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Background: This subgroup analysis of the Cancer-VTE Registry, a nationwide, large-scale, multicenter observational study with a 1-year follow-up, assessed real-world data on venous thromboembolism (VTE) among Japanese patients with breast cancer. Methods: Patients with stage II–IV pretreatment breast cancer screened for VTE at enrollment were included. During the 1-year follow-up period, incidences of VTE, bleeding, and all-cause death, and background factors associated with VTE risk were examined. Results: Of 9,630 patients in the Cancer-VTE Registry analysis set, 993 (10.3%) had breast cancer (973 [98.0%] did not have and 20 [2.0%] had VTE at baseline). The mean age was 58.4 years, 73.4% of patients had stage II cancer, and 94.8% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0. Risk factors for VTE at baseline by univariable analysis were age ≥ 65 years, ECOG PS of 2, VTE history, and D-dimer > 1.2 μg/mL. During follow-up, the incidence of symptomatic VTE was 0.4%; incidental VTE requiring treatment, 0.1%; composite VTE (symptomatic VTE and incidental VTE requiring treatment), 0.5%; bleeding, 0.2%; cerebral infarction/transient ischemic attack/systemic embolic event, 0.2%; and all-cause death, 2.1%. One patient with symptomatic VTE developed pulmonary embolism (PE) and died. Incidences of VTE and all-cause death were higher in patients with VTE vs without VTE at baseline. Conclusions: In Japanese patients with breast cancer, VTE screening before initiating cancer treatment revealed a 2.0% prevalence of VTE. During follow-up, one patient had a fatal outcome due to PE, but the incidences of VTE were low. Clinical trial registration: UMIN000024942; UMIN Clinical Trials Registry: https://www.umin.ac.jp/ctr/. [ABSTRACT FROM AUTHOR]

Background: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Methods: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. Results: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380–1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390–1.463). Conclusions: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. Clinical trial registration: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer. Methods: We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer Results: Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + (OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P <.0001). However, according to time-dependent Cox model that was used to reduce guarantee-time bias, CIA was not a statistically significant prognostic factor in both ER-positive and ER-negative patients. Conclusion: Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

The histological classification of breast tumors by the General Rule Committee of the Japanese Breast Cancer Society has been revised in the General Rules for Clinical and Pathological Recording of Breast Cancer (18th edition). In this article, the contents of the General Rules 18th edition are presented, and its revised points are briefly described in comparison with the classification of the General Rules 17th edition. The present classification takes into consideration the classification of breast tumors by the World Health Organization 4th edition, however, some differences remain. These differences will be briefly mentioned. [ABSTRACT FROM AUTHOR]

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

Objective: The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy.Methods: We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL.Results: Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia.Conclusions: We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses.Trial Registration Number: C000000416. [ABSTRACT FROM AUTHOR]

Background: Although there are a large number of epidemiological studies investigating the etiological role of lifestyle factors in breast cancer, there are few studies on the association between lifestyle factors and breast cancer prognosis. To investigate the influence of lifestyle factors such as diet and physical activity, use of complementary and alternative medicine, and psychosocial factors on prognosis, we designed a large-scale cohort study of female breast cancer patients in Japan. Methods: The planned sample size is 7200. The cohort is being conducted in collaboration with several clinical trials, a cancer registry, and daily practice. Information on clinical factors, treatment, and follow-up will be obtained from the clinical trials and participating hospitals. A self-administered questionnaire is given to subjects before, immediately after, or 1 to 5 years after surgery. Blood and tissue samples are also collected. The primary endpoint is disease-free survival. The secondary endpoints are overall survival and health-related quality of life. The follow-up period will be at least 5 years after the last participant is enrolled. Recruitment began in November 2007. Current status: As of April 2017, there are 5852 patients enrolled in the study along with 1430 biological samples and the study is still ongoing. The number of subjects enrolled in the study is already the largest in the world. Conclusions: The ROK study will provide much important evidence for breast cancer survivorship. [ABSTRACT FROM AUTHOR]

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

Background: The results from a phase III trial conducted outside of Japan demonstrated a significant improvement in time to progression (TTP) when lapatinib was combined with capecitabine compared with capecitabine alone in patients with HER2-positive advanced or metastatic breast cancer. In this clinical study of lapatinib in combination with capecitabine, efficacy, safety, pharmacokinetics (PK) and biomarkers were investigated in Japanese patients with HER2-positive advanced or metastatic breast cancer treated with prior trastuzumab. Methods: Eligible women received lapatinib 1250 mg once daily and capecitabine 1000 mg/m twice daily on days 1 through 14 of a 21-day cycle. The primary endpoint was the clinical benefit rate (CBR: complete response, partial response or stable disease for at least 24 weeks). Results: Lapatinib in combination with capecitabine was well tolerated in the 51 patients enrolled in this study. CBR was 59 % (95 % CI 44.2, 72.4), and the median TTP in the Kaplan-Meier estimate was 36 weeks (95 % CI 27.1, 48.0). The majority of drug-related adverse events were mild to moderate (grade 1 or 2); the most common adverse events reported were palmar-plantar erythrodysesthesia syndrome (76 %), diarrhea (67 %) and stomatitis (41 %). Conclusions: Lapatinib in combination with capecitabine in Japanese HER2-positive breast cancer patients was well tolerated. Overall, our findings on the efficacy, safety and PK were similar to those reported from the overseas studies. [ABSTRACT FROM AUTHOR]

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

The research question of this investigation is whether the reduction rate of Ki-67 after neoadjuvant chemotherapy (NAC) could indicate a survival in patients with non-pCR. A total of 455 patients had received NAC, and subsequent surgery was analyzed retrospectively. Patients with non-pCR were divided into three subgroups according to Ki-67 change: High-reduction (the absolute value of Ki-67 was reduced by >80 % compared with that prior to NAC), Low-reduction (the absolute value of Ki-67 was reduced by 0-80 % compared with that prior to NAC), and Increase group (the absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. pCR was achieved in 93 patients (20.4 %). In patients with non-pCR, the median reduction rate of Ki-67 was 60 %. A total of 15 % of patients were in the High-reduction, 63 % in the Low-reduction, and 22 % in the Increase group. The median follow-up period was 64.5 months. The 5-year RFS rates among the three groups were significantly different ( p < 0.0001), and the differences were also observed in the HER2 ( p = 0.033), triple-negative ( p = 0.034), and luminal-like subtypes ( p = 0.001). Patients in the High-reduction group showed comparable RFS to that of patients with pCR ( p = 0.363). In patients with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of cancer subtypes. Therefore, patients who are non-pCR but who achieve a high reduction of Ki-67 can be expected to have a favorable prognosis similar to that of patients with pCR. [ABSTRACT FROM AUTHOR]

In a neoadjuvant setting, three parameters for Ki-67 could be obtained: pre-treatment Ki-67, post-treatment Ki-67 and Ki-67 change between pre- and post-treatments. It is uncertain which of the three parameters has the greatest prognostic significance, and whether this parameter has significance in each subtype of breast cancer. A total of 385 patients who received neoadjuvant anthracycline followed by taxane chemotherapy and subsequent surgery for breast cancer were analyzed retrospectively. By immunohistochemistry (IHC), patients were divided into four subtypes (Luminal A, Luminal B, Triple negative, and HER2). Ki-67 was examined by IHC in pre-treatment core needle samples and post-treatment surgical excision specimens. The relapse-free survival (RFS) rate was compared among each subtype. The median follow-up period was 56 months. The rate of pathological complete response was higher for HER2 (34.8 %) and Triple negative (24.3 %) subtypes than for Luminal B (8.3 %) and Luminal A (3.8 %) subtypes ( p < 0.0001). A reduction in Ki-67 was observed in 58.5, 83.4, 70.2, and 74.2 % of patients in the Luminal A, Luminal B, Triple negative, and HER2 subtypes, respectively. Ki-67 change between pre- and post-treatments was an independent prognostic factor, but pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis. The RFS was significantly different between patients whose Ki-67 was reduced and those not reduced for Luminal B (81.4 vs. 50.0 %, p = 0.006), Triple negative (74.8 vs. 43.5 %, p = 0.006) and HER2 (82.7 vs. 59.0 %, p = 0.009). However, for Luminal A, the difference in RFS was not associated with changes of Ki-67 (78.8 vs. 75.3 %, p = 0.193). Ki-67 change between pre- and post-neoadjuvant chemotherapy is an independent prognostic factor in patients of Luminal B, Triple negative, and HER2 subtypes. Pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural effusion is a common and devastating complication of metastatic breast cancer. This occurs in about 30% of patients with metastatic breast cancer during the clinical course, and chemical pleurodesis is sometimes performed to relieve dyspnea. However, the long-term outcome of pleurodesis and factors affecting successful pleurodesis have not been clarified. Objectives: The aim of this analysis is to evaluate the long-term outcome of pleurodesis and to identify risk factors associated with success. Methods: Data on 75 patients who had undergone chemical pleurodesis with OK-432 for pleural effusion due to metastatic breast cancer were reviewed retrospectively. The primary outcomes were success rate and pleural progression-free survival (PPFS) rate. Results: The median duration of follow-up was 134 days (range 8-975 days). During this period, 22 patients re-accumulated pleural fluid. The overall success rate was 70.5%. The 4-, 8- and 12-week PPFS rates were 88.0, 84.0 and 78.7% respectively. Multivariate analysis identified three unfavorable factors that were independently associated with unsuccessful pleurodesis, including estrogen-receptor negative status, a 24-h drainage volume of more than 100 mL before extubation and NSAID use. The PPFS rate at median follow-up was 93.5% in the low-risk group ( n = 41, 0 or 1 unfavorable factor) and 55.1% in the high-risk group ( n = 34, 2 or 3 unfavorable factors). The difference between the PPFS curves of the two risk groups was statistically significant ( P < 0.001). Conclusions: Pleurodesis for metastatic breast cancer was efficacious in controlling malignant pleural effusion. Our simple new risk model warrants further studies. [ABSTRACT FROM AUTHOR]

Background: For targeting anti-HER-2, trastuzumab-incorporated chemotherapy is the standard for HER-2-overexpressing breast cancer in adjuvant settings. But there are few data on trastuzumab in elderly patients. We evaluated the incidence of adverse events among an elderly population of trastuzumab-treated HER-2-positive breast cancer patients in adjuvant settings. Methods: Data on 39 elderly HER-2 overexpressing breast cancer patients treated with both curative surgery and adjuvant trastuzumab were retrospectively collected from a Japanese multicenter study. The loading dose was 8 mg/kg body weight, and the maintenance dose was 6 mg/kg every 3 weeks; or the loading dose was 4 mg/kg followed by 2 mg/kg weekly as maintenance. Results: After a median follow-up of 20.0 (2.4-53.9) months, a total of 32 patients (82.1%) completed 1-year trastuzumab treatment. The median treatment duration was 12.0 months (range 2-12; mean 10.5). Adverse events occurred in 11 patients (28.2%). Four (10.2%) discontinued or interrupted treatment after experiencing toxicity. One patient died because of interstitial pneumonia. Three patients (7.7%) had congestive heart failure (CHF), one of whom had a history of angina. Three patients (7.7%) had a lower left ventricular ejection fraction (LVEF), and brain natriuretic peptide elevation was totally observed in three patients (7.7%). Three patients with lower LVEF had received chemotherapy containing doxorubicin before trastuzumab. Of the three patients, two discontinued therapy because of CHF, but all recovered with proper medication containing a diuretic agent. Conclusions: Elderly patients tolerated trastuzumab well, although careful management is needed. [ABSTRACT FROM AUTHOR]

To investigate whether the health-related quality of life (HRQOL) of patients switching from tamoxifen to anastrozole in a randomized trial is identical to that of those who continued tamoxifen after 1-4 years of adjuvant tamoxifen in Japanese postmenopausal breast cancer patients. Eligible patients for the randomized trial, the National Surgical Adjuvant Study of Breast Cancer 03, were recurrence-free postmenopausal women who had received definitive surgery for primary breast cancer with positive hormone receptor(s), and had been taking tamoxifen for 1-4 years postoperatively. They were randomly assigned to continue tamoxifen or to switch to anastrozole for a total duration of five years. Subjects were asked to reply to a self-administered QOL questionnaire survey to assess HRQOL (FACT-B [breast cancer scale], FACT-ES [endocrine symptom scale]) and psychological distress (CES-D: Center for Epidemiologic Studies Depression scale) at randomization (baseline), 3 months, 1, and 2 years after randomization, respectively. At baseline 694 patients (346 in the tamoxifen group and 348 in the anastrozole group) responded to the survey. The total scores of FACT-G, FACT-ES, and those of the FACT-G physical well-being subscale were statistically significantly better in the tamoxifen group than in the anastrozole group ( P = 0.042, 0.038, and 0.005, respectively). However, there was no statistically significant difference between the treatment groups in the CES-D scores. Continuation of tamoxifen treatment after adjuvant tamoxifen for 1-4 years may provide Japanese breast cancer patients with better HRQOL than by switching to anastrozole. [ABSTRACT FROM AUTHOR]

HER2-positive tumors account for approximately 18–20% of all breast cancers. These tumors tend to be more aggressive than HER2-negative tumors and are associated with a poorer prognosis. HER2 overexpression, as determined by either 3+ immunohistochemical staining for HER2 protein or HER2 gene amplification by fluorescence in situ hybridization, should be used to select patients for anti-HER2 therapy. Trastuzumab-containing regimens as first-line therapy should be recommended to women with HER2-positive metastatic breast cancer. The continuation of trastuzumab plus capecitabine provided a significant clinical benefit compared with capecitabine alone in women who experienced progression during trastuzumab treatment. An adjuvant trastuzumab-containing regimen should be also recommended to all intermediate- or high-risk women with HER2-positive early breast cancer. Cardiac function should be serially monitored during this treatment. Many anti-HER2 drugs against breast cancer are being developed. The basic mechanisms of their action and resistance emergence are being clarified step by step. Over the mid- or long term, clinical trials comparing these drugs will be conducted until drugs that are clinically effective and easy to use in the true sense survive. Biomarkers are being aggressively searched for concerning individual drugs under development. A position of the “proper drug for the proper patient” will be more firmly established. [ABSTRACT FROM AUTHOR]

Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival (DFS) than tamoxifen in postmenopausal early breast cancer. Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences, assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted. This open-label, randomized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer, who had received tamoxifen for 1 to 4 years as adjuvant therapy. This study was closed early after entry of ~28% of the initially planned patients. They were randomly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years. Primary endpoints were DFS and adverse events. At a median follow-up of 42 months, the unadjusted hazard ratio was 0.69 (95% confidence interval, 0.42–1.14; P = 0.14) for DFS and 0.54 (95% CI, 0.29–1.02; P = 0.06) for relapse-free survival (RFS), both in favor of anastrozole. The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high. Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients. Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese. [ABSTRACT FROM AUTHOR]

Recently, randomized trials revealed that trastuzumab as adjuvant treatment was effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Safety information on adjuvant trastuzumab use in Japanese patients, especially cardiac toxicity data, is needed. We retrospectively reviewed 48 patients with early-stage HER2-positive breast cancer who were treated with curative surgery and adjuvant trastuzumab at the National Cancer Center Hospital East (Kashiwa, Japan). The cardiac safety as well as the short-term efficacy of trastuzumab were evaluated. The median age of the patients was 54 years. All patients received adjuvant or neoadjuvant cytotoxic chemotherapy. Twenty-seven patients (56%) received adjuvant radiation therapy. Forty-four patients (92%) received trastuzumab without concurrent cytotoxic chemotherapy and 4 patients (8%) on taxanes received trastuzumab concurrently. Twenty-five patients completed 1 year of trastuzumab treatment and 5 patients completed 2 years of trastuzumab treatment. Nine patients discontinued trastuzumab treatment, because of progressive disease (1 patient), decrease in left ventricular ejection fraction (LVEF; 2 patients), patient’s refusal (4 patients), and other reasons (2 patients). There were five cardiac events. A decrease in LVEF to less than 50% was seen in 2 patients. The relationship between trastuzumab treatment and the cardiac events was unclear in 3 patients. The median follow-up time was 21.2 months. The disease-free survival (DFS) was 97.5% at 1 year and 92.9% at 2 years. The incidence of cardiac events caused by trastuzumab treatment was low in our analysis. Adjuvant trastuzumab treatment for up to at least 1 year should be safe for Japanese breast cancer patients. [ABSTRACT FROM AUTHOR]

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

Estimation of the cancer cell fraction in breast cancer tissue is important for exclusion of samples unsuitable for multigene prognostic assays and a variety of molecular analyses for research. Here, we aimed to establish a breast cancer cell fraction marker based on DNA methylation. First, we screened genes unmethylated in non-cancerous mammary tissues and methylated in breast cancer tissues using microarray data from the TCGA database, and isolated 12 genes. Among them, four genes were selected as candidate marker genes without a high incidence of copy number alterations and with broad coverage across patients. Bisulfite pyrosequencing analysis of additional breast cancer biopsy specimens purified by laser capture microdissection (LCM) excluded two genes, and a combination of SIM1 and CCDC181 was finally selected as a fraction marker. In further additional specimens without LCM purification, the fraction marker was substantially methylated (≥ 20%) with high incidence (50/51). The cancer cell fraction estimated by the fraction marker was significantly correlated with that estimated by microscopic examination (p < 0.0001). Performance of a previously established marker, HSD17B4 methylation, which predicts therapeutic response of HER2-positive breast cancer to trastuzumab, was improved after the correction of cancer cell fraction by the fraction marker. In conclusion, we successfully established a breast cancer cell fraction marker based on DNA methylation. [ABSTRACT FROM AUTHOR]