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Background: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice., Methods: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival., Results: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively., Conclusion: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice., (© 2024. The Author(s).)

Background: Mastectomy has been the standard surgical treatment for ipsilateral breast tumor recurrence (IBTR). Recently, there has been growing interest in repeat breast-conserving surgery (rBCS) for IBTR among breast surgeons; however, there is currently little information regarding patient preferences for surgical procedure for IBTR. The purpose of this study was to evaluate preference for surgical procedure (mastectomy vs. rBCS) among breast cancer patients who had undergone salvage surgery for IBTR., Methods: Overall, 100 breast cancer patients who had undergone salvage surgery for IBTR were asked about their preferred surgical methods for IBTR and the reason. The association of patient preference and the reasons related to various clinical and pathological factors were assessed., Results: Of the 100 respondents, only 11 patients (11%) preferred rBCS. Patients who had undergone rBCS and radiotherapy for IBTR were significantly more likely to prefer to undergo rBCS than other groups (p = 0.030). The most frequent reason for choosing rBCS was the patient's desire to minimize breast deformity and surgical wounds., Conclusions: Our study revealed that there is a low rate of patients who opt to undergo rBCS among patients who had undergone salvage surgery for IBTR. Discrepancies in perceptions regarding the surgical procedure for IBTR between patients and their surgeons may exist., (© 2024. Society of Surgical Oncology.)

Background: It is important to assess whether the early detection of breast cancer affects medical care costs. However, research remains scant on the actual medical care costs associated with breast cancer treatment in Japan. This study aimed to determine the medical care costs of breast cancer treatment based on its stage using national health insurance claims data., Methods: This was an observational study including patients with breast cancer who had undergone breast cancer treatment, as defined by the disease name and related treatment codes. Between August 2013 and June 2016, patients who underwent surgical treatment without axillary lymph node dissection and other radical treatment were classified as the curable group, while those who underwent palliative treatment were classified as the non-curable group. Patients were further stratified by subtype. The total and treatment-specific medical care costs for the five years were calculated using the national health insurance claims data of Hachioji City between August 2013 and May 2021., Results: The mean total medical care costs for the curable and non-curable groups for the 5 years were JPY 3958 thousand (standard deviation 2664) and JPY 8289 thousand (8482), respectively. The mean medical care costs for specific breast cancer treatment for the curable and non-curable groups were JPY 1142 (728) thousand and JPY 3651 thousand (5337), respectively. Further, human epidermal growth factor receptor 2 + , Hormone + patients had the highest mean cost over the 5 years., Conclusions: The results suggest that the early detection of breast cancer may reduce medical care costs at the patient level., (© 2023. The Author(s).)

Purpose: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study., Methods: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion., Results: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred., Conclusion: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

A 49-year-old woman who had surgery for left breast cancer and subsequently underwent a two-stage deep inferior epigastric perforator(DIEP)flap reconstruction. One month postoperatively, she became aware of abdominal distention and visited a local hospital. CT scan revealed subcutaneous fluid accumulation with capsular formation in the lower abdomen. Imaging findings and physical examination showed no abdominal wall scar hernia. After multiple puncture aspirations, fluid accumulation was observed again, and the possibility of a chronic expanding hematoma was considered. Later, hematoma removal, including the capsules, was performed; pathological findings showed no evidence of malignancy. No fluid retention was observed postoperatively. In cases where imaging evaluation reveals hematoma formation with capsules, hematoma removal, including the capsules, should be performed to avert the possibility of a chronic expanding hematoma.

Real-world evidence for clinical outcomes and treatment patterns in patients with hormone receptor-positive(HR+)and human epidermal growth factor receptor 2-negative(HER2-)early breast cancer(EBC)in Japan is limited. We aimed to provide recent evidence in this population using the National Database of Health Insurance Claims and Specific Health Check-ups of Japan(NDB). Adults ≥20 years old who were diagnosed with HR+/HER2- breast cancer and underwent breast resection surgery were followed up. Patient characteristics and treatment patterns were evaluated. Durations of overall post-operative endocrine therapy(ET)and luteinizing hormone-releasing hormone(LH-RH)agonist therapy, and time to metastasis/recurrence after surgery were analyzed using Kaplan-Meier method. Overall, 294,904 patients were included. Cyclophosphamide and tamoxifen were the most common peri-operative chemotherapeutic and ET drugs. Median(95% confidence interval[CI])duration of post-operative ET and LH-RH agonist therapy was 5.01(5.01-5.01)years and 2.13 (2.12-2.14)years, respectively. Five-year cumulative rate(95% CI)of any recurrence was 8.6%(8.5-8.7), visceral metastasis being the most common. Nation-wide treatment patterns were described, which were consistent with guideline recommendations for patients with HR+, HER2- EBC. Further discussion is required to delay metastasis/recurrence and improve clinical outcomes(Fig. 1: Plain language summary of the study).

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis., Methods: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38)., Results: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients., Conclusions: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance., (© 2023. The Author(s).)

Background: Tumor-infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. However, the TIL level can be determined at a few facilities. By contrast, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are easily and objectively determined from the results of full blood counts. We conducted a retrospective study to investigate whether TILs, NLR, and PLR predict NAC efficacy and whether NLR and PLR could be surrogate markers for TILs in TNBC., Methods: Of the 266 patients diagnosed with TNBC between 2013 and 2019, 66 who underwent radical surgery after sequential administration of anthracycline and taxane as NAC were included in the study. TILs, NLR, and PLR were evaluated as predictors of pathologic complete response (pCR) using cutoff values determined from receiver operating characteristic curves., Results: The cutoff values of TILs, NLR, and PLR were 20%, 2.6, and 180, respectively. High TIL level was associated with low NLR (P = 0.01) and low PLR (P = 0.01). High TIL level (odds ratio [OR] 4.28 [95% CI 1.40-13.1]; P = 0.01), low NLR (OR 5.51 [95% CI 1.60-18.9]; P = 0.01), and low PLR (OR 3.29 [95% CI 1.13-9.57]; P = 0.03) were associated with pCR. Low NLR predicted pCR independently (OR 6.59 [95% CI 1.45-30.0]; P = 0.01)., Conclusions: TILs, NLR, and PLR predicted NAC efficacy against TNBC. TIL level was associated with NLR and PLR. NLR was an independent predictive factor and may be a useful surrogate marker for TILs when predicting pCR., (© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Background: The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear., Methods: We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS., Results: The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS., Conclusions: In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: In recent years, the survival of patients with breast cancer has improved. However, few published studies have a longer than 10-year follow-up. Conditional relative survival (CRS), which is relative survival (RS) of patients who have survived beyond a certain period after diagnosis, is useful for assessing excess mortality among long-term survivors compared with the general population., Methods: This was a retrospective observational cohort study. Population-based cancer registry data in Osaka, Japan were used to determine 15-year RS and 5-year CRS of women with breast cancer diagnosed between 2001 and 2002 and followed up for at least 15 years. Fifteen-year RS and age-standardized RS (ASR) were calculated by Ederer II and cohort methods. Five-year CRS according to age group and extent of disease (localized, regional, and distant) was estimated for every year from diagnosis to 10 years., Results: In the cohort of 4006 patients, the ASR declined progressively, the 5-year ASR being 85.8%, 10-year ASR 77.3%, and 15-year ASR 71.6%. The overall 5-year CRS exceeded 90% at 5 years after diagnosis, reflecting a small excess mortality compared with the general population. The 5-year CRS of patients with regional and distant disease did not reach 90% within 10 years of follow-up (89.4% for regional and 72.9% for distant disease 10 years after diagnosis), indicating that these patients had substantial excess mortality., Conclusion: Long-term survival data can help cancer survivors plan their lives and receive better medical care and support., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment., Methods: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate., Results: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer., Conclusion: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/aim: Currently, several ongoing prospective studies are investigating the safety of breast surgery omission in patients with breast cancer who are exceptional responders to neoadjuvant chemotherapy. However, there is little information about the preferences of these patients regarding omission of breast surgery., Patients and Methods: We conducted a questionnaire survey to assess preferences regarding omission of breast surgery among patients with breast cancer who had human epidermal growth factor receptor 2-positive or estrogen receptor-negative tumors and good clinical response after neoadjuvant chemotherapy. Patients' estimation of the risk of ipsilateral breast tumor recurrence (IBTR) after definitive surgery or breast surgery omission was also assessed., Results: Of 93 patients, only 22 (23.7%) said they would omit breast surgery. Under the scenario of omitting breast surgery, the 5-year IBTR rate estimated by patients who said they would omit breast surgery was significantly lower (median, 10%) than the rate estimated by patients who preferred undergoing definitive surgery (median, 30%) (p=0.017)., Conclusion: The proportion of our surveyed patients who were willing to omit breast surgery was low. Patients who said they preferred to omit breast surgery overestimated the 5-year IBTR risk., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The aim was to understand real-world cyclin-dependent kinase (CDK) 4 and 6 inhibitor use in Japan., Methods: This retrospective observational study used a Japanese administrative claims database and included patients with presumptive hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) prescribed CDK4 and 6 inhibitor therapy between December 2017 and March 2021. Patient characteristics, treatment patterns, and selected clinical and safety outcomes were descriptively summarized. Time to discontinuation (TTD) and chemotherapy-free survival (CFS) were examined using Kaplan-Meier estimates., Results: The study cohort (N = 6442) was predominantly female (99.4%; median [range] age 64 [26-99] years) with records of metastases (79.6%) within 1 year prior to initiating CDK4 and 6 inhibitor therapy. In total, 4463 (69.3%) and 1979 (30.7%) were prescribed palbociclib and abemaciclib, respectively, as their first CDK4 and 6 inhibitor, most commonly in combination with fulvestrant (n = 3801; 59.0%). Overall, 3756 patients initiated a subsequent anticancer treatment, of whom 748 (19.9%) initiated a different CDK4 and 6 inhibitor in combination with the same or different endocrine therapy. Median TTD (95% confidence interval) was 9.7 (9.3, 10.1) months for the first CDK4 and 6 inhibitor therapy. Median CFS was 26.1 (24.6, 27.8) months. Incidence of clinically relevant diarrhea was higher after abemaciclib initiation (9.8%) than after palbociclib initiation (1.5%). More patients experienced dose reduction with palbociclib (69.3%) than with abemaciclib (53.0%)., Conclusion: The data provide insights into current clinical practices for CDK4 and 6 inhibitor use in Japan that could help establish future treatment strategies for ABC., (© 2022. The Author(s).)

Background/aim: The efficacy of endocrine therapy combined with abemaciclib for hormone receptor-positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI., Patients and Methods: This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI., Results: Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005]., Conclusion: Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT)., Methods: Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed., Results: We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15-9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32-26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing HRQoL deterioration at 36 months (P = 0.717)., Conclusion: Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Trastuzumab monotherapy could be considered for older patients who reject chemotherapy., Competing Interests: Declaration of competing interest YU reports honoraria for consulting from Chugai pharmaceutical Co., Ltd. TT reports honoraria for lectures from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K·K., AstraZeneca K·K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K·K., and Daiichi Sankyo Co., Ltd. TN reports fees for Non-CME services and honoraria for lectures from Chugai pharmaceutical Co., Ltd., AstraZeneca K·K., Novartis Pharma K·K., Eli Lilly Japan K·K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, and Eisai Co., Ltd. TM reports fees for non-CME services and honoraria for lectures from AstraZeneca K·K, Chugai pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K·K., Daiichi Sankyo Co., Ltd., Nippon Kayaku Co., Ltd., and Pfizer Japan Inc. HI reports honoraria for lectures from Chugai pharmaceutical Co., Ltd. HM reports honoraria from AstraZeneca K·K, Pfizer Japan Inc, Takeda Pharmaceutical Company Limited, Daiichi Sankyo Co., Ltd and Taiho Pharmaceutical Co., Ltd; and research grants from the Japanese government, Daiichi Sankyo Co., Ltd, Eisai Co., Ltd, Nippon Kayaku Co., Ltd and Pfizer Japan Inc, outside the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately., Methods: We investigated the relationship between TILs and the peripheral blood markers, PLR and NLR, in the same patients, using surgical specimens from 502 patients with invasive breast carcinoma without preoperative chemotherapy. For analysis of triple-negative breast cancer (TNBC) patient outcomes, 59 patients who received preoperative chemotherapy were also examined. For immune cell profiling, multiplexed fluorescent immunohistochemistry (mfIHC) of CD3, CD4, CD8, FOXP3 and T-bet, was conducted., Results: A positive correlation between PLR and TIL was observed in TNBC (P = 0.013). On mfIHC, tumors in patients with high PLR and NLR contained more CD3 + CD4 + FOXP3 + T-cells (P = 0.049 and 0.019, respectively), while no trend was observed in CD8 + T-cells. TNBC patients had different patterns of outcomes according to TIL and PLR, with the TIL-high/PLR-low group having the lowest rate of disease relapse and death, and the longest distant metastasis-free and overall survivals, while the TIL-low/PLR-high group had the shortest survivals., Conclusions: Our data suggest that the combination of PLR with TIL assessment may enable more accurate prediction of patient outcomes with TNBC., (© 2022. The Author(s).)

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

Background: There is little information on the oncological outcomes of breast-conserving surgery (BCS) with immediate reconstruction using a latissimus dorsi myocutaneous flap (LDMF) for breast cancer compared with BCS alone., Patients and Methods: We conducted a retrospective cohort study from a single institution comparing the margin positivity rates after initial surgery, re-excision rates, and local recurrence (LR) between BCS with immediate LDMF reconstruction (n = 145) and BCS alone (n = 1040) performed from 2012 to 2017 for newly diagnosed stage 0-3 breast cancer., Results: The positive rates of surgical margin after initial surgery were significantly lower in the BCS with LDMF group than in the BCS alone group (4.1 vs. 10.8%; P = .006). There were no marked differences in the re-excision rates between the BCS with LDMF and BCS alone groups (P = .1). At a median follow-up of 61 months, the surgical method (BCS with LD vs. BCS alone) was not associated with the LR-free survival after adjusting for various clinicopathologic factors (P = .8)., Conclusion: Our findings suggest that BCS with immediate LDMF reconstruction is oncologically safe for breast cancer compared with BCS alone. However, further studies are needed., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

We report a case of primary breast rhabdomyosarcoma. A 16-year-old girl noticed tumor of her right breast and consulted a local clinic. From the result of core needle biopsy, breast sarcoma was suspected, so she attended our hospital. Breast ultrasonography showed a mosaic pattern tumor occupying the whole right breast. CT images revealed an axillary node metastasis and no distant organ metastasis. Immunohistochemical staining of the tumor yielded positive results for desmin, MyoD1, and myogenin. Based on reverse transcription polymerase chain reaction(RT-PCR), she was diagnosed as an alveolar rhabdomyosarcoma with PAX3-FKHR(FOXO1)fusion transcripts[t(2;13)(q35;q14)]. She underwent total mastectomy and dissection of axillary lymph nodes. After surgery, the whole-body magnetic resonance imaging(MRI) demonstrated metastases of sacrum and left foot, so she was under systemic chemotherapy.

The ACOSOG Z0011 trial has resulted in the omission of axillary lymph node dissection (ALND) in early breast cancer patients with one or two metastatic sentinel lymph nodes (SLNs). There has been increasing interest in the necessity of intraoperative assessment of SLNs in patients treated based on the Z0011 criteria. We evaluated the utility of intraoperative assessment in these eligible patients. A total of 1396 patients were treated following the Z0011 criteria from April 2012 to December 2019. We examined the proportion and clinicopathological features of patients who underwent ALND due to three or more metastatic SLNs and the sensitivity of intraoperative assessment. Only 16 (1.1%) patients had three or more metastatic SLNs diagnosed by intraoperative assessment, and they immediately underwent ALND. Of the clinicopathological factors, high clinical tumor stage (p = 0.002) and high Ki-67 labeling index value (p = 0.056) were more likely to be associated with the presence of three or more metastatic SLNs. The major independent risk factor for three or more metastatic SLNs was high clinical tumor stage (OR 3.94 [95% CI 1.42-11.0]; p = 0.009). Intraoperative assessment had low sensitivity (70.5%) and a high false-negative rate (29.5%) in detecting SLN metastases. The main finding of our study was the small proportion of patients who required ALND due to three or more metastatic SLNs according to the Z0011 criteria. The Z0011 strategy enables intraoperative assessment of SLNs to be omitted in early breast cancer patients., (© 2021 Wiley Periodicals LLC.)

Background: Tumour-infiltrating lymphocyte (TIL)-high breast tumours have a high rate of pathological complete response (pCR) with neoadjuvant chemotherapy. In our routine pathological diagnoses of biopsy specimens from pCR cases, we have observed a high infiltration of plasma cells (PCs). A positive correlation of PCs with favourable patient outcome has recently been reported, but little is known about how PCs contribute to local tumour immunity., Methods: We retrospectively examined biopsy specimens from 146 patients with invasive breast cancer who received neoadjuvant chemotherapy. CD138 + PC infiltration was assessed by immunohistochemistry. Multiplexed fluorescent immunohistochemistry (mfIHC) with T and B cell markers was also conducted to elucidate the profile of immune cells., Results: Greater PC infiltration was observed in the pCR group (p = 0.028) and this trend was confirmed in another patient cohort. With mfIHC, we observed significantly more CD8 + , T-bet + CD4 + , and CD8 + FOXP3 + T cells, total B cells and PCs in pCR cases. Such cases were also characterised by high expression of both PD-1 and PD-L1 on B cells and PCs. In patients with hormone receptor-negative tumours, high PC infiltration was correlated with significantly longer disease-free survival (p = 0.034)., Conclusions: We found that higher PC infiltration in biopsy specimens before neoadjuvant chemotherapy was associated with pCR. With mfIHC, we also revealed that the local cytotoxic immune response was clearly enhanced in pCR cases, as was the infiltration of B cells including PCs. Moreover, higher PC levels were correlated with favourable outcomes in hormone receptor-negative breast cancer patients., (© 2021. The Author(s).)

Carcinoma with apocrine differentiation is an androgen receptor (AR)-positive subset of triple-negative breast carcinomas. In addition to carcinoma with apocrine differentiation, other AR-positive triple-negative breast carcinomas occur, albeit less frequently. We found that α-methylacyl-CoA racemase (AMACR), also known as P504S, is overexpressed in carcinoma with apocrine differentiation and non-neoplastic apocrine metaplasia. We aimed to evaluate AMACR as a possible marker of carcinoma with apocrine differentiation. We immunohistochemically examined the expression of AMACR in carcinoma with apocrine differentiation and nonapocrine carcinomas and compared it with that of gross cystic disease fluid protein-15 (GCDFP-15). In total, 212 breast carcinomas were evaluated: 39 carcinomas with apocrine differentiation, 28 ductal carcinomas in situ with apocrine morphology (ADCIS), and 145 nonapocrine breast carcinomas. AMACR was expressed in 38 of 39 (97.4%) carcinomas with apocrine differentiation and in 27 of 28 (96.4%) ADCIS, consistent with the expression of GCDFP-15. However, in nonapocrine carcinomas, AMACR expression was observed in 32 of 145 (22.0%) lesions, whereas GCDFP-15 expression was observed in 91 of 145 (62.7%) lesions. For carcinoma with apocrine differentiation, AMACR was as sensitive as GCDFP-15 (both 97.1%) but more specific (77.9% versus 37.2%). In selected cases, AMACR messenger RNA (mRNA) levels were quantitatively determined relative to that of TATA-binding protein mRNA, and they comprised 5.23, 1.33, and 0.60 for carcinomas with apocrine differentiation, nonapocrine carcinomas, and normal breast tissue, respectively. CONCLUSION: Our findings demonstrate that AMACR expression may be used for differentiating carcinoma with apocrine differentiation from nonapocrine carcinomas and indicate that AMACR is a more sensitive carcinoma with apocrine differentiation marker than GCDFP-15., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX), a novel taxane formulation, was developed to avoid cremophor/ethanol-associated toxicities including peripheral neuropathy and hypersensitivity. At least 35 phase II studies using combined nab-PTX and anthracycline in neoadjuvant settings are registered in Japan. We analyzed the efficacy and safety of nab-PTX based on patient characteristics in these studies., Methods: We conducted a meta-analysis using individual patient data (IPD) to investigate the average efficacy of nab-PTX-containing regimens as neoadjuvant chemotherapy for operable breast cancer. IPD were provided by principal investigators who agreed to participate. The primary endpoint was pathological complete response (pCR) rate of each breast cancer subtype., Results: We analyzed the data of 16 studies involving 753 patients. The overall crude frequencies of pCR (ypT0 ypN0, ypT0/is ypN0, and ypT0/is ypNX) were 18.1, 26.0, and 28.6%, respectively. Specifically, the frequencies were 6.7, 10.2, and 13.4% for luminal (n = 343); 40.5, 63.5, and 68.9% for human epidermal growth factor receptor 2 (HER2)-rich, (n = 74); 21.9, 40.6, and 42.7% for luminal/HER2 (n = 96); and 26.3, 31.5, and 32.3% for triple-negative breast cancers (TNBC) (n = 232). The multivariate analyses indicated that HER2 positivity, TNBC, high Ki-67, high nuclear grade, and weekly nab-PTX administration were significantly associated with the pCR. The proportion of hematological toxicities (neutropenia (39.7%) and leukopenia (22.5%)), peripheral sensory neuropathy (9.7%), myalgia (5.7%), and arthralgia (4.7%) was higher than grade 3 adverse events, but most patients recovered., Conclusions: Nab-PTX is a safe and acceptable chemotherapeutic agent in neoadjuvant settings, particularly for aggressive cancers. UMIN-CTR#: UMIN000028774., (© 2021. The Author(s).)

Purpose: We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC)., Patients and Methods: Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher's test or mixed-model repeated-measures., Results: Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% v 48%; P = .016) and 12 months (19% v 38%; P = .009). In group T, the Hospital Anxiety and Depression Scale score ( P = .003) and the proportion of severe sensory peripheral neuropathy ( P = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher ( P = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items., Conclusion: Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months., Competing Interests: Yukari UemuraHonoraria: Chugai Pharma, Teijin PharmaConsulting or Advisory Role: Pfizer, Ono Pharmaceutical, Zeria Pharmaceutical, Daiichi SankyoSpeakers' Bureau: PfizerTravel, Accommodations, Expenses: Pfizer, Chugai Pharma Tsuyoshi SaitoSpeakers' Bureau: Chugai Pharma, Pfizer Hiroko BandoHonoraria: Chugai Pharma, Kyowa Hakko Kirin Co, Ltd, Eisai, AstraZeneca Japan, Novartis, Lilly Japan, Nippon Kayaku, Pfizer Masato TakahashiHonoraria: AstraZeneca, Eisai, Pfizer, Lilly, Chugai Pharma, Nippon KayakuResearch Funding: Taiho Pharmaceutical, Kyowa Hakko Kirin, Eisai, Nippon Kayaku Miki YamaguchiSpeakers' Bureau: Chugai Pharma, Pfizer, Novartis Tsutomu TakashimaHonoraria: Eisai, Taiho Pharmaceutical, Chugai Pharma, Kyowa Hakko Kirin Co, Ltd, Pfizer, Novartis, AstraZeneca Japan, Daiichi Sankyo Takahiro NakayamaHonoraria: Chugai Pharma, Novartis, Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Nihonkayaku, Eisai, Daiichi Sankyo Masahiro KashiwabaSpeakers' Bureau: Chugai Pharma, Kyowa Hakko Kirin, Novartis, Pfizer, AstraZeneca, Eisai, Asahi Kasei, Daiichi Sankyo, Taiho Pharmaceutical, Shionogi, Lilly Japan Toshiro MizunoHonoraria: Chugai Pharma, Nippon Kayaku, Daiichi Sankyo, Ono Pharmaceutical, AstraZeneca, Pfizer, Lilly Japan, Kyowa Hakko Kirin, Genomic Health Yutaka YamamotoHonoraria: Chugai Pharma, AstraZeneca, Novartis, Kyowa Hakko Kirin, Eisai, Lilly Japan, Pfizer, Takeda, Nippon KayakuConsulting or Advisory Role: AstraZeneca, Novartis, Chugai Pharma, Lilly, Pfizer, Daiichi Sankyo, Nippon KayakuResearch Funding: Lilly, MSD Oncology, Daiichi Sankyo, Chugai Pharma, Nippon Kayaku, Taiho Pharmaceutical, Maruho Hiroji IwataHonoraria: Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Lilly Japan, Kyowa Hakko Kirin, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharma, Daiichi Sankyo, Pfizer, AstraZeneca, Lilly Japan, Kyowa Hakko Kirin, NovartisResearch Funding: MSD, AstraZeneca, Kyowa Hakko Kirin, Daiichi Sankyo, Chugai Pharma, Nihonkayaku, Lilly Japan, Novartis, Bayer, Pfizer, Boehringer Ingelheim, Sanofi Yasuo OhashiLeadership: Statcom, EP-Cruse Co, Ltd, EP-TechnoStock and Other Ownership Interests: StatcomHonoraria: Chugai Pharma, Sanofi, Daiichi Sankyo, Shionogi, KowaResearch Funding: Medical Members System Hirofumi MukaiHonoraria: Pfizer, Daiichi Sankyo, Taiho Pharmaceutical, TakedaResearch Funding: Daiichi SankyoNo other potential conflicts of interest were reported.

Background: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer., Methods: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken., Results: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months., Conclusions: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings., Trial Registration: UMIN000038296 ; registered on 15 October 2019.

We experienced a case of breast cancer in which liver metastases spread rapidly and the patient died of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is a fatal cancer-associated respiratory complication disease. To reveal genetic alterations of the clinical course, we performed next generation sequencing of the serial specimens using the Ion AmpliSeqTM Comprehensive Cancer Panel and RNA sequencing for transcriptomic data, followed by gene set analysis. The analysis revealed an oncogenic TP53 R213* mutation in all specimens and STK11 loss in tissues sampled after disease progression. Immunohistochemistry with an anti-STK11 antibody confirmed no STK11 expression in the samples after progression. Transcriptome analysis showed a significant downregulation of proteins associated with apoptosis in the specimens with STK11 loss. STK11 loss may have triggered the rapid progression of PTTM from a comprehensive genomic analysis.

Background: Attention has been focused on attempts to eliminate breast surgery for breast cancer patients who achieve a pathologic complete response after neoadjuvant chemotherapy (NAC). However, there are few data on ipsilateral breast tumor recurrence (IBTR) among patients with triple-negative or epidermal growth factor receptor 2-positive (HER2+) tumors who achieve a pathologic complete response after NAC and breast-conserving treatment., Methods: Using a multi-institutional retrospective database, this study evaluated the risk factors for IBTR among patients with newly diagnosed stages 1 to 3 breast cancer involving triple-negative or HER2+ tumors who achieved ypT0 after NAC and breast-conserving treatment., Results: During a median follow-up period of 4.8 years (range, 0.1-15.5 years), the 5-year IBTR-free survival rate was 95.5%. The breast cancer subtype was not associated with IBTR-free survival. Patients younger than 40 years at diagnosis had significantly worse IBTR-free survival than those who were 40 years of age or older (5-year IBTR-free survival, 87.7 vs 96.9%; p = 0.002)., Conclusions: This retrospective study demonstrated that age at diagnosis was independently associated with IBTR-free survival. Special caution is needed when clinical trials analyzing omission of breast surgery after NAC are enrolling younger patients (UMIN-CTR No. UMIN000037067).

Purpose: To correlate peritumoral fat content using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with histologic prognostic factors in breast carcinoma., Materials and Methods: This study consisted of 100 patients who were diagnosed with invasive carcinoma of breast and underwent breast MRI including IDEAL before surgery. The scan time of IDEAL fat fraction (FF) map imaging was 33 s. Four regions of interests (ROIs), which are a distance of 5 mm from the tumor edge, and one ROI in the mammary fat of the healthy side were set on the FF map. Then average peritumoral FF values (FFt), average FF values in the healthy side (FFh), and peritumoral fat ratio (pTFR: defined as FFt/FFh) were calculated. Histologically, the presence of lymph node metastasis and the MIB-1 index were evaluated., Results: FFt and pTFR for breast carcinoma with lymph node metastasis (79.27 ± 10.36 and 0.897 ± 0.078) were significantly lower than those without (86.23 ± 4.53 and 0.945 ± 0.032) (P < 0.001 and P = 0.005). Spearman rank correlation suggested that the FFt correlated with the MIB-1 index (r = -340, P = 0.001)., Conclusion: Quantification of peritumoral fat using IDEAL-iron quantification is associated with the histologic prognostic factors, and may be a practical tool for therapeutic strategy of breast carcinoma.

Purpose: To investigate the effectiveness and safety of bevacizumab-paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice., Methods: In this prospective multicenter observational study, bevacizumab-paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors., Results: Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8-23.6) months in eligible patients; 25.2 (22.4-27.4) months and 13.2 (11.3-16.6) months in cohorts A and B, respectively; and 24.4 (21.9-27.2) months and 17.6 (15.2-20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44-2.14), second-line therapy (1.35, 1.13-1.63), ECOG performance status ≥ 1 (1.28, 1.04-1.57), taxane-based chemotherapy (0.65, 0.49-0.86), cancer-related symptoms (0.56, 0.46-0.68), and visceral metastasis (0.52, 0.40-0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively., Conclusions: In Japanese clinical practice, combined bevacizumab-paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously., Trial Registration: Trial no. UMIN000009086.

Purpose: In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup., Methods: This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed., Results: At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9-37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3-90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1-not evaluable). Treatment was well tolerated, with no new safety signals detected., Conclusions: Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.

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

Purpose: Adjuvant trastuzumab monotherapy has not been compared with trastuzumab + chemotherapy. We investigated the relative value of trastuzumab monotherapy for older patients with breast cancer., Methods: This study was an open-label, randomized controlled study with a treatment selection design in which a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2-positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST)., Results: The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P = .51). At 3 years, RMST differed by -0.39 months between arms (95% CI, -1.71 to 0.93; P = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P = .53). Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% ( P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009)., Conclusion: The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients.

Despite advances in the treatment of hormone receptor-positive, HER2- metastatic breast cancer, the disease is rarely curable. In this review, we focus on the use of CDK4/6 inhibitors, examining clinical experience and the mechanisms underlying the development of resistance, and evaluating treatment options after failure to respond to CDK4/6 inhibitors. Current basic research supports the use of mammalian target of rapamycin inhibitors after CDK4/6 inhibitor failure; however, more data are needed, particularly regarding treatment sequencing. Real-world data studies may help to fill the current knowledge gap, particularly where large-scale randomized controlled studies are not feasible.

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

The incidence of breast cancer among Japanese women is substantially increasing. This study evaluated the effects of reproductive and lifestyle factors with respect to breast cancer overall and separately among pre- and postmenopausal women using data from the Three-Prefecture Cohort Study of Japan.A total of 33,410 women aged 40 to 79 years completed a self-administered questionnaire, which included items about menstrual and reproductive history and other lifestyle factors. The follow-up period was from 1984 to 1992 in Miyagi and 1985 to 2000 in Aichi Prefectures. We used Cox proportional hazards regression models to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounding factors.After 9.8 mean years of follow-up, 287 cases of breast cancer were recorded. In the overall analysis, later menarche (≥16 years) and parity were significantly associated with a decreased risk of breast cancer, with HRs of 0.69 (95% CI 0.48-0.99) and 0.72 (95% CI 0.52-0.99), respectively. Further, there was a significant decline in the risk of breast cancer with increasing number of birth among parous women (P for trend = .010). On the contrary, a family history of breast cancer in the mother was significantly associated with an increased risk of breast cancer (HR 3.22, 95% CI 1.52-6.84). Analyses based on menopausal status at baseline indicated that height (≥160 cm) and weight (≥65 kg) were significantly associated with an increased risk of postmenopausal breast cancer, with HRs of 1.34 (95% CI 0.72-2.50) and 3.13 (95% CI 1.75-5.60), respectively. Risk associated with BMI significantly differs by menopausal status.Our findings suggest the important role of reproductive factors in the development of breast cancer in Japanese women; however, body mass index (BMI) may have different effects on breast cancer in Japanese women compared with western women.

Background: Ductal carcinoma in situ (DCIS) of the breast is heterogeneous in terms of the risk of progression to invasive ductal carcinoma (IDC). To treat DCIS appropriately for its progression risk, we classified individual DCIS by its profile of genomic changes into 2 groups and correlated them with clinicopathological progression factors., Methods: We used surgically resected, formalin-fixed, paraffin-embedded tissues of 22 DCIS and 30 IDC lesions. We performed immunohistochemical intrinsic subtyping, array-based comparative genomic hybridization, and unsupervised clustering., Results: The samples were divided into 2 major clusters, A and B. Cluster A showed a greater number of gene and chromosome copy number alterations, a larger IDC/DCIS ratio, a higher frequency of nonluminal subtype, a lower frequency of luminal subtype, and a higher nuclear grade, when compared with cluster B. However, there was no difference in the frequencies of lymph node metastasis between clusters A and B. We identified 9 breast-cancer-related genes, including TP53 and GATA3, that highly contributed to the discrimination of A and B clusters., Conclusion: Classification of breast tumors into rapidly progressive cluster A and the other (cluster B) may contribute to select the treatment appropriate for their progression risk., (© 2018 S. Karger AG, Basel.)

The introduction of immune checkpoint inhibitors in cancer treatment highlights the negative regulation of anti-tumor immunity, such as effector T-cell exhaustion in the tumor microenvironment. However, the mechanisms underlying the induction and prevention of T-cell exhaustion remain largely unknown. We found that CD69, a type II glycoprotein known to regulate inflammation through T-cell migration and retention in tissues, plays an important role in inducing the exhaustion of tumor-infiltrating T cells. Cd69-/- mice showed reduced tumor growth and metastasis in a 4T1-luc2 murine breast cancer model, in which increased numbers of tumor-infiltrating lymphocytes, relatively little T-cell exhaustion, and enhanced IFNγ production were observed. Anti-CD69 monoclonal antibody treatment attenuated the T-cell exhaustion and tumor progression in tumor-bearing mice. These findings highlight a novel role of CD69 in controlling the tumor immune escape mediated by T-cell exhaustion and indicate that CD69 is a novel target for cancer immunotherapy.

Background: Recent improvements in 5-year survival of breast cancer have been reported in Japan and other countries. Though the number of long-term breast cancer survivors has been increasing, recent improvements in 10-year survival have not been reported. Moreover, the degree of improvement according to age and disease stage remains unclear., Methods: We calculated long-term survival using data on breast cancer diagnosed from 1993 through 2006 from six prefectural population-based cancer registries in Japan. The recent increase in 10-year relative survival was assessed by comparing the results of period analysis in 2002-2006 with the results of cohort analysis in 1993-1997. We also conducted stratified analyses by age group (15-34, 35-49, 50-69, and 70-99 years) and disease stage (localized, regional, and distant)., Results: A total of 63,348 patients were analysed. Ten-year relative survival improved by 2.4% (76.9% vs 79.3%) from 1993 through 2006. By age and stage, 10-year relative survival clearly improved in the age 35-49 years (+2.9%; 78.1% vs 81.0%), 50-69 years (+2.8%; 75.2% vs 78.0%) and regional disease (+3.4%; 64.9% vs 68.3%). In contrast, the degree of improvement was small in the age 15-34 years (+0.1%; 68.2% vs 68.3%), 70-99 years (+1.0%; 87.6% vs 88.6%), localized disease (+1.1%; 92.6% vs 93.7%) and distant metastasis (+0.9%; 13.8% vs 14.7%)., Conclusions: These population-based cancer registry data show that 10-year relative survival improved 2.4% over this period in Japan. By age and stage, improvement in the age 15-34 years and distant metastasis was very small, which suggests the need for new therapeutic strategies in these patients.

Background: In patients undergoing breast-conserving surgery and having positive sentinel lymph nodes (SLNs), the ACOSOG Z0011 trial showed equivalent loco-regional outcomes for patients receiving SLN dissection (SLND) alone and those receiving axillary lymph node dissection (ALND). We conducted a prospective single-arm study to confirm the applicability of the Z0011 criteria to Japanese patients with breast cancer., Methods: Patients meeting the Z0011 inclusion criteria and providing consent to receive no additional ALND were prospectively enrolled at the Osaka International Cancer Institute from April 2012 to December 2016. Cumulative incidence of loco-regional recurrence was estimated and compared to that of the Z0011 study., Results: Among a total of 881 patients who underwent breast-conserving surgery, 189 fulfilling the Z0011 criteria were enrolled and eligible for the subsequent analysis. Adjuvant chemotherapy was given to 113 (59.8%) patients, adjuvant hormone therapy to 170 (89.9%), and whole breast irradiation to 183 (96.8%). The frequency of tumors with positive lymphovascular invasion (p < 0.0001) and macrometastases in SLNs (p < 0.0001) were significantly higher in our study than in the Z0011 study. At the median follow-up of 36 months (range 10-64 months), only 2 of 189 patients (1.1%) experienced loco-regional recurrence. The 5-year cumulative rate of loco-regional recurrences was 1.3% (95% CI 0-3.1%), and the 3-year distant DFS rate was 96.8% (95% CI 94.0-99.6%)., Conclusions: Our prospective study showed that it is feasible to apply the Z0011 strategy to Japanese patients with clinically node-negative breast cancer undergoing breast-conserving surgery with planned whole breast irradiation.

Background: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule., Methods: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m 2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m 2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated., Results: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events., Conclusion: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule., Clinical Trial Registration: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).

Purpose: This phase II study evaluated the efficacy and safety of anastrozole concurrent with tegafur/uracil (UFT) as neoadjuvant therapy for ER-positive postmenopausal breast cancer., Methods: Postmenopausal Japanese women with ER-positive, HER2-negative, T2,N0-1,M0 breast cancer seen at tertiary hospitals were eligible for this open-label, randomized, multicenter study. Patients were randomized 1:1 by minimization to orally receive either anastrozole (1 mg once daily) plus UFT (tegafur/uracil combination in 1:4 molar ratio; 270 mg/m 2 /day in two divided doses) or anastrozole (as above) alone for 24 weeks. Tumor response was assessed by investigator and central review as per RECIST v1.1. The primary endpoint was the proportion of patients with best overall response of CR or PR [clinical response rate (RR)] determined by central radiologic review., Results: The study was prematurely terminated due to Grade ≥ 3 liver dysfunction reported in 3 patients receiving anastrozole/UFT. Of 57 patients randomized before termination (29 anastrozole/UFT, 28 anastrozole), all were analyzed for safety and 56 (28 each group) for tumor response. Compared with anastrozole alone, anastrozole/UFT did not achieve significantly higher RR [39.3% (90% CI 23.8-56.5%) vs 14.3% (90% CI 5.0-29.8%); p = 0.0683, Fisher's exact test], but produced significantly greater tumor shrinkage (mean tumor reduction rate 31.0 vs. 14.2%; p = 0.0181, unpaired t-test). Grade ≥ 3 adverse events were more common with anastrozole/UFT than with anastrozole (17.2 vs. 0%)., Conclusion: Although the study was terminated owing to the altered liver function, it showed that there was a trend to greater shrinkage of tumor in the combination group for ER-positive, HER2-negative postmenopausal breast cancer.

We examined the proportion of screen-detected breast cancer cases and clinical stage distribution by age group among female breast cancer cases in Osaka, Japan using population-based cancer registry from the period 1980 to 2012. The proportion of local cases increased and that of regional cases decreased gradually during the study period. The proportion of distant cases leveled off. The proportion of in situ cases increased rapidly after 2003. This increase was noticeable for women aged 30-39, 40-49, 50-59, and 60-69 years. The proportion of in situ cases for women aged 40-49, 50-59, and 60-69 years reached 15.4, 11.3, and 9.9% in 2010-2012, respectively. Regarding screening status, the proportion of screen-detected cases before 1988 was under 3%. Between 1989 and 2003, it leveled off at around 5%. After 2003, the proportion increased noticeably, and reached 25.4%:34.0% in aged 40-49 years, 32.8% in aged 50-59 years, and 26.7% in aged 60-69 years. The increase in local cases and decrease in regional cases would be due to awareness of breast cancer, probably a result of developments in medical diagnostic technology. On the other hand, the steep increase of in situ cases might be due to screening. We need careful monitoring of the trends in breast cancer incidence by clinical stage.

Objective: The aim of this study was to evaluate the reliability of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression levels in Cellprep® (CP)., Study Design: We evaluated the stability of immunocytochemistry (ICC) of ER and HER2 for primary or recurrent breast cancer samples rinsed in CP vials. Samples were prepared from CP vials stored for 1-30 or 160-240 days. ER and HER2 statuses were determined after 1-30 days (26 and 25 tests, respectively) or 160-240 days (15 and 18 tests, respectively) with the same protocols as immunohistochemistry (IHC), and were compared with the corresponding surgically resected specimens., Results: ER statuses according to CP samples showed perfect agreement (1-30 days: kappa, κ = 1; 160-240 days: κ = 1). HER2 statuses also showed good agreement (1-30 days: κ = 0.79; 160-240 days: κ = 0.64), although there were more equivocal HER2 cases in CP than in the surgically resected specimens., Conclusion: ER ICC in CP vials is reliable regardless of the preservation period. HER2 ICC in CP has more equivocal cases than HER2 IHC in surgically resected specimens. Both improvement of the immunostaining protocol and further validation study of in situ hybridization are indispensable for the practical application of ICC in CP., (© 2018 S. Karger AG, Basel.)

Objectives: Patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery have a poor prognosis. There is little information regarding the prognostic impact of the tumor size in patients with IBTR., Methods: A total of 143 patients who had histologically confirmed IBTR without distant metastases and who underwent salvage surgery between 1989 and 2013 in our hospital were included. Distant disease-free survival (DDFS) was calculated according to the invasive tumor size of IBTR. The median follow-up period was 4.6 years., Results: Patients with pT1b or more advanced IBTR have a high (≥20%) 5-year distant recurrence risk. There were significant differences in DDFS between patients with pTis or pT1a and those with pT1b or a more advanced stage (5-year DDFS: 94.4 vs. 70.1%, respectively, p value = 0.006). This significance remained after adjusting for other clinicopathological factors (p value = 0.04)., Conclusion: Patients with pTis or pT1a IBTR have a good prognosis after salvage surgery for IBTR, and the omission of adjuvant chemotherapy could be considered. Further research and validation studies are needed., (© 2017 S. Karger AG, Basel.)

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

Background: There is little information on the local recurrence risk of patients who undergo repeat lumpectomy without radiotherapy after salvage surgery for ipsilateral breast tumor recurrence (IBTR)., Patients and Methods: Sixty-five patients who underwent repeat lumpectomy without radiotherapy after IBTR were retrospectively analyzed. The risk factors of second IBTR, including the breast cancer subtype of IBTR defined by the estrogen receptor (ER) and HER2 status, were assessed., Results: The median follow-up period was 62 months. The 5-year second IBTR-free survival rate was 83%. Patients with the ER-positive/HER2-negative subtype of IBTR had a significantly better second IBTR-free survival rate than those with other subtypes of IBTR (88% vs. 75%, respectively, p=0.02). Multivariate analysis revealed that the breast cancer subtype of IBTR was a significantly independent predictive factor of second IBTR-free survival (p=0.003). A low-risk group for second IBTR, defined by the breast cancer subtype of IBTR and margin status of primary surgery, was detected (5-year second IBTR-free survival rate: 100%)., Conclusion: Patients in the low-risk group defined by the breast cancer subtype of IBTR and margin status of primary surgery could safely undergo repeat lumpectomy without radiotherapy for IBTR., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168)., Methods: Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan-Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model., Results: Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and ≥fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. ≥fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74-0.86; P < 0.001), longer period from AMBC diagnosis to F500 use (≥3 vs. <3 years; HR 0.60, 95% CI 0.51-0.70; P < 0.001), and no prior palliative chemotherapy administered for unresectable or metastatic breast cancer (no vs. yes; HR 0.69, 95% CI 0.60-0.80; P < 0.001) were associated with significantly longer TTF. Among 691 patients, where information on histologic/nuclear grade was available, a low grade was also associated with a longer TTF, but this finding was not maintained among patients with recurrent breast cancer (N = 558). Among women with recurrent breast cancer, a longer DFI between a patient's initial breast cancer diagnosis and their recurrence was associated with a longer TTF on F500 therapy., Conclusions: Our study showed that treatment period of F500 was longer when used in earlier-line treatment. For patients on F500, TTF was also longer for patients who had not received prior palliative chemotherapy and for those who had a longer period from their AMBC diagnosis to F500 use.

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m 2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m 2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5-11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4-13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m 2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)