Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

Health-related quality of life and estimation of the minimally important difference in the Functional Assessment of Cancer Therapy-Endocrine Symptom score in postmenopausal ER+/HER2- metastatic breast cancer with low sensitivity to endocrine therapy.

BACKGROUND: The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. METHODS: Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. RESULTS: Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. CONCLUSIONS: Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET.

Prognosis and effectiveness of chemotherapy for medullary breast carcinoma.

PURPOSE: We aimed to determine the prognosis and potential benefit of postoperative chemotherapy according to subtype of medullary breast carcinoma (MedBC), a very rare invasive breast cancer. METHODS: A cohort of 1518 female patients with unilateral MedBC and 284,544 invasive ductal carcinoma (IDC) cases were enrolled from the Japanese Breast Cancer Registry. Prognosis of MedBC was compared to IDC among patients with estrogen receptor (ER)-negative and HER2-negative subtype (553 exact-matched patients) and ER-positive and HER2-negative subtype (163 MedBC and 489 IDC patients via Cox regression). Disease free-survival (DFS) and overall survival (OS) were compared between propensity score-matched adjuvant chemotherapy users and non-users with ER-negative and HER2-negative MedBC. RESULTS: Among ER-negative and HER2-negative subtype patients, DFS (hazard ratio (HR) 0.45; 95% confidence interval (95% CI), 0.30-0.68; log-rank P < 0.001) and OS (HR 0.51; 95% CI 0.32-0.83; log-rank P = 0.004) were significantly better in MedBC than IDC. Patients treated with postoperative chemotherapy showed better DFS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) and OS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) compared to those without. For the ER-positive and HER2-negative subtype, the point estimate for HR for DFS was 0.60 (95% CI 0.24-1.22) while that for OS was 0.98 (95% CI 0.46-1.84) for MedBC. CONCLUSION: In ER-negative and HER2-negative MedBC, the risk of recurrence and death was significantly lower than that of IDC, about half. Postoperative chemotherapy reduced recurrence and mortality. ER-positive and HER2-negative MedBC may have a lower risk of recurrence compared to IDC.

Prospective Cohort Study of Combination Therapy With Abemaciclib and Hormonal Therapy for Chemotherapy-Treated Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

Background: Combination therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and hormonal therapy as the first-line and second-line treatments has already been shown to be effective in patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in clinical trials. On the other hand, in clinical practice, CDK4/6 inhibitors are used not only as first-/second-line but also as later-line hormonal therapies, or for patients receiving prior chemotherapy in metastatic setting. However, the efficacy and safety of combination therapy in these patients remain unclear. In this study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. Methods: This multi-institutional prospective cohort study will involve a total of 300 chemotherapy-treated patients with HR+ HER2- MBC. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, clinical benefit rate, and adverse events. The preplanned subpopulation analysis is the number of chemotherapy regimens for HR+ HER2- MBC (two or less vs. three or more), prior treatment history with CDK4/6 inhibitors other than abemaciclib (presence vs. absence) and menopausal status (pre vs. post). We also planned to determine PFS of the subpopulation treated with abemaciclib as maintenance therapy after chemotherapy. Discussion: In this multi-institutional prospective cohort study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. We also evaluate this combination therapy as maintenance therapy in patients who respond to early-line chemotherapy.

Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

BACKGROUND: To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). METHODS: Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). RESULTS: A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001). CONCLUSION: QoL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m2. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017916.

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

BACKGROUND: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). PATIENTS AND METHODS: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. RESULTS: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 µl (0.8) remained significant. CONCLUSIONS: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.

Randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

BACKGROUND: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin-bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. METHODS: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was <0.75 or >1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. RESULTS: One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42-1.28) in MD220 vs SD260, 0.77 (95% CI 0.47-1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56-1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. CONCLUSIONS: Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC.

The efficacy of sequential second-line endocrine therapies (ETs) in postmenopausal estrogen receptor-positive and HER2-negative metastatic breast cancer patients with lower sensitivity to initial ETs.

PURPOSE: Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. METHODS: This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks. RESULTS: Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6-10.6). CONCLUSION: Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

[Is the LHRH Agonist Recommended for Fertility Preservation ?].

The POEMS reportedan effect of goserelin for fertility preservation. The Clinical Practice Guideline for Breast Cancer by The Japanese Breast Cancer Society indicates that the use of the LHRH agonist (LHRHa) for preventing chemotherapy-induced early menopause is a grade C-1 recommendation, and its use for fertility preservation is a grade C-2 recommendation. Results from previous studies on the effects of LHRHa for fertility preservation have varied owing to differences in chemotherapy regimens, definitions of ovarian failure, and dosages of tamoxifen. In the POEMS, the primary endpoint of ovarian failure at 2 years was significantly lower, and the secondary endpoint of pregnancy outcomes was better in the combination group; however, precise interpretation is difficult because many cases were excluded. Currently, it is not necessary to revise The Clinical Practice Guideline; however, desirable results from future studies may allow the recommendation of a specific dosage of LHRHa for fertility preservation.

Anastrozole versus tamoxifen as adjuvant therapy for Japanese postmenopausal patients with hormone-responsive breast cancer: efficacy results of long-term follow-up data from the N-SAS BC 03 trial.

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.

Incidence of contralateral breast cancer in Japanese patients with unilateral minimum-risk primary breast cancer, and the benefits of endocrine therapy and radiotherapy.

BACKGROUND: Tamoxifen is recommended as adjuvant endocrine therapy for patients with minimum-risk breast cancer. It is primarily effective at prevention of contralateral and ipsilateral breast cancer recurrence after breast-conserving surgery. The incidence of contralateral breast cancer and the absolute benefit of endocrine therapy among patients with unilateral minimum-risk breast cancer in Japan, where the incidence of breast cancer is low, are unknown. PATIENTS AND METHODS: We retrospectively studied the incidence of contralateral breast cancer, and the efficacy of endocrine therapy, in a cohort of 2074 Japanese women with unilateral breast cancer whose primary tumor was pTis (n = 1905) or pT1mic (n = 169) (unknown for endocrine therapy, n = 4; unknown for radiotherapy, n = 2). We also assessed the efficacy of endocrine therapy and radiotherapy for prevention of ipsilateral and contralateral breast cancer recurrence in 1205 patients who underwent breast-conserving surgery (unknown for endocrine therapy, n = 2; unknown for radiotherapy, n = 2). RESULTS: The incidence of contralateral breast cancer per 1000 person-years was 5.1 (95 % confidence interval (CI), 3.7-7.1) among patients without endocrine therapy (n = 1364) and 3.6 (95 % CI 2.1-6.1) among those with endocrine therapy (n = 706). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.2 (95 % CI 6.5-13) among patients without endocrine therapy (n = 753) and 4.2 (95 % CI 2.2-8.1) among those with endocrine therapy (n = 450). The incidence of ipsilateral breast cancer recurrence after breast-conserving surgery per 1000 person-years was 9.9 (95 % CI 6.3-15.6) among patients without radiotherapy (n = 380) and 5.9 (95 % CI 3.9-9.0) among those with radiotherapy (n = 823). CONCLUSION: The incidence of contralateral breast cancer among minimum-risk breast cancer patients in Japan, where the incidence of breast cancer is low, was similar to that in Western countries. Endocrine therapy is indicated for this population.

The current status and future perspectives of CSPOR-BC.

The Comprehensive Support Project for Oncology Research in Breast Cancer (CSPOR-BC) was initiated in 2000 as part of the investigation project of the Stress Science Research Institute, which was founded by the Public Health Research Foundation. The main objective of CSPOR-BC is to comprehensively support investigator-initiated clinical trials, research related to health-related quality of life (HR-QOL), and epidemiological research for breast cancer. After its initiation, 6 randomized controlled trials (RCTs) on adjuvant therapy for breast cancer and 2 RCTs on metastatic breast cancer have been conducted. To date, patient recruitment has been completed in 3 trials on adjuvant therapy and 1 trial on metastatic breast cancer. In addition to the assessment of efficacy and quality of life, treatment-related side effects have been evaluated. Large cohort studies have been accompanied by some RCTs to evaluate the effect of lifestyle, use of complementary and alternative medicine, sociopsychological factors, and supportive therapies on prognoses of patients with primary breast cancer. These subanalyses are unique to clinical trials conducted by CSPOR-BC. In this report, the current status and future perspectives of CSPOR-BC are described.

The effects of natural S-equol supplementation on skin aging in postmenopausal women: a pilot randomized placebo-controlled trial.

OBJECTIVE: The aim of this study was to investigate the effects of the natural S-equol supplement on skin aging in equol-nonproducing Japanese postmenopausal women. METHODS: A randomized, double-blind, placebo-controlled trial examined the use of the natural S-equol supplement for 12 weeks in 101 postmenopausal Japanese women who were equol nonproducers. They were randomly assigned to one of three groups: placebo (n = 34), 10 mg S-equol/day (EQL10; n = 34), or 30 mg S-equol/day (EQL30; n = 33). Skin parameters of crow's-feet wrinkles (area and depth), hydration, transepidermal water loss, and elasticity were measured at baseline and at monthly intervals during treatment. Vaginal cytology, endometrial thickness, and mammography were performed before and after treatment. Serum hormone concentrations were measured at the same time as skin parameters. RESULTS: The EQL10 and EQL30 groups showed significant reductions in wrinkle area compared with the placebo group (P < 0.05). There was a significant difference in wrinkle depth between the placebo group and the EQL30 group (P < 0.05). Other skin parameters did not show significant differences after the treatment in any group. There were no abnormal results in hormone status or gynecological examinations. CONCLUSIONS: Our data suggest that natural S-equol supplementation (EQL10 and EQL30) may have a beneficial effect on crow's-feet wrinkles in postmenopausal women without serious adverse events.

Health-related quality of life and psychological distress of breast cancer patients after surgery during a phase III randomized trial comparing continuation of tamoxifen with switching to anastrozole after adjuvant tamoxifen for 1-4 years: N-SAS BC 03.

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.

Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study.

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 approximately 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.