Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study.

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.

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition.

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.

Deregulation of protein phosphatase 2A inhibitor SET is associated with malignant progression in breast cancer.

To understand the mechanism underlying metastasis, identification of a mechanism-based and common biomarker for circulating tumour cells (CTCs) in heterogenous breast cancer is needed. SET, an endogenous inhibitor of protein phosphatase 2A, was overexpressed in all subtypes of invasive breast carcinoma tissues. Treatment with SET-targeted siRNAs reduced the motility of MCF-7 and MDA-MB-231 cells in transwell assay. SET knockdown reduced the number of mammospheres by 60-70% in MCF-7 and MDA-MB-231 cells, which was associated with the downregulation of OCT4 and SLUG. Hence, we analysed the presence of SET-expressing CTCs (SET-CTCs) in 24 breast cancer patients. CTCs were enriched using a size-based method and then immunocytochemically analysed using an anti-SET antibody. SET-CTCs were detected in 6/6 (100%) patients with recurrent breast cancer with a median value of 12 (12 cells/3 mL blood), and in 13/18 (72.2%) patients with stage I-III breast cancer with a median value of 2.5, while the median value of healthy controls was 0. Importantly, high numbers of SET-CTCs were correlated with lymph node metastasis in patients with stage I-III disease. Our results indicate that SET contributes to breast cancer progression and can act as a potential biomarker of CTCs for the detection of metastasis.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.

PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. TRIAL REGISTRATION: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study.

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.

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

PURPOSE: We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition. METHODS: The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting. RESULTS: The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ. CONCLUSION: The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.

Dose-dense adjuvant chemotherapy: a systematic review and meta-analysis of the Japanese Breast Cancer Society Clinical Practice Guideline, 2018 edition.

Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles may enhance efficacy. Dose-dense chemotherapy, which is adopted as adjuvant chemotherapy of high-risk breast cancer, is addressed in the Japanese Breast Cancer Society Clinical Practice Guideline for breast cancer, 2018 edition (in Japanese). To evaluate the benefits and safety of dose-dense adjuvant chemotherapy described in the guideline, we performed a systematic review and meta-analysis of data of randomized trials using the same drugs, doses, and numbers of cycles. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting randomized trials published until November 2016. Overall survival (OS), disease-free survival (DFS), and toxicity were assessed. Three trials comprising 5190 patients were included. Compared with conventional chemotherapy, dose-dense chemotherapy lengthened OS (RR = 0.76; 95% CI = 0.64-0.90) and DFS (RR = 0.83; 95% CI = 0.75-0.92) and increased the risk of anemia (RR = 4.56; 95% CI = 2.01-10.34). We conclude that dose-dense chemotherapy can be highly recommended as adjuvant chemotherapy for patients with breast cancer with a high risk of recurrence risk and sufficient bone marrow function.

TS-1 add-on therapy in Japanese patients with triple-negative breast cancer after neoadjuvant or adjuvant chemotherapy: a feasibility study.

Purpose We examined the feasibility, efficacy, and safety of TS-1 add-on therapy (TAT) in Japanese patients with triple-negative breast caner (TNBC). Methods TAT (TS-1, 80 mg/m2/day, BID, PO), consisting of the 21-day cycles of 14-day consecutive administration followed by 7-day drug holiday, was conducted for 365 days. The median follow-up was 75.2 months (range, 7.3-103.3 months). The primary endpoint was the feasibility of TAT. The secondary endpoints included relapse-free survival (RFS), overall survival (OS), and safety. Results 63 Japanese patients with TNBC (median age, 52.5 years; range, 23.7-68.6 years) were examined. Among them, 34 (54.0%) were postmenopausal, 54 (93.7%) had TNBC of common histological type, 51 (81.0%) had T1 to 3 tumors, 63 (100%) had undergone standardized surgery, and 44 (69.8%) and 19 (30.2%) had undergone neoadjuvant chemotherapy and adjuvant chemotherapy, respectively. The 365-day cumulative rate of TS-1 administration was 68.3% (95% confidence interval, 55.3-79.4), being comparable to 65.8% previously reported for gastric cancer. The 5-year RFS rates were 52.3% and 84.2% in the neoadjuvant and adjuvant chemotherapy groups, respectively, and the 5-year OS rates were 68.0% and 89.5%, respectively. The most common adverse events (AEs) were leucocyte count decreased (50.8%), total bilirubin decreased (44.4%), and pigmentation (42.9%). AEs were manageable clinically, and any grade 4 AEs did not develop. Conclusions The 365-day cumulative rate of TS-1 administration in TNBC patients was comparable to that in gastric cancer patients despite previous chemotherapy with anthracyclines and/or taxanes. TAT was feasible for TNBC patients after standard primary therapy.

A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients.

BACKGROUND: NK105 is a novel nanoparticle drug delivery formulation that encapsulates paclitaxel (PTX) in polymeric micelles. We conducted an open-label phase III non-inferiority trial to compare the efficacy and safety of NK105 and PTX in metastatic or recurrent breast cancer. METHODS: Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m2) or PTX (80 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS), with a non-inferiority margin of 1.215. RESULTS: A total of 436 patients were randomised and 211 patients in each group were included in the efficacy analysis. The median PFS was 8.4 and 8.5 months for NK105 and PTX, respectively (adjusted hazard ratio: 1.255; 95% confidence interval: 0.989-1.592). The median overall survival and overall response rates were 31.2 vs. 36.2 months and 31.6% vs. 39.0%, respectively. The two groups exhibited similar safety profiles. The incidence of peripheral sensory neuropathy (PSN) was 1.4% vs. 7.5% (≥Grade 3) for NK105 and PTX, respectively. The patient-reported outcomes of PSN were significantly favourable for NK105 (P < 0.0001). CONCLUSIONS: The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01644890.

A Real-World Retrospective Cohort Study of Combined Therapy with Bevacizumab and Paclitaxel in Japanese Patients with Metastatic Breast Cancer.

OBJECTIVE: Combined therapy with bevacizumab and paclitaxel (BP regimen) as a first-line treatment has proven highly effective with good tolerance for patients with metastatic breast cancer (MBC). The objective of this study was to examine the efficacy and safety of the BP regimen for Japanese patients with MBC in real-world clinical settings. METHODS: From June 2012 through May 2014, we recruited 94 patients at 10 medical institutions. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and safety. Objective response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0-Japan Clinical Oncology Group. RESULTS: Nighty patients with MBC (mean 58 years, range: 34-80 years) were enrolled, and 60 (66.6%) and 52 (57.7%) had undergone prior chemotherapy as adjuvant treatment and treatment for MBC, respectively. Median TTF was 6.2 months (95% confidence interval [CI], 4.2-8.3 months), and median OS was 15.4 months (95% CI, 12.0-18.9 months). The overall response rate was 67.8% (95% CI: 57.1-77.2%). A total of 28 patients (31.1%) required a dose reduction of paclitaxel. Forty-five, 42, and 3 patients received the initial doses of 90, 80, and 60 mg/m2, respectively. Among patients who received the initial doses of 90 mg/m2, 13 patients (28.9%) unexpectedly required a dose reduction of ≥20 mg/m2. The BP regimen was discontinued for 66 (73.3%) of the 90 patients, 52 (57.7%) of whom experienced "disease progression." Grade 3/4 hematologic AEs developed in 51 patients (56.6%), with leukopenia and neutropenia in 16 patients (17.8%) and 21 patients (23.3%), respectively. Grade 3 nonhematologic AEs developed in 8 patients (8.9%), with the most common nonhematologic AE of peripheral neuropathy in 4 patients (4.4%). No Grade 4 nonhematologic AEs developed. Peripheral neuropathy [56 patients (62.2%) ], nail discoloration [53 patients (58.9%) ], and fatigue [51 patients (56.7%) ] were the most predominant AEs-the known AEs of paclitaxel. CONCLUSIONS: The BP regimen was active and well tolerated in the real-world clinical settings. As many as 28.9% of patients who received the initial dose of 90 mg/m2 required a dose reduction of paclitaxel by 20 mg/m2. Therefore, there is a need to find a therapeutic regimen that is less likely to result in dose reductions for patients with MBC who undergo a BP regimen using the initial paclitaxel dose of 90 mg/m2.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Analysis of complete response by MRI following neoadjuvant chemotherapy predicts pathological tumor responses differently for molecular subtypes of breast cancer.

In the present study, clinical tumor response following neoadjuvant chemotherapy (NAC) was diagnosed by magnetic resonance imaging (MRI) and clinicopathological factors, including molecular subtypes at baseline, were analyzed for correlations with pathological tumor responses. In addition, clinicopathological factors were analyzed for a correlation with the MRI capacity to predict pathological complete response (pCR). Clinical tumor response evaluated by MRI following NAC was determined as a clinical CR (cCR) or a residual tumor. cCR was confirmed if no gadolinium enhancement or an enhancement equal to or less than that of glandular tissue was observed in any phase of the MRI. Pathological tumor responses following NAC were classified into grades 0 (no change) to 3 (no residual invasive cancer) according to criteria of the Japanese Breast Cancer Society. pCR was defined as grade 3 in the present study. Of 264 cases of invasive breast cancer in 260 patients (4 synchronous bilateral breast cancer cases), 59 (22%) were diagnosed by MRI following NAC as cCR and 98 (37%) were pathologically diagnosed as pCR. In terms of predicting pCR by MRI, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 44, 90, 73, 73 and 73%, respectively. Tumor size, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype and histological type were significantly correlated with pathological tumor responses. pCR rates increased in the following order: luminal/HER2-negative (14%), luminal/HER2-positive (32%), triple-negative (46%) and non-luminal/HER2-positive (73%) tumors. Sensitivity and specificity were the highest (60 and 100%, respectively) in triple-negative tumors. PPV decreased in the following order: triple-negative (100%), non-luminal/HER2-positive (92%), luminal/HER2-positive (46%) and luminal/HER2-negative (33%) tumors. In conclusion, MRI evaluation is useful for predicting pCR following NAC, particularly for triple-negative tumors.