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Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. Results: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI < 25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses.Trial registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

Trastuzumab may convert human epidermal growth factor receptor-2 (HER2)-positive primary breast tumors to HER2-negative tumors after chemotherapy. This study determined whether trastuzumab increases the number of patients with conversion to HER2-negative status and assessed the effect of neoadjuvant chemotherapy.We retrospectively reviewed 46 patients diagnosed with HER2-overexpression in primary breast cancers at Tokai University Hospital, receiving neoadjuvant chemotherapy by immunohistochemistry and fluorescence in situ hybridization (FISH). Surgical specimens of patients achieving less than pathological complete response (pCR) were verified for sufficient residual tissue to evaluate post-treatment HER2 status by dual-color in situ hybridization (DISH).pCR was achieved in 8 of the 46 (17.4%) patients. The residual tumor was sufficient for a ssessing post-treatment HER2 status in 25 patients. DISH of pretreatment specimens confirmed HER2 amplification prior to therapy. Of the 25 HER2-positive patients, DISH revealed 3 were HER2 negative in pretreatment specimens. No post-treatment tumors were HER2-negative according to DISH in HER2-positive pre-treatment tumors. Among HER2-negative pretreatment tumors, 1 post-treatment tumor was HER2 positive and 2 had stable HER2 status.HER2 status determined by DISH was stable between pretreatment breast tumors and residual tumors. However, a small discrepancy regarding HER2 status determined by immunohistochemistry and DISH existed.

Background Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. Methods In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. Results Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. Conclusion In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

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

Cancer of unknown primari (CUP) are said to account for 2% of all carcinomas. Here we report a rare case of CUP confined to the retroperitoneum.A 51-year-old man consulted a nearby physician for back pain. The malignant tumor could not be denied by MRI, and she was referred to our hospital. CT and MRI revealed uneven enhanced tumor structures protruding into the L2/3 disc. Part of the tumor was continuous with the left iliopsoas muscle. A CT-guided needle biopsy was performed. Histologically, the sheet-like proliferation of atypical cells was observed. Immunohistochemistry showed that atypical cells were positive for cytokeratin AE13, CK7, CD10, GATA3, glypican 3, Hep Par 1, carbonic anhydrase 9 (focal), and vimentin (focal) but negative for CK20, CD56, chromogranin A, synaptophysin, TTF1, HMB45, melan A, and PSA. The pathological diagnosis was poorly differentiated carcinoma. However, it was difficult to determine the primary site from the pathological findings. Positron emission tomography (PET) scan showed no distant metastases. He was diagnosed as poorly differentiated cancer localized to the lumbar spine from the retroperitoneum. Paclitaxel plus carboplatin (TC) was started. After completing 3 kr of TC, she was hospitalized urgently due to worsening lumbago. CT and MRI at admission showed an increase in the main lesion and exacerbation of bone invasion. Radiation therapy was given for curative purposes. Eventually, he died seven months after visiting our hospital and five months after starting TC therapy.CUP has various disease states, and it is necessary to finish the examination immediately and shift to treatment. More effective treatment including immune checkpoint inhibitor for CUP is needed in the future.

The Japanese Breast Cancer Society (JBCS) registry began data collection in 1975, and it was integrated into National Clinical Database in 2012. As of 2016, the JBCS registry contains records of 656,896 breast cancer patients from more than 1400 hospitals throughout Japan. In the 2016 registration, the number of institutes involved was 1422, and the total number of patients was 95,870. We herein present the summary of the annual data of the JBCS registry collected in 2016. We analyzed the demographic and clinicopathologic characteristics of registered breast cancer patients from various angles. Especially, we examined the registrations on family history, menstruation, onset age, body mass index according to age, nodal status based on tumor size and subtype, and proportion based on ER, PgR, and HER2 status. This report based on the JBCS registry would support clinical management for breast cancer patients and clinical study in the near future.

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients that received POC to those that had not and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated by an oncologist over 8 weeks between groups. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. Results: There were no significant differences in PFS between the POC and Control Groups ( P = 0.801). A BMI < 25 mg/m 2 and non-visceral metastasis were associated with longer PFS ( P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS ( P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI < 25 mg/m 2 , and who did not receive BMA while receiving EVE and EXE may have better prognoses. Trial registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov (NCT02376985).

In recent years, human immunodeficiency virus(HIV)-negative Pneumocystis pneumonia(PCP)onset has been occasionally seen in breast cancer. In particular, dose-dense epirubicin and cyclophosphamide(EC: ddEC)therapy, in which EC is administered every 2 weeks, has been generally used in clinical practice for early stage breast cancers. PCP may develop before and during postoperative chemotherapy. We report the cases of 2 patients who developed PCP during postoperative adjuvant chemotherapy. Case 1: A 62-year-old woman, who underwent postoperative EC therapy, developed PCP during the 4th EC cycle. During EC therapy, steroids(prednisolone[PSL])were administered at an average dose of 11.4mg/day, and the number of lymphocytes at the initiation of the 4th EC cycle was 516/mL. Case 2: After receiving 4 cycles of postoperative ddEC, a 27-year-old woman developed PCP after 1 cycle of docetaxel(DTX)administration. During ddEC therapy, PSL was administered at a dose of 17.14mg/day, and the number of lymphocytes at DTX administration was 311/mL. The onset of PCP is presumed to be related to the steroid dose administered and the number of lymphocytes. Therefore, determining effective indicators in patients at a high risk of PCP onset is important.

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

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

Background: Neoadjuvant chemotherapy (NAC) for breast cancer has been improved and pathological complete response (pCR) achieved in about 50% of Her2 positive tumor and over 30% of triple negative tumor. It is possible that not to perform surgery if pCR is diagnosed accurately. This study was performed to examine diagnostic ability of core needle biopsy (CNB) to detect pCR by NAC. (Study registry number: UMIN000012035) Methods: In this multicenter study, we registered histologically proved breast cancer patients who were diagnosed as clinical complete response (cCR) after NAC. The cCR was diagnosed by contrast-enhanced magnetic resonance imaging (MRI) after NAC by radiologists in each facility. Regimens of NAC were not specified by study protocol. A clip marker was not placed in the tumor before NAC. At the operating table, ultrasound-guided CNB is performed before starting the surgery. The CNB was performed with 14 gauge needle without vacuum assistance and requiring three biopsy specimens. The concordance of pathological results between a core needle biopsy and a surgical specimen is examined by pathologists at each facility. The pathological diagnosis was categorized as i) no carcinoma (pCR), ii) carcinoma in situ (CIS) and iii) invasive carcinoma. Results: The study included 86 women from 10 facilities, accrued from December 2013 to March 2017. Median age was 53.5 (31-75) years and median tumor size before NAC was 2.3 (0.9-7.3) cm. Estrogen receptor was positive in 32 (37%). HER2 was positive in 40 (47%). The clinical stage before NAC was stage I 19 (22%), II 48 (56%), III 16 (19%) and IV 3 (3%). All cases were administered cytotoxic agents. Both anthracycline and taxane were given in 70 cases (81%), and trastuzumab was administered in 35 (41%) cases. As for breast surgery, partial resection was performed in 53 cases (62%), whereas 33 cases (38%) underwent mastectomy. Pathological examination on surgical specimen revealed pCR (i) in 41 cases (48%), CIS (ii) in 17 cases (20%) and invasive carcinoma (iii) in 28 cases (32%). Results of pathology of CNB and surgical specimens are shown in table 1. Table 1. Pathological diagnosis of CNB and surgical specimens Surgical specimen No carcinoma (pCR)Residual carcinomaTotalCNBNo carcinoma (pCR)41 (NPV=63%, spec.=100%)24 (FNR=53%, 14 were CIS)65 (76%) Residual carcinoma021 (PPV=100%, sens.=47%)21 (24%)Total41 (48%)45 (52%)86 (100%)CNB: core needle biopsy, FNR: false-negative rate, CIS: carcinoma in situ, NPV: negative predictive value, PPV: positive predictive value, sens.: sensitivity, spec.: specificity. The kappa value was 0.455 which was not enough for accurate diagnosis. In 24 discordant cases, residual tumor was found in surgical specimen but not in CNB, residual disease was CIS in 14 cases. Conclusions: Up to 10% false negative rate of pCR may allow us to proceed to an observational study without performing surgery.This study revealed that the ultrasound-guided CNB for cCR cases by MRI was not accurate enough to omit surgery. Thus, imaging diagnosis and biopsy methods need to be improved. However, it is still possible to consider because the post-operative radiotherapy may compensate for surgery in cases with CIS after NAC. Citation Format: Narui K, Ishikawa T, Hasegawa Y, Kaise H, Kawate T, Yamada K, Suzuki Y, Niikura N, Kohno N, Kimoto T, Sugae S, Yamada A, Kosaka Y, Miyashita M, Okamura T, Shimizu D, Tanino H, Sakamaki K, Tokuda Y. Feasibility study to diagnose pathological complete response by neoadjuvant chemotherapy in breast cancer adding core needle biopsy (KBOG1301 supported by JONIE) [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 P5-22-09.

Background: Postmastectomy radiotherapy (PMRT) has been shown to be beneficial in node-positive breast cancer patients. However, the role of PMRT for patients receiving modern neoadjuvant chemotherapy (NAC) are controversial. We aimed to evaluate the efficacy of radiotherapy for breast cancer patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry. Methods: Patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer were included in this analysis. We assessed locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) using the Kaplan-Meier method and compared them between the groups with and without PMRT by nodal status after NAC; ypN0, ypN1, and ypN2-3. We also performed multivariable cox regression analysis to evaluate the association of radiotherapy and these outcomes adjusting for baseline patient and cancer characteristics. Results: Of the 145,530 patients registered from 2004 to 2009, we identified 3,226 patients who met our inclusion criteria with the 5-year follow-up information including 1,299 ypN0, 1,036 ypN1, and 879 ypN2-3 cases. PMRT was performed in 185 patients (14.2%) with ypN0, 265 patients (25.6%) with ypN1, and 543 patients (61.8%) with ypN2-3. There was no difference in LRR, DDFS, and OS between the groups with and without radiotherapy for ypN1 patients who received NAC (P=0.72, P=0.29, and P=0.36, respectively). For patients with ypN2-3 breast cancer, radiotherapy significantly improved LRR (P Effect of PMRT on locoregional recurrence by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN00.8550.4581.5960.623ypN10.8320.5491.2620.387ypN2-30.6080.4520.8180.001 Effect of PMRT on overall survival by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN01.3250.8412.0870.224ypN10.8800.5991.2930.514ypN2-30.6850.5310.8850.004 Radiotherapy was not associated with OS among patients with ypN0 [HR: 1.325, 95% CI: 0.841–2.087, P=0.224] and ypN1 [HR: 0.880, 95% CI: 0.599–1.293, P=0.514]. There was no significant difference in DDFS with the addition of radiotherapy for all ypN subgroups. Conclusions: The results from this nationwide database study of breast cancer patients following modern NAC showed that PMRT did not improve survival for patients with ypN1 and ypN0. Radiotherapy might be only beneficial for ypN2-3 breast cancer patients who received NAC and mastectomy in the modern era. Randomized clinical trials are needed to optimize the use of PMRT for breast cancer patients treated with neoadjuvant chemotherapy. Citation Format: Miyashita M, Niikura N, Kumamaru H, Miyata H, Ishida T, Kinoshita T, Tsuda H, Nakamura S, Tokuda Y. Role of postmastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A study from the Japanese breast cancer registry [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 P2-11-11.

Background Historically, humoral immunity was considered unimportant in anti-tumor immunity, and the differentiation and anti-tumor activity of B cells in breast cancer are poorly understood. However, it was recently discovered that B cells participate in tumor immunity through both antibody production and immunosuppressive mechanisms. We analyzed the expression of B-cell differentiation markers in detail using fluorescence-activated cell sorting to investigate the relationship between B-cell subsets and breast cancer etiology. Methods Blood samples were taken from breast cancer patients and healthy donors, and peripheral blood mononuclear cells were collected. B cells at various stages of differentiation were identified by the expression of combinations of the cell surface markers CD5, CD19, CD21, CD24, CD27, CD38, CD45, and IgD. Statistical analysis of the proportions of each B-cell subtype in the different patient groups was then performed. Results Twenty-seven breast cancer patients and 12 controls were considered. The proportion of total B cells was significantly higher in cancer patients than in controls (11.51 ± 2.059 vs 8.905 ± 0.379%, respectively; p = 0.001). Breast cancer patients were then classified as High-B or Low-B for further analysis. A significantly higher proportion of memory B cells was found in the High-B group than in the Low-B or control groups (p = 0.003 and p = 0.043, respectively). Conclusions Breast cancer patients generally have a higher proportion of B cells than healthy controls, but this is highly variable. Analysis of the major B-cell surface markers indicates that memory B cells in particular are significantly expanded, or more robust, in breast cancer patients. Electronic supplementary material The online version of this article (10.1007/s12282-017-0824-6) contains supplementary material, which is available to authorized users.

BACKGROUND Despite treatment advances, up to 50% of patients with advanced HER2+ BC develop BM (Zimmer. Cancer Rep. 2020). Patients with HER2+ BC with BM have a worse prognosis than patients without BM. In DESTINY-Breast01, T-DXd demonstrated efficacy in the overall population and preliminary efficacy in a subgroup with stable BM, with a confirmed objective response rate (ORR) of 61.4% and an extracranial confirmed ORR by independent central review (ICR) of 58.3%, median progression-free survival (PFS) of 19.4 and 18.1 mo, and median duration of response (DOR) of 20.8 and 16.9 mo (Modi. Cancer Res. 2021; Jerusalem. Ann Oncol. 2020). Here we describe a trial evaluating T-DXd in patients with previously treated advanced/metastatic HER2+ BC ±BM. DESIGN DESTINY-Breast12 (NCT04739761) is an open-label, multicenter, international (86 sites in the US, Europe, Australia, and Japan), phase 3b/4 study assessing T-DXd 5.4 mg/kg q3w efficacy and safety in patients with previously treated advanced/metastatic HER2+ BC ±BM that progressed with ≥1 prior anti-HER2–based regimen and received ≤2 lines of therapy in the metastatic setting (excluding patients with prior tucatinib). Patients (n=250/cohort) will be enrolled in cohort 1 (−BM at baseline) or 2 (+BM at baseline). BM must be untreated and not needing immediate local therapy or previously treated and stable or progressing. Primary endpoints are ORR (cohort 1) and PFS (cohort 2) (both by RECIST version 1.1 per ICR). Secondary endpoints are OS, DOR, time to progression, duration of subsequent therapy, PFS2, safety, and changes in symptoms, functioning, and QOL in both cohorts; incidence of new symptomatic CNS metastasis (CNSM) in cohort 1; and ORR and CNS ORR by RECIST 1.1 per ICR, CNS PFS and DOR, and time to new CNSM in cohort 2. This is an encore; the original presentation will be at The European Society for Medical Oncology 2021.

// Rin Ogiya 1 , Naoki Niikura 1 , Nobue Kumaki 2 , Hiroyuki Yasojima 3 , Tsutomu Iwasa 4 , Chizuko Kanbayashi 5 , Risa Oshitanai 1 , Michiko Tsuneizumi 6 , Ken-ichi Watanabe 7 , Akira Matsui 8 , Tomomi Fujisawa 9 , Shigehira Saji 10 , Norikazu Masuda 3 , Yutaka Tokuda 1 and Hiroji Iwata 11 1 Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan 2 Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan 3 Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan 4 Department of Medical Oncology, Kindai University School of Medicine, Osaka, Japan 5 Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan 6 Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, Japan 7 Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan 8 Department of Surgery, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan 9 Department of Breast Oncology, Gunma Prefectural Cancer Center, Gunma, Japan 10 Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan 11 Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan Correspondence to: Naoki Niikura, email: niikura@is.icc.u-tokai.ac.jp Keywords: breast cancer, brain metastases, tumor infiltrating lymphocytes, PD-L1, immune microenvironment Received: July 11, 2017 Accepted: September 20, 2017 Published: October 27, 2017 ABSTRACT Background: Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. Results: The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1–70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t -test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t -test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04). Materials and Methods: We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed. Conclusions: There are significantly fewer TILs in brain metastases than in primary breast tumors.

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P

Introduction Axillary lymph node dissection is standard therapy for patients with positive-node breast cancer, and can be performed with an electrocautery scalpel and suture ligation in most cases. However, knot slipping can occur during suture ligation and this can spread thermal damage to peripheral tissues. The LigaSureTM Small Jaw vessel-sealing system was developed as an alternative to suture ligatures, staplers, and other energy-dependent devices for sealing blood and lymphatic vessels, but its use in axillary dissection for breast cancer is limited. We prospectively compared the duration until drain removal after surgery, total lymph fluid drainage volume, intraoperative blood loss, and incidence of complications after axillary dissections, between this device and conventional methods. Methods This prospective randomized study was conducted at the Department of Breast and Endocrine Surgery at Tokai University School of Medicine, Kanagawa, Japan, between October 2011 and March 2015. Major eligibility criteria included (1) pathologically confirmed breast cancer diagnosis, (2) age ≥20 and ≤80 years, and (3) a signed informed consent form. The primary endpoint was duration until drain removal after surgery. The secondary endpoints were total lymph fluid drainage volume, intraoperative blood loss, and incidence of postoperative surgical complications. We defined the criterion for drain removal as a lymph fluid drainage volume of Results Initially, 100 patients were assigned as eligible; however, two patients were later excluded because of the exclusion criteria. Of 98 patients, 49 were randomized to the study group, and 49 to the control group. The mean duration until drain removal after surgery was 5.2 days in the study group and 5.0 days in the control group (p=0.573). The mean total lymph fluid drainage volumes were 260.3 and 233.5 mL (p=0.502), and the mean intraoperative blood loss volumes were 17.8 and 18.0 mL (p=0.949), for the study and control groups, respectively. No significant differences were found between the two groups regarding drain removal duration, total drainage volume, and intraoperative blood loss volume. Both groups had low incidence rates of postoperative hematoma, wound infection, lymphedema, and pain, and had similar incidence rates of seroma formation after drain removal. Conclusion Our study results indicated that the use of the LigaSureTM Small Jaw in axillary dissection for breast cancer was as safe as conventional methods. However, using the LigaSureTM Small Jaw did not improve surgical outcomes such as duration until drain removal and total lymph fluid drainage volume compared with conventional methods. Citation Format: Okamura T, Niikura N, Yokoyama K, Ogiya R, Oshitanai R, Terao M, Morioka T, Tsuda B, Saito Y, Suzuki Y, Tokuda Y. Utility of LigaSureTM vessel-sealing device in axillary dissection for breast cancer surgery: A randomized single center study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-11.

Background: Breast cancer bone metastasis (BCBM)-specific genes have been reported without considering biological differences based on estrogen receptor (ER) status. The aims of this study were to identify BCBM-specific genes using our patient dataset and validate previously reported BCBM-specific genes, and to determine whether ER-status-related biological differences matter in identification of BCBM-specific genes. Methods: We used Affymetrix GeneChips to analyze 365 primary human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer specimens. Genes that were differentially expressed between patients who developed bone metastasis and those who developed non-bone metastasis were identified using Cox proportional hazards model, and differential expression of gene sets was assessed using gene set analysis. We performed gene set analysis to determine whether biological function associated with bone metastasis were different by ER status using 2,246 functionally annotated gene sets assembled from Gene Ontology data base. Results: Among 16,712 probe sets, 592 were overexpressed in the bone metastasis cohort compared to the non-bone-metastasis cohort (false discovery rate ≤ 0.05). However, no BCBM-specific genes met our significance tests when the cancers were stratified by ER status. In ER-positive and ER-negative breast cancers, 151 and 125 gene sets, respectively, were overexpressed for BCBM and the majority of BCBM-related pathways were different. Of significant gene sets, only 13 gene sets were overlapped between ER-positive and -negative cohorts. Conclusion: ER-positive and ER-negative breast cancers have different biological pathways in BCBM development. We have yet to explore BCBM-related biomarkers and targets considering the biological features associated with BCBM depending on the ER status.

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

Background: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. Patients and methods: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I–IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1–L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were (1) rate of change in the lumbar spine (L1–L4) BMD after 2, 3, 4, and 5 years; (2) rate of change in the femoral neck BMD; (3) rate of change in radius BMD (determined using an ultrasonic bone densitometer); (4) changes in calcium and bone metabolism markers (TRAP 5b, bone alkaline phosphatase, and pentosidine); (5) development of pathological fracture within 3 years; (6) disease-free survival; (7) overall survival (OS); (8) adverse events; and (9) quality of life. Ethics and dissemination: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. Trial registration: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Background Immunoglobulin (Ig) G4-related sclerosing disease is a pathological concept proposed in Japan during the early 2000s. This lesion-forming disease may exhibit characteristics of a systemic disease but often affects a single organ. To date, IgG4-related sclerosing disease in the mammary gland, or IgG4-related mastitis (IgG4-RM), has rarely been reported. Case presentation Here, we describe the case of a female patient who was admitted to our hospital with the main complaints of left breast and axillary lymphadenopathy. A careful diagnostic imaging examination led to an initial suspicion of breast cancer. However, a needle biopsy led to a diagnosis of IgG4-RM. Subsequently, the patient was successfully treated with predonin. Conclusions The treatment requirements for breast cancer and IgG4-RM differ considerably. This is a good example of a case wherein unnecessary surgical treatment, which is indicated for breast cancer, was avoided by needle biopsy. Accordingly, the patient was appropriately treated with steroids following a correct diagnosis.

A 49-year-old woman, with a medical history of rheumatism, was admitted to our hospital with chief complaints of bilateral enlargement and redness of breasts. She underwent weekly breast examinations. Mammography findings were reported as category 3 for both breasts. Breast ultrasonography, magnetic resonance imaging, and chest contrast computed tomography revealed a massive tumor in the left BD region, however, there were no findings for suspected malignancy. Needle biopsy did not yield histologically malignant cells in both breasts. Mammary interstitium was edematous, and capillary-like slit structures were observed. The stroma stained with alcian blue and destained with hyaluronidase treatment. Since the stroma tested positive for vimentin, calponin, and CD34 and negative for CD31, the patient was diagnosed as (PASH). Because both breasts had similar diagnosis based on histopathologic findings, bilateral mastectomy was performed. Details about the origin of bilateral PASH are unknown but it may be related to the development of rheumatoid arthritis. Additionally, systemic autoimmune diseases like rheumatism may be the reason for repeated contraction and enlargement of PASH.

Background The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus‐induced oral mucositis. Materials and Methods This randomized, multicenter, open‐label, phase III study evaluated the efficacy of POC in preventing everolimus‐induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8‐week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2‐sided type I error rate of 5% and 80% power to detect 25% risk reduction. Results Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction. Conclusion POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT 02069093. Implications for Practice The Oral Care‐BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor‐positive, HER2‐negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus., Oral mucositis is a clinically significant complication of mucotoxic cancer therapy. This article focuses on the effect of dental intervention, before everolimus treatment, on oral mucositis.

Aim Lymphocyte predominant breast cancer (BC) is associated with higher pathological complete response (pCR) rate after neoadjuvant therapy (NAT) and favorable outcome in triple negative breast cancer (TNBC) and HER2+ BC. The predictive and prognostic impact of stromal tumour-infiltrating lymphocytes (TILs) after NAT and the change of TILs before (pre-) and after (post-) NAT are not well studied. We aimed to assess the predictive and prognostic value of pre- and post-NAT TILs, as well as their pharmacodynamics modulation and their change for TNBC and HER2+ BC. Materials and methods Two-hundred and nine consecutive patients (n = 80 TNBC, n = 129 HER2+ BC) who received NAT between 2001 and 2009 in a single institution were included. We evaluated the association between pre-NAT TILs and pCR, and the association between pre- and post-NAT TILs, as well as their immunodynamics change with relapse-free survival (RFS) for patients with residual disease (RD). Results Low pre-NAT TILs compared to int/high were significantly associated with lower pCR rate (TNBC: 4.0% vs 43.6%; HER2+ BC: 26.0% vs 51.9%). The median follow-up period was 98 months. In TNBC with RD, low pre-NAT TILs showed significant association with shorter RFS (HR = 3.844 [1.190–12.421], p = 0.024) in multivariate analysis. Low post-NAT TILs showed borderline significant association with shorter RFS (HR = 2.836 [0.951–8.457], p = 0.061). The change in TILs was not associated with RFS. In HER2+ BC, low pre-NAT TILs were not associated with RFS. Conclusion In TN and HER2+ BCs, low pre-NAT TILs tumours had a low likelihood of achieving pCR. In TNBC with RD, both low pre- and post-NAT TILs were associated with shorter RFS. These results suggest that TILs information should be taken into account when additional therapies may be given in the post-neoadjuvant setting.

The role of postmastectomy radiotherapy (PMRT) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is controversial. We aimed to evaluate the effectiveness of radiotherapy in patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry. We enrolled patients who received NAC and mastectomy for cT1–4 cN0–2 M0 breast cancer. We evaluated the association between radiotherapy and outcomes, locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) based on ypN status by multivariable analysis. Of the 145,530 patients, we identified 3226 who met the inclusion criteria. Among ypN1 patients, no differences were found in LRR, DDFS, or OS between groups with and without radiotherapy (p = 0.72, p = 0.29, and p = 0.36, respectively). Radiotherapy was associated with improved LRR-free survival (p

TPS1103 Background: Modulating estrogen synthesis and/or ER activity is the mainstay of treatment for pts with ER+ BC. Despite substantial progress, many pts experience relapse during/after adjuvant endocrine therapy. However, even though resistant to aromatase inhibitors (AIs) or tamoxifen, growth and survival of the majority of tumors are thought to remain dependent on ER signaling. Therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment after progression on prior therapy (Di Leo 2010; Baselga 2012). Therapeutic resistance can arise from mutations in ESR1, which can drive estrogen-independent transcription and proliferation. The highly potent, non-steroidal oral selective ER degrader giredestrant achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data indicate that giredestrant is well tolerated, with encouraging activity as a single agent and in combination with the CDK4/6 inhibitor palbociclib (Lim 2020). Single-agent activity was observed after prior treatment with fulvestrant and/or a CDK4/6 inhibitor (Jhaveri 2019). Methods: persevERA BC (NCT04546009) is a double-blind, placebo-controlled, randomized, multicenter phase III study designed to evaluate the efficacy and safety of first-line giredestrant + palbociclib in pts with ER+/HER2– LA/mBC. Randomization: 1:1 to either giredestrant (30 mg PO) plus letrozole placebo QD or letrozole (2.5 mg PO) plus giredestrant placebo QD on Days 1–28 of each 28-day cycle, with palbociclib (125 mg PO QD) on Days 1–21 of each 28-day cycle. Men and premenopausal women will receive an LHRH agonist. Eligibility: females or males ≥18 years old with measurable disease or evaluable bone disease and no prior treatment for advanced disease. Pts who received prior fulvestrant or who have relapsed within 12 months of completion of (neo)adjuvant therapy with an AI and/or prior therapy with CDK4/6 inhibitor are not eligible; relapse during tamoxifen therapy but > 24 months after the start of tamoxifen therapy is allowed. Stratification: site of disease, disease-free interval since the end of (neo)adjuvant therapy, menopausal status, and geographic region. Primary efficacy endpoint: progression-free survival (determined locally by the investigator per RECIST v1.1). Secondary endpoints include overall survival, objective response rate, duration of response, clinical benefit rate, QoL, and safety. Enrollment is open (first patient in: Oct 9, 2020); target recruitment is 978 pts across all sites in a global enrollment phase. After completion of the global enrollment, additional pts may be enrolled in China. Clinical trial information: NCT04546009 .

BackgroundThis randomized, controlled, multicenter, open-label, phase III study was conducted to determine whether professional oral care (POC) reduces oral mucositis in estrogen receptor-positive metastatic breast cancer patients treated with everolimus and exemestane.MethodsOne hundred seventy-four patients were randomized into the POC group (n = 86) or the control group (n = 88). Four patients in the POC group and one patient in the control group were excluded from the study because they did not receive the protocol treatment. Thus, 169 patients (POC group: 82 patients; control group: 87 patients) were evaluated for efficacy and safety. The POC group received oral health instruction (OHI), professional mechanical tooth and tongue cleaning, gargling with a benzethonium chloride mouthwash, and dexamethasone ointment when grade 1 mucositis manifested. The control group received OHI and gargling. Eight weeks after everolimus and exemestane were administered, the patients were evaluated for oral status (based on the Oral Assessment Guide [OAG] criteria) and oral mucositis status (assessed with Common Terminology Criteria for Adverse Events [CTCAE] functional and clinical examinations).ResultsThe incidences of oral mucositis of any grade and severe mucositis of grade 2 were significantly lower in the POC group (p = 0.034 and p = 0.013, respectively), based on the CTCAE functional and CTCAE clinical examinations (p = 0.034 and p # These authors contributed equally to this work.

Background Preoperative chemotherapy in combination with trastuzumab and pertuzumab is a preferred regimen for treating patients (pts) with HER2-positive, invasive, early breast cancer (BC). Pts who have received such treatment but still have residual invasive disease in the breast or lymph nodes at surgery are at greater risk for disease recurrence or death than those with a pathological complete response. The antibody-drug conjugate (ADC) T-DM1 was recently approved as a postneoadjuvant treatment for pts with residual invasive disease (in the breast and/or axillary nodes) after optimal neoadjuvant chemotherapy and trastuzumab (or trastuzumab with pertuzumab). T-DXd is a potent HER2-targeted ADC with a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker and a drug-to-antibody ratio of ≈ 8. Recently, T-DXd was approved for the treatment of adult pts with HER2-positive, unresectable or metastatic BC who have received ≥ 2 prior anti-HER2─based regimens in the metastatic setting (US) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). These approvals were based on a phase 2 study in which T-DXd demonstrated an objective response rate (ORR) of 60.9% (112/184 pts) and duration of response of 14.8 months in pts with HER2-positive (IHC 3+ or ISH+), unresectable or metastatic BC previously treated with T-DM1 (Modi et al. N Engl J Med. 2020;382:610-621). Here, we describe a randomized phase 3 trial evaluating T-DXd vs T-DM1 as postneoadjuvant treatment for high-risk pts with HER2-positive primary BC who have residual invasive disease following neoadjuvant therapy. Study Description DESTINY-Breast05 is a multicenter, open-label, randomized, phase 3 trial comparing the efficacy and safety of T-DXd with those of T-DM1 in pts with HER2-positive (IHC 3+ or ISH+, centrally confirmed on pretreatment biopsy), invasive BC with pathological evidence of residual invasive disease in the breast or axillary lymph nodes after neoadjuvant therapy. Additionally, pts must be at higher risk for recurrence, having either inoperable (clinical stages T4, N0-3, M0 or T1-3, N2-3, M0) or operable BC at presentation (clinical stages T1-3, N0-1, M0) with axillary node-positive disease after optimal neoadjuvant chemotherapy and anti-HER2 treatment. The trial is recruiting pts from ≈ 400 sites globally. Approximately 1600 pts will be randomized (1:1) to T-DXd or T-DM1. Randomization is stratified by operative status, hormone receptor status, pathological nodal status following neoadjuvant therapy, and type of HER2-targeted neoadjuvant therapy (single vs dual). T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg will be administered intravenously once every 3 weeks for 14 cycles. Invasive disease-free survival based on investigator assessment is the primary efficacy endpoint; disease-free survival is the key secondary efficacy endpoint. Other secondary endpoints are overall survival, distant recurrence-free interval, and brain metastasis-free interval. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, on-study chest imaging (to screen for pneumonitis), and clinical laboratory parameters. The pharmacokinetics of T-DXd, biomarkers, and health-related quality of life will also be evaluated. Long-term follow-up will continue after the primary analysis every 6 months until death, withdrawal of consent, loss to follow-up, or trial closure. Citation Format: Charles E Geyer, Jr, Michael Untch, Aleix Prat, Priya Rastogi, Naoki Niikura, Elton Mathias, Lee Anne McLean, Yibin Wang, Sibylle Loibl. Trastuzumab deruxtecan (T-DXd; DS-8201) vs trastuzumab emtansine (T-DM1) in high-risk patients with HER2-positive, residual invasive early breast cancer after neoadjuvant therapy: A randomized, phase 3 trial (DESTINY-Breast05) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-01.

This is a randomized, multi-center, open-label, phase III study to evaluate the efficacy of professional oral care in preventing oral mucositis induced by everolimus in postmenopausal estrogen receptor-positive metastatic breast cancer. Patients will be randomized into professional oral care and control groups (1:1 ratio). All patients will receive everolimus with exemestane and will continue everolimus until disease progression. In the professional oral care group, patients will receive teeth surface cleaning, scaling and tongue cleaning before starting everolimus, and will continue to receive professional oral care weekly from oral surgeons throughout the 8 week treatment. In the control group, patients will brush their own teeth and gargle with 0.9% sodium chloride solution or water. The primary endpoint is the incidence of all grades of oral mucositis. Target accrual is 200 patients with a two-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

The rate of breast cancer screening for women of all ages in Japan is increasing. However, little is known about the biological differences between screen- and self-detected tumors. We used data from the Japanese Breast Cancer Registry (JBCR), a nationwide registry of newly diagnosed breast cancer cases in Japan, to investigate patients diagnosed between January 1, 2004 and December 31, 2011. We compared the clinicopathological features of tumors and assessed yearly trends regarding the proportion of screen-detected cases during the study period. We found that 31.8 % (65,358/205,544) of cancers were detected by screening. Asymptomatic tumors detected by screening (asymptomatic) were more likely to have favorable prognostic features than those that were self-detected (ductal carcinoma in situ [DCIS]: 19.8 versus 4.1 %, node-negative: 77.0 versus 61.6 %, and estrogen receptor-positive [ER+]: 82.0 versus 72.9 %, respectively). All these findings were statistically significant (p

Background We investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data. Patients and methods Records of more than 300 000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21 755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization. Results pCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10 973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward. Conclusion We confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy.

Background: Tumor infiltrating lymphocytes (TIL) in subtypes of breast cancer may provide clinically important information on chemotherapy response and prognosis. However, the standardized methodology for immunohistochemical (IHC)-TIL has not yet been established, reproducible and objective method of evaluation of TIL such as gene expression profiles is warranted. We evaluated whether IHC-TIL level was associated with gene expression profiles and whether such profiles could be used to predict chemotherapy response and prognosis according to subtypes of breast cancers. Methods: To select TIL associated genes, we used 40 samples with both IHC-TIL information and gene expression profiling data. The degree of TIL at the edges of the tumor mass, in the tumor mass, or in the stroma surrounding the expanding mammary ducts packed by carcinoma cells was evaluated as score 0, 1, and 2, when TIL was not unrecognizable (0%), sparse (0 << 50%) and dense (50% ≤), respectively. We selected 22 genes as the TIL-gene signature (GS), by comparing expression profiles between TIL score 2 and 0 tumors. We showed the associations between the TIL-GS levels and subtypes of breast cancers (Estrogen receptor: ER / Human Epidermal growth factor 2: HER2). The chemotherapy sensitivity analysis was performed on cohorts of 625 patients with stage I–III breast cancer who received neo adjuvant chemotherapy (NAC) based on Anthracycline and Taxane containing regimen. Data from 1,586 tumors were used to evaluate the association between distant metastasis free survival (DMFS) and the TIL-GS in a Kaplan-Meier analysis. Results: The TIL-GS for ER negative (-)/HER2- and HER2 positive (+) cases were significantly higher expression level than luminal types (p-value Conclusions: Higher TIL-gene signature of 22 genes appeared to be associated with aggressive subtypes and pCR rate (except luminal-low) of breast cancers. This approach may improve the reproducibility of assessment on tumor TIL level and thus serve the clinical applications for breast cancers. Citation Format: Kochi M, Niikura N, Iwamoto T, Bianchini G, Mizoo T, Nogami T, Shien T, Motoki T, Taira N, Masuda S, Doihara H, Fujiwara T, Tokuda Y, Matsuoka J. Tumor Infiltrating lymphocytes (TIL) related genomic signature associated with chemotherapy response and prognosis in subtypes of breast cancer. [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 P5-08-14.

Few studies have reported the association between body mass index (BMI) and outcome among Asian breast cancer patients. We analyzed data for 20,090 female invasive breast cancer patients who had been followed‐up for a median period of 6.7 years entered in the National Clinical Database–Breast Cancer Registry between 2004 and 2006. We used mainly the WHO criteria for BMI (kg/m2) categories

Background Immune checkpoint therapy only benefits a fraction of patients, thus huge efforts have been made to develop predictive biomarkers to identify those patients. Immune biomarkers like PD-L1 expression are extremely dynamic and the timing of evaluation, on primary or metastatic disease, may be critical. We have already shown that tumour-infiltrating lymphocytes (TILs) decrease during metastatic progression in triple-negative (TN) and human epidermal growth factor-2 positive (HER2+) breast cancers (Ogiya R, ASCO 2015), suggesting that mechanisms of immune escape contribute and favour the metastatic progression. In this work we aimed to characterize the modulation and changes of specific immune markers during the metastatic spread comparing paired samples from primary and recurrent breast cancers. Methods We retrospectively identified 25 patients with HER2+ (n = 14) and TN (n = 11) early breast cancer diagnosed between 1990 and 2009 at Tokai University Hospital, and who subsequently experienced a first regional or distant recurrence confirmed by tumour biopsy/resection. Haematoxylin and eosin-stained slides of these paired samples were evaluated for stromal TILs. Immunohistochemical staining was performed using primary antibodies against CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA-class I. Results The sites of first recurrence was the skin (n = 7), brain (n = 6), lymph node (n = 4), lung (n = 3), bone (n = 2), and one of each of bone marrow, liver and muscle. Immunohistochemical evaluations could not be performed in 5 primary tumours and 2 recurrent tumours because of the small quantity of the specimens. The percentage of CD8+ T cells staining in the primary tumours was significantly higher (median 16%) than that in recurrent tumours (median 10%) (paired t-test, p = 0.008) Similarly, the percentage of CD4+ T cells staining in the primary tumours was significantly higher (median 40%) than that in recurrent tumours (median 25%) (p = 0.026). The percentage of Foxp3+ T cells was low ( Comparison of positivity rate between primary and recurrent tumours for each antibody Primary tumourRecurrent tumourPTotal breast tumours (N)2023 TILs positivity rate, median (%) CD440%25%.03CD816%10%.01Foxp3 Conclusions Tumours at first metastatic recurrence in HER2+ and TN breast cancers have a lower percentage of both CD8+ and CD4+ T cells compared to primary tumours, confirming a potential role of immune escape in tumour progression. Other immune markers, including PD-L1, were not found to change significantly, but negative/positive conversions were observed. This suggest that an evaluation of disease at the time of immunotherapy administration might be more informative. These findings warrant larger confirmation studies. Citation Format: Ogiya R, Niikura N, Kumaki N, Bianchini G, Kitano S, Iwamoto T, Hayashi N, Yokoyama K, Oshitanai R, Terao M, Morioka T, Tsuda B, Okamura T, Saito Y, Suzuki Y, Tokuda Y. Difference of immune microenvironment between primary and recurrent tumours in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-13.

Background: The standard treatment for estrogen receptor-positive, HER2-negative inoperable and/or recurrent breast cancers is a combination of endocrine therapy and a CDK4/6 inhibitor (abemaciclib). When abemaciclib is administered, 80%-90% of patients experience diarrhea, resulting in the reduction of patient QOL and compliance. Loperamide is recommended for abemaciclib-induced diarrhea as well as chemotherapy induced diarrhea. However, previous reports showed that approximately 40% patients had constipation due to supportive treatment of loperamide. Moreover, the side effects of molecular targeted drugs, including abemaciclib, are not clear in the mechanism, and the effectiveness of coping therapy similar to chemotherapy and the treatment for side effects have not been clearly established. Thus developing new measures to effectively manage abemaciclib-induced diarrhea is an important clinical task, especially prevention of diarrhea without increasing adverse events such as constipation will be important to maintain QOL of patients receiving abemaciclib. Trial Design: This is a multicenter, randomized, open-label Phase II study to evaluate the efficacy and safety of probiotics (bifidobacterial formulation) and trimebutine maleate in treatment of abemaciclib-induced diarrhea. Both Arms A and B will receive hormone therapies (selected by physician in charge*) as directed along with abemaciclib 150 mg bid over the course of 28 days, and simultaneously to initiation of abemaciclib administration, will be given two pills of Biofermin® tid in Both Arms. Once patients experience diarrhea that is grade 6 or greater on the Bristol scale (higher grade than loose stool), salvage therapy using loperamide will be administered in Arm A. In contrast, participants from Arm B will be administered 100 mg trimebutine maleate. Thereafter, following meals, trimebutine maleate tid will be given throughout the trial period of 28 days. Eligibility Criteria: Key eligibility criteria for this trial are: Histologically diagnosed estrogen receptor-positive, HER2-negative breast cancer. Stage IIIB/IIIC breast cancer that is not subjected to surgery for curative intent, Stage IV breast cancer suitable for endocrine therapy. No prior treatment with CDK 4/6 inhibitors, and any type and number of previous treatments will be allowed in the selection criteria except CDK4/6 inhibitors. Specific Aims: The primary endpoint is the percentage of patients who experienced Grade 2 or greater diarrhea during the trial duration of 28 days and key secondary endpoints include safety, frequency and duration of all-grade diarrhea, frequency of emesis and constipation, comparative usage of loperamide in Arms A and B, and QOL/PRO in the 28-day study duration Statistical Design: By using the 40% threshold as the null hypothesis, appropriate statistical analysis will be performed based on a binomial distribution. The significance level will be 2.5%, determined using a one-tailed test. Interval estimation will be appropriately deduced from a binomial distribution. If either arm shows a significant reduction compared with the threshold value, as secondary validation, intergroup comparison of the primary endpoint percentage of diarrhea onset will be performed. In this case, the significance level will be 10%, determined using a two-tailed test. Target Accrual: A total of 50 patients will be enrolled and duration of enrollment will be 1 year. This trial will open to accrual in September 2019. Contact Information: Hiroko Masuda, Showa University Hospital, Tokyo, Japan, hmasuda@med.showa-u.ac.jp Citation Format: Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani. Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B [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 OT2-02-09.

Background: Fulvestrant is one of the standard treatments for first- and second-line endocrine therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC). Palbociclib inhibits cyclin dependent kinase (CDK) 4 and CDK6 in vitro, resulting in loss of RB1 phosphorylation. Palbociclib has high activity in HR-positive breast cancer cell lines and is synergistic in combination with endocrine therapies. The PALOMA-3 trial enrolled patients with metastatic estrogen receptor (ER)-positive breast cancer with resistance to aromatase inhibitor. The results demonstrated that palbociclib combined with fulvestrant was associated with significantly longer progression-free survival (PFS) than fulvestrant alone. However, patients in the trial reported higher rates of adverse events, such as neutropenia and alopecia, compared with fulvestrant monotherapy. We investigate in this prospective cohort study that the addition of palbociclib to fulvestrant is effective and safe in HR-positive and HER2-negative advanced breast cancers that progressed during fulvestrant monotherapy. Specific Aims: Primary objective: To observe the PFS in patients with resistance to fulvestrant monotherapy who were treated with fulvestrant plus palbociclib. Secondary Objective: To observe the PFS in patients treated with fulvestrant as the first and second line therapy. We also aim to observe overall survival and safety. A prospective translational research is also planned to assess the correlations between biomarkers and response. Trial Design: Single arm exploratory trial Eligibility Criteria: Eligible patients must have historically confirmed ER-positive and HER2-negative MBC who received fulvestrant as first or second line therapy. Prior chemotherapy in the neoadjuvant and adjuvant settings and up to one line of chemotherapy in MBC is permissible. Patients who received CDK4/6 inhibitor as metastatic therapy are excluded. Statistical Design: We aim to set the lowest limit of the therapeutic effect at a median PFS of 5 months, which is the value reported in the PALOMA-3 study. If we assume that the expected median PFS is 8 months, at least 63 patients are required to reject the null hypothesis (5 months) with a power of 80% under a one-sided alpha at 0.05. The length of the accrual period and follow-up period are set at 12 and 18 months, respectively. Target Accrual: First registration: 200 patients with fulvestrant monotherapy as the first and second line setting. Second registration: 70 patients with combined palbociclib and fulvestrant. (UMIN 000029294) Citation Format: Kokoro Kobayashi, Naoki Niikura, Shigehira Saji, Takayuki Iwamoto, Nobutaka Iwakuma, Yuichiro Kikawa, Norikazu Masuda, Kenichi Watanabe, Takashi Takeshita, Mari Oba, Shinji Ohno. Fulvestrant with additional palbociclib in advanced or metastatic hormone receptor-positive HER2-negative breast cancer after progression to fulvestrant monotherapy: JBCRG- M07 (FUTURE trial) [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 OT2-02-07.

Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

A population-based cancer registry has been used for the planning and evaluation of cancer control activities based on administration and the care of individual cancer patients by those in the medical profession. The Japanese Breast Cancer Society (JBCS) registry was started in 1975. In 2004, the registry system was moved to a new system using web registration with the cooperation of the Non-Profit Organization Japan Clinical Research Support Unit and Public Health Research Foundation (Tokyo, Japan). Comprehensive individual patient data were recorded according to the Unio Internationalis Contra Cancrum (UICC) TNM classification [1] and the World Health Organization histological classification [2]. The details are described elsewhere [3]. Annual reports on this registry have since been published in Japanese and publicized through the JBCS web site to active members of the JBCS [4]. We herein report the results of a 5-year prognostic analysis of cases registered in 2005 (Figs. 1, 2, 3, 4, 5, 6, 7, 8 and 9; Supplementary Tables 1–9). The number of facilities involved in the 2005 registration was 354 and the total number of cases was 20,786. The estimated incidence of breast cancer was reported to be 50,695 cases in 2005 by the National Cancer Center [5]. Therefore, approximately Electronic supplementary material The online version of this article (doi:10.1007/s12282-015-0645-4) contains supplementary material, which is available to authorized users.

Background The aims of this study were to determine clinicopathological factors associated with postoperative upstaging to invasive carcinoma in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS) and to develop a model to predict the risk of upstaging. Methods Pre- and post-operative pathological diagnoses and radiological findings were assessed for 1,187 consecutive patients. Results Of the patients, 306 (25.8%) were upstaged on the surgical specimen. In multivariate analysis, the following four factors were significantly associated with upstaging: 1) the presence of sclerosing adenosis on the preoperative biopsy specimen (odds ratio [OR] 0.46, P = 0.013); 2) pleomorphic calcifications on the mammogram (OR 1.68, P = 0.009); 3) a mass suspicious for invasive carcinoma on ultrasonography and/or MRI (OR 2.13, P

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

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.

Background Inflammatory breast cancer is a rare and aggressive presentation of breast cancer. Bone is a common metastatic site in breast cancer, and bone-only metastatic disease is clinically considered to have a better prognosis than visceral metastasis. However, bone-only metastasis in IBC (bone-only IBC) has not been compared with bone-only metastasis in non-IBC (bone-only non-IBC) in terms of clinical features and outcome. Because of the intrinsically aggressive nature of IBC, we hypothesized that bone-only IBC has a poorer prognosis than does bone-only non-IBC. Patients and Methods We retrospectively identified patients with stage III primary diagnosed breast cancer who, between January 1997 and December 2012, had a first recurrence located only in the bone. Among the 197 patients that we defined as a study cohort, 50 patients had IBC and 147 patients had non-IBC. Progression-free survival (PFS) and overall survival (OS) from the date of recurrence were estimated using the Kaplan–Meier method, and patient characteristic groups were compared using the log-rank test. Results OS did not differ significantly between the 2 groups (P = .2467), but a shorter PFS was seen in patients with bone-only IBC than in patients with bone-only non-IBC (P = .0357). Among patients with estrogen receptor (ER)-positive disease, a much shorter PFS was seen in bone-only IBC than in bone-only non-IBC (P = .0159). Conclusion Bone-only IBC has a poorer prognosis than does bone-only non-IBC, particularly in those with ER-positive tumors. We might need to consider more aggressive intervention (eg, chemotherapy) for IBC patients with ER-positive bone-only metastatic disease.

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.

Background: In patients with estrogen receptor (ER)-positive advanced breast cancer, everolimus plus exemestane prolongs progression-free survival compared to exemestane monotherapy. However, as an adverse event from everolimus, oral mucositis (all grades) has been reported in 58% of all patients and 81% of Asian patients. Although no established prevention method is available, a previous study reported that professional oral care might prevent oral mucositis, and dentists have hypothesized that such care can reduce the occurrence of oral mucositis induced by everolimus. To evaluate this hypothesis, we compare the incidence of oral mucositis with and without professional oral care. Method: This is a randomized, multi-center, open-label, phase III study to evaluate the efficacy of professional oral care in preventing oral mucositis induced by everolimus in postmenopausal ER-positive metastatic breast cancer (MBC). Patients will be randomized into professional oral care and control groups (1:1 ratio). All patients will receive everolimus (10 mg daily) with exemestane (25 mg daily) and will continue everolimus until disease progression. Before the initiation of everolimus, instruction on a professional brushing method will be provided to both groups by specialists. In the professional oral care group, patients will receive teeth surface cleaning, scaling, and tongue cleaning before starting everolimus, and will continue to receive professional oral care weekly from oral surgeons throughout the 8 week treatment. In the control group, patients will brush their own teeth and gargle with 0.9% sodium chloride solution or water. The primary endpoint is the incidence of all grades of oral mucositis. The secondary endpoints are the incidence of over grade 2 and over 3 oral mucositis as determined by an oncologist and oral surgeons. The endpoints include onset and duration of oral mucositis. Major eligibility criteria include: 1) Postmenopausal women with ER positive MBC, and 2) No more than one prior chemotherapy treatment for MBC. Target accrual is 200 patients with a two-sided type I error rate of 5% and 80% power to detect 25% risk reduction. This study has just begun, and 5 of a planned 200 patients have been enrolled. (This study was registered with the UMIN 000016109). Citation Format: Niikura N, Ohta Y, Hayashi N, Naito M, Kashiwabara K, Watanabe K, Yamashita T, Mukai H, Umeda M. Evaluation of the use of oral care to prevent oral mucositis in estrogen receptor positive metastatic breast cancer patients treated with everolimus: Phase III randomized control trial. [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 OT1-03-02.

Many different options for adjuvant chemotherapy are recommended in guidelines for the treatment of breast cancer. Therapeutic strategies vary among physicians. The major goals for this project were to gain a better understanding of how biomarkers are integrated into practice and how physicians select adjuvant chemotherapy.We assembled a questionnaire with 23 example scenarios of breast cancer cases, including 6 items relevant to postoperative adjuvant therapy. During October-November 2012, the questionnaire was submitted to 131 physicians engaged in breast cancer treatment in Kanagawa Prefecture, Japan.Forty-eight physicians responded to the questionnaire, 46 of whom provided valid responses. Their responses revealed a notable lack of consensus regarding therapeutic choices. We analyzed 6 scenarios relevant to postoperative adjuvant therapy. In general, the selection of postoperative adjuvant therapy appeared to be based on hormone sensitivity, human epidermal growth factor receptor 2 (HER2) expression, lymph node metastasis, tumor size, histological/nuclear grade, vascular/lymphatic system invasion, Ki67 level, Oncotype DX score, and the patient's age.Given the varied therapeutic choices that we observed, clinical research is needed to provide appropriate, unified therapeutic strategies.