si PiN diodes. This suggests that conduction losses of traditional high-voltage circuits which conventionally use series-connected devices can be drastically reduced by replacing the series-connected devices with a single 13-kV class SiC JBS diode. Moreover, the reverse recovery current waveform of the 13-kV class SiC JBS diode shows that these diodes have lower reverse recovery losses than a 13-kV SiC PiN diode.

Background: There are few randomized clinical trials examining adjuvant treatment in elderly breast cancer patients. While obtaining informed consent is essential for participation in clinical studies, there is little information on the frequency of agreement to participate among elderly patients. Furthermore, elderly patients might have specific reasons to decline participation. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized clinical trial in women over 70 years with HER2-positive primary breast cancer. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with the combination of trastuzumab and chemotherapy. Key inclusion criteria were as follows: women between 70 and 80 years old with HER2-positive breast cancer; underwent curative operation; stage I to IIIA; with sufficient organ function. Patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, health-related quality of life, and cost effectiveness (NCT01104935). It was not possible to predict the number of patients who would agree to participate. In order to comprehensively assess the effect of postoperative adjuvant therapy, we evaluated the reasons why eligible patients declined to participate. The patients were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). This study examined the obtaining of informed consent for N-SAS BC 07 and the reasons for declining participation, and compared the clinicopathological backgrounds between the N-SAS BC 07 and 07-Cohort groups. Results: 398 eligible patients have been recruited. Informed consent to participate in N-SAS BC 07 has been obtained from 275 patients (69%) and 123 patients (31%) who declined to participate in the RCT have been registered in the 07-Cohort. The common reasons to decline participation in the RCT were "cannot choose the treatment option (55%)", "refused chemotherapy (16%)", "wanted chemotherapy (9%)", "anxious about clinical studies (9%)" and "family opposition (8%)". The mean ages of the patients in N-SAS BC 07 and 07-Cohort were 73.9 and 74.6 years old, respectively. There were no differences in stage, surgical procedure, lymph node metastasis, or co-morbidities between the groups. ER-positive rate was higher in 07-Cohort group compared with N-SAS BC 07 group (53% vs. 37%, p=0.017, χ2 test). Conclusion: While we expected the number of registrants to be small, since N-SAS BC 07 investigated whether elderly patients with HER2-positive breast cancer should undergo chemotherapy, almost 70% of the patients accepted informed consent. The most common reason to decline participation in N-SAS BC 07 was "cannot choose the treatment option" and the majority refused chemotherapy. Furthermore, ER-positivity was higher in the 07-Cohort group, which suggested that ER expression in the patients with HER2-positive breast cancer might influence their decision to participate in the study or to choose the treatment option. Citation Format: Sagara Y, Sawaki M, Taira N, Saito T, Kashiwaba M, Iwata H, Kobayashi K, Nakayama T, Bando H, Mizuno T, Yamamoto Y, Tsuneizumi M, Takahashi M, Yamaguchi M, Kawashima H, Takashima T, Uemura Y, Hozumi Y, Sagawa N, Mukai H, Ohashi Y. A randomized clinical trial of postoperative adjuvant therapy for elderly breast cancer patients: Conditions of obtaining informed consent and reasons for declining participation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-18-01.

Background: Health-related quality of life (HRQoL) is one of the important outcomes in cancer control trials and has increasingly become the one of the primary foci. Obtaining informed consent from participants is essential for participation in randomized controlled trials (RCTs), but the participation in these RCTs may directly influence HRQoL, because treatment options are determined according to the allocation schedule. To date, only a few studies have compared HRQoL between clinical trial participants and decliners. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized controlled trial in women with HER2-positive primary breast cancer who are over 70 years of age. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with combination therapy using trastuzumab and chemotherapy. The study concept and design were published in concept paper (Sawaki M. et al., Jpn J Clin Oncol. 2011). In this study, patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, HRQoL, comprehensive geriatric assessment (CGA) and cost effectiveness (protocol ID; NCT01104935). HRQoL and CGA were assessed at registration (baseline), 2 month, 1 year, and 3 years after the start of protocol treatments using the Functional Assessment of Cancer Therapy-General (FACT-G), Hospital Anxiety and Depression Scale (HADS), EuroQol 5 Dimension (EQ-5D), Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence, and the Philadelphia Geriatric Center (PGC) Morale Scale. The patients who declined to participate in N-SAS BC 07 were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). The same questionnaire that was used in N-SAS BC 07 was used in 07-Cohort to evaluate HRQoL and CGA at entry. Results: Patients were enrolled from October 2012 to October 2016. During this period, 275 and 123 patients were registered in N-SAS BC 07 and 07-Cohort, respectively. The mean age at entry of the patients in the N-SAS BC 07 and 07-Cohort groups was 73.9 and 74.6 years, respectively. The questionnaire response rates at baseline in the patients in N-SAS BC 07 and 07-Cohort groups were 89% and 82%, respectively. There were no significant differences in FACT-G, HADS, EQ-5D, or TMIG index of competence at baseline between the groups, but the mean (standard deviation) scores of PGC Morale Scale in N-SAS BC 07 and 07-Cohort groups were 10.8 (3.3) and 9.9 (3.7), respectively, with the scores being significantly greater in the N-SAS BC 07 group (p=0.020, t-test). Conclusion: The PGC Morale Scale provides a multidimensional approach to assess the psychological state of older people. This study indicated that participation in the RCT did not affect the baseline QoL of elderly patients but suggested that the baseline QoL of the RCT participants was better than decliners. Citation Format: Saito T, Sawaki M, Hozumi Y, Sagawa N, Iwata H, Kashiwaba M, Kawashima H, Kobayashi K, Taira N, Takashima T, Takahashi M, Tsuneizumi M, Nakayama T, Baba S, Bando H, Mizuno T, Yamaguchi M, Yamamoto Y, Uemura Y, Ohashi Y, Mukai H. A randomized controlled trial of postoperative adjuvant therapy for elderly breast cancer patients: Comparison of health-related quality of life between clinical trial participants and decliners. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-09.

In this study, we developed a superior 15 kV silicon carbide (SiC) metal-oxide-semiconductor field-effect transistor (MOSFET) with a current spreading layer (CSL) implanted with nitrogen ions. This MOSFET was developed for high-frequency applications. The CSL and junction field-effect transistor (JFET) regions were optimized using device simulations to reduce reverse transfer capacitance without increasing on-resistance. A SiC MOSFET with a CSL and a die with a size of 5 mm × 5 mm was fabricated. We simultaneously obtained a specific on-resistance of 191 mΩ cm2, a blocking voltage of 15.0 kV, and a reverse transfer capacitance of 0.75 pF for a narrow JFET width of 1.2 μm. In addition, threshold voltage shifts were kept within ±0.1 V for 1000 h at a gate voltage of −15 V and at a temperature of 200 °C.

Background: Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy for 2-3 years is the treatment of choice for hormone-receptor-positive breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may reduce the risk of breast cancer recurrence. Methods: We conducted a prospective randomized multi-center open-label phase III trial to assess the effect of the extended use of anastrozole for an additional 5 years. Postmenopausal patients with stageI-III, hormone-receptor-positive breast cancer, disease-free after 5 years of either anastrozole alone or tamoxifen 2-3 years followed by anastrozole 3-2 years were randomized to continual group with anastrozole for an additional 5 years or stop group without an additional anastrozole. Our primary end point was disease-free survival. Results: We enrolled 1697 women. After a median follow up of 4.9 years, there were 149 events involving disease recurrence or the occurrence of contralateral breast cancer (51 in continual group and 98 in stop group) and 7 deaths (3 in continual group and 4 in stop group). The 5-year disease-free survival rate was 91.9% (95% confidence interval [CI], 89.4 to 93.8) in continual group and 84.4% (95% CI: 80.0 to 88.0) in stop group (hazard ratio for disease-free survival,0.548 ;P=0.0004. by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, institution, and choice of anastrozole or tamoxifen). The rate of 5-year overall survival was 99.5% in continual group and 99.6% in stop group. (hazard ratio,1.389 ;P=0.665). The rate of 5-year distant disease-free survival was 97.2% in continual group and 94.3% in stop group (hazard ratio,0.514 ;P=0.0077). Bone-related adverse events were observed more frequently among patients in continual group than among patients in stop group, including a higher incidence of bone pain, stiff joints, bone fractures, and new-onset osteoporosis. Conclusion: The extension of treatment with an adjuvant aromatase inhibitor (anastrozole) to 10 years resulted in significantly higher rates of disease-free survival and distant disease-free survival than those with no additional anastrozole, but the rate of overall survival was not different between two groups. Our study shows that it is safe and beneficial for postmenopausal patients with hormone-receptor-positive breast cancer to take an anastrozole as adjuvant therapy for an additional 5 years after initial treatment. (UMIN:000000818) Citation Format: Ohtani S, Iijima K, Higaki K, Sato Y, Hozumi Y, Hasegawa Y, Takei H, Tanaka M, Yagata H, Masuoka H, Tanabe M, Egawa C, Komoike Y, Saji S, Nakamura T, Yanagita Y, Ohtsu H, Mukai H, Iwase T. A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years - Results from 1697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-04.

Although improved long-term prognoses for patients with metastatic breast cancer (MBC) have been demonstrated, few reports address overall survival (OS) with sufficient follow-up. Furthermore, the relevance of immunohistological subtypes to OS in MBC has not been clarified. We evaluated, retrospectively, the OS of patients who had been initiated on systemic therapy for MBC between 2000 and 2008. The subjects of this study were 527 patients with MBC treated by systemic therapy. The median survival time (MST) was 55.5 months. The MST for each immunohistological subtype was as follows: luminal, 59.9 months; luminal-HER2, not reached; triple-negative, 18.6 months; and HER2-enriched, 49.9 months. According to multivariate analysis, metastasis-free intervals of ≥2 years and treatment with anthracycline for MBC were predictive of better OS. The predictors of shorter OS included disease progression after first-line treatment for MBC, triple-negative, and all histological factors, except papillotubular carcinoma, with liver metastasis, and having three or more initial metastatic sites. The prognosis of the patients with MBC in this series was better than that reported before 2000, which is probably attributable to the use of novel, improved pharmacological agents. For example, luminal-HER2 tumors can be treated using both aromatase inhibitors and trastuzumab. Because of the lower toxicities, it is now possible to administer these agents for longer periods, resulting in better prognoses.

Background: HER2-positive breast cancer has a high risk of developing brain metastasis compared to other subtypes of breast cancer. However, the clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine clinicopathological factors associated with prognosis of HER2-positive patients developed brain metastasis. Methods: A retrospective large dataset of 432 HER2-positive patients who were diagnosed with brain metastases between 2001 and 2012 were collected from 24 institutions of the Japan Clinical Oncology Group: Breast Cancer Study Group. We assessed the clinicopathological factors associated with prognosis of these populations with brain metastases. Results: The median age of the 432 patients was 54 years (range, 20–86 years). Of the patients, 162 patients (37.5%) had ER-positive/HER2-positive (ER+HER2+) breast cancer and 270 patients (62.5%) had ER-negative/HER2-positive (ER-HER2+) breast cancer. Nineteen of the 162 patients with ER+HER2+ (12%) and 53 of the 270 patients with ER-HER2+ (20%) underwent surgery for brain metastases. After the diagnosis of brain metastasis, 108 patients with ER+HER2+ (63%) and 175 patients with ER-HER2+ (64%) received HER2-targeting agents, including trastsuzumab and/or lapatinib. The median brain metastasis-free survival period from the diagnosis of primary breast cancer was 33.5 month in both subtypes. In 63.4% of patients with ER+HER2+subtype and 75.6% of patients with ER-HER2+, brain metastases were detected within 2 years after development of first distant metastasis. Eighty-four patients with ER+HER2+ subtype (52%) and 133 patients with ER-HER2+ (49%) had more than 3 brain metastases at the diagnosis. The median survival period after developing brain metastasis was 16.5 months (95% confidence interval [CI], 11.9–21.1 months) in patients with ER+HER2+ and 11.5 months (95% CI, 9.1–13.8 months) in patients with ER-HER2+ (p = 0.117). Patients with more than 3 brain metastases had significantly shorter OS period than patients with equal or less than 3 brain metastases in both of ER+HER2+ (p < 0.001) and ER-HER2+ (p = 0.018). According to receiving HER2-targeting agents, patients receiving both of trastsuzumab and lapatinib had significantly longer survival period than patients who had received trastsuzumab alone, lapatinib alone, or no HER2-targeting agent (p < 0.001). Conclusions: Our results showed that HER2-positive patients with more than 3 brain metastases at the diagnosis had poor prognosis regardless of ER-positivity, and receiving both of trastsuzumab and lapatinib might improve their survival. Further studies are needed to determine the best treatment strategy including these HER2-targeting agents for these populations. Citation Format: Naoki Hayashi, Naoki Niikura, Norikazu Masuda, Seiki Takashima, Rikiya Nakamura, Ken-Ichi Watanabe, Chizuko Kanbayashi, Mayumi Ishida, Yasuo Hozumi, Michiko Tsuneizumi, Naoto Kondo, Yoichi Naito, Yayoi Honda, Akira Matsui, Tomomi Fujisawa, Risa Oshitanai, Hiroyuki Yasojima, Hideko Yamauchi, Shigehira Saji, Hiroji Iwata. Prognostic factor of HER2-positive breast cancer patients developed brain metastasis: A multicenter retrospective analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-08.

The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20–86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER−HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER−HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p < 0.001) and ER−HER2+ (p = 0.018) groups. Treatment with trastuzumab before developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p < 0.001). For HER2-positive patients with brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.

This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment. 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. 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%. Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective. UMIN CTR C000000416 . Registered on May 10, 2006.

In this paper, a 13-kV SiC MOSFET with a retrograde doping profile in junction field-effect transistor (JFET) regions, which were implanted by nitrogen ions with multiple energies, has been developed for power supplies of X-ray generators and electron guns with an accelerating voltage greater than 10 kV. A JFET region was optimized with device simulation to reduce on-resistance. A SiC MOSFET with an optimized JFET region was fabricated with a 5 mm × 5 mm die size. The specific on-resistance (R onA ) was estimated to be 169 mΩ·cm2. The blocking voltage (BV DSS ) of 13.1 kV was obtained at 10 μA/cm2. Owing to a low electric field in the gate oxide (E ox ), a threshold voltage (V th ) shift within ± 0.06 V was achieved at the gate voltage of −15 V (equal to an electric field of −3 MV/cm) and 200 °C for 1000 hours. The dynamic test with inductive load resulted in turn-off and turn-on switching speeds of 75 kV/μs and 114 kV/μs, respectively, for the DC bus voltage of 10 kV at room temperature.

Pathological complete response (pCR) is considered to be a useful prognostic marker for neoadjuvant chemotherapy to improve the survival rate of patients with operable breast cancer. In the present study, we identified differentially expressed microRNAs (miRNAs) between pCR and non-pCR groups of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received neoadjuvant chemotherapy with trastuzumab. Expression profiles were examined by miRNA microarrays using total RNA extracted from formalin-fixed, paraffin-embedded tissues from pretreatment biopsy specimens. Significant differences were observed in miRNAs associated with pCR between the luminal B-like (HER2-positive) and HER2-positive (nonluminal) subtypes, which were further classified according to their estrogen receptor (ER) status. Prediction models constructed with differentially expressed miRNAs performed well. In conclusion, the combination of miRNA profiles and ER status may improve the accuracy of pCR prediction in patients with HER2-positive breast cancer and enable the development of personalized treatment regimens.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Aromatase inhibitors are superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. We report the follow-up efficacy results from the N-SAS BC 03 trial (UMIN CTRID: C000000056) where anastrozole was compared with tamoxifen as adjuvant therapy in postmenopausal Japanese patients with hormone-responsive early breast cancer. The full analysis set contained 696 patients (anastrozole arm, n = 345; tamoxifen arm, n = 351). The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS); Kaplan–Meier estimates were calculated. The treatment effects were estimated by Cox’s proportional hazards model. To examine time-varying effect of hazard ratios, we estimated time-varying hazard ratios at time t [HR(t)] using data from time t up to 12 months. After a median follow-up of 98.5 months, hazard ratios (95 % CIs) were 0.90 (0.65–1.24; log-rank p = 0.526) for DFS and 0.83 (0.56–1.23; log-rank p = 0.344) for RFS. Hazard ratios (95 % CIs) for DFS and RFS up to 36 months were 0.69 (0.40–1.17) and 0.54 (0.27–1.06) and those after 36 months were 1.06 (0.70–1.59) and 1.05 (0.64–1.73), respectively. Time-varying hazard ratios for both DFS and RFS showed that hazard ratios were initially in favor of anastrozole and approached 1.0 at around 36 months. Superior efficacy of anastrozole to tamoxifen suggested by the initial analysis was not confirmed in the present analysis after a long-term follow-up period. Advantage of anastrozole was the greatest immediately after switching from tamoxifen and then decreased thereafter.

To define prognostic factors for breast cancer patients with brain metastases, compare their clinical courses and prognoses according to breast cancer subtypes, and analyze the causes of death in such patients. We retrospectively analyzed 1,466 patients diagnosed with brain metastases between April 1, 2001 and December 31, 2012, from 24 institutions of the Japan Clinical Oncology Group. Overall, 1,256 patients with brain metastases were included. The median overall survival (OS) was 8.7 months (95 % confidence interval [CI] 7.8–9.6 months). Univariate and multivariate analyses revealed that patients diagnosed with brain metastasis within 6 months of metastatic breast cancer diagnoses, asymptomatic brain disease, or HER2-positive/estrogen receptor-positive tumors had increased OS. Median OS after the development of brain metastases was 9.3 months (95 % CI 7.2–11.3) for the luminal type, 16.5 months (95 % CI 11.9–21.1) for the luminal-HER2 type, 11.5 months (95 % CI 9.1–13.8) for the HER2 type, and 4.9 months (95 % CI 3.9–5.9) for the triple-negative type. Luminal-HER2 type patients had significantly longer OS than patients with the luminal type (hazard ratio [HR] = 1.50, P

We investigated the disease-free survival (DFS) of HER2-positive primary breast cancer patients treated with neoadjuvant chemotherapy plus trastuzumab, as well as predictive factors for DFS and pathologic response. Data from 829 female patients treated between 2001 and 2010 were collected from 38 institutions in Japan. Predictive factors were evaluated using multivariate analyses. The 3-year DFS rate was 87 % [95 % confidence interval (CI) 85-90]. The pathologic complete response (pCR: ypT0/is + ypN0) rate was 51 %. The pCR rate was higher in the ER/PgR-negative patients than in the ER/PgR-positive patients (64 vs. 36 %, P < 0.001). Patients with pCR showed a higher DFS rate than patients without pCR (93 vs. 82 %, P < 0.001). Multivariate analysis revealed three independent predictors for poorer DFS: advanced nodal stage [hazard ratio (HR) 2.63, 95 % CI 1.36-5.21, P = 0.004 for cN2-3 vs. cN0], histological/nuclear grade 3 (HR 1.81, 95 % CI 1.15-2.91, P = 0.011), and non-pCR (HR 1.98, 95 % CI 1.22-3.24, P = 0.005). In the ER/PgR-negative dataset, non-pCR (HR 2.63, 95 % CI 1.43-4.90, P = 0.002) and clinical tumor stage (HR 2.20, 95 % CI 1.16-4.20, P = 0.017 for cT3-4 vs. cT1-2) were independent predictors for DFS, and in the ER/PgR-positive dataset, histological grade of 3 (HR 3.09, 95 % CI 1.48-6.62, P = 0.003), clinical nodal stage (HR 4.26, 95 % CI 1.53-13.14, P = 0.005 for cN2-3 vs. cN0), and young age (HR 2.40, 95 % CI 1.12-4.94, P = 0.026 for ?40 vs. >40) were negative predictors for DFS. Strict pCR (ypT0 + ypN0) was an independent predictor for DFS in both the ER/PgR-negative and -positive datasets (HR 2.66, 95 % CI 1.31-5.97, P = 0.006 and HR 3.86, 95 % CI 1.13-24.21, P = 0.029, respectively). These results may help assure a more accurate prognosis and personalized treatment for HER2-positive breast cancer patients.

1083 Background: Anthracycline regimens and taxane have been first line chemotherapeutic options for HER2 negative metastatic breast cancer. In a previous phase III trial (SELECT BC), non-inferiority of S-1 was demonstrated in terms of overall survival (OS). The SELECT BC-CONFIRM study was designed to confirm the results of the SELECT BC study and to combine the two randomized studies. Methods: Patients (n = 618) in the first trial were randomly assigned (1:1) to the S-1 group or the taxane group. Patients (n = 230) in the second trial (SELECT BC-CONFIRM) were randomly assigned to the anthracycline group or the S-1 group. Treatment continued until tumor progression, unacceptable toxic effects, or completion of six courses in the standard regimen group and four courses in the S-1 group. The primary endpoint was OS and secondary endpoints were progression-free survival (PFS), time to treatment failure, adverse events, HRQOL and cost-effectiveness. A pooled analysis of the two studies was predefined to confirm the results of the SELECT BC study. Results: 1. The HR for the anthracycline group was 1.09 [95%CI 0.80-1.48] in SELECT BC-CONFIRM, and the estimated predictive posterior probability that the HR does not exceed the threshold 1.333 was 90.27%. 2. Median OS was 32.7 months (S-1 group) and 36.3 months (standard treatment group). S-1 was not inferior to standard treatment in terms of OS (p non-inferiority = 0.0062). Median PFS was 11.2 months (S-1 group) and 11.2 months (standard treatment group). 3. Treatment was discontinued due to adverse events (i.e., neutropenia, febrile neutropenia, fatigue and edema) in 5.7% in the S-1 group and 6.6% in the standard treatment group 4. The EORTC QLQ-C30 questionnaire (global health status) revealed that there was no difference between the S-1 and anthracycline groups (p = 0.257), but there was a significant difference between the S-1 and taxane groups (p = 0.0039). Conclusions: S-1 is not inferior to taxane or anthracycline with respect to OS as a first-line treatment for MBC. S-1 should be considered a new option as a first-line chemotherapy for HER2-negative metastatic breast cancer patients. Clinical trial information: UMIN000005449.

In this study, we developed a superior 15 kV silicon carbide (SiC) metal-oxide-semiconductor field-effect transistor (MOSFET) with a current spreading layer (CSL) implanted with nitrogen ions. This MOSFET was developed for high-frequency applications. The CSL and junction field-effect transistor (JFET) regions were optimized using device simulations to reduce reverse transfer capacitance without increasing on-resistance. A SiC MOSFET with a CSL and a die with a size of 5 mm × 5 mm was fabricated. We simultaneously obtained a specific on-resistance of 191 mΩ cm2, a blocking voltage of 15.0 kV, and a reverse transfer capacitance of 0.75 pF for a narrow JFET width of 1.2 μm. In addition, threshold voltage shifts were kept within ±0.1 V for 1000 h at a gate voltage of −15 V and at a temperature of 200 °C.

(Background) After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is uncertain which of endocrine therapy is the most appropriate. (Methods) A randomized, open-label, multicenter phase II study was conducted to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, with exemestane 25 mg (EXE), a steroidal aromatase inhibitor. After disease progressed with assigned drug, the patients were subsequently treated with the other drug if patients were suitable for continuation with endocrine treatment. The primary endpoint was clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), toxicity and antitumor effect of subsequent endocrine treatment. To prove a probability of 90% that TOR120 was superior to EXE, 41 patients were required for each group. To account for dropouts and protocol violation, we planned to recruit 90 patients (45 in each group). (Results) Initially, a total of 91women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there was no statistical difference between TOR120 (n = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%, p = 0.14), ORR (10.8% vs. 2.2%, p = 0.083), and OS (Hazard ratio (HR) 0.60, p = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (HR 0.61, p = 0.045). Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women with TOR120 was stopped after a few days because of nausea, general fatigue, hot flash and night sweating. Twenty-four patients received subsequent TOR120 after failure of initial EXE treatment. Of these patients, ORR and CBR were 4.2% (1/24) and 33.3% (8/24), respectively. In 23 patients who received EXE after TOR120, ORR and CBR were 17.4% (4/23) and 30.4% (7/23), respectively. (Conclusion) TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could be equal to or potentially be more beneficial than EXE. In addition, about one third of patients who progress on either TOR120 or EXE could obtain clinical benefit from subsequent EXE or TOR120. Trial registration number: UMIN000001841. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-01.