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.
Patients were randomly assigned in a 1:1 ratio to receive either NK105 (65 mg/m
) or PTX (80 mg/m
) 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.
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).
The primary endpoint was not met, but NK105 had a better PSN toxicity profile than PTX.
ClinicalTrials.gov: NCT01644890.
Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening ...toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population. We enrolled 481 patients who had been treated with trastuzumab and carried out a GWAS using 11 cases (with cardiotoxicity) and 257 controls (without cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed the smallest p values in GWAS (p = 7.60 × 10−7 − 2.01 × 10−4) were further examined using replication samples consisted of 14 cases and 199 controls. The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (rs9316695 on chromosome 13q14.3, rs28415722 on chromosome 15q26.3, rs7406710 on chromosome 17q25.3, rs11932853 on chromosome 4q25, and rs8032978 on chromosome 15q26.3, Pcombined = 6.00 × 10−6, 8.88 × 10−5, 1.07 × 10−4, 1.42 × 10−4, 1.60 × 10−4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity using the five marker SNPs. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was significantly higher (42.5%) compared to that in patients with score ≤ 4 (1.8%) (p = 7.82 × 10−15, odds ratio = 40.0). These findings suggest the potential to improve the ability of physicians to avoid the trastuzumab-induced cardiotoxicity for patients with HER2-positive cancer.
No standard options existed for human epidermal growth factor receptor 2 (HER2)‐positive advanced breast cancer that progresses after second‐line trastuzumab emtansine therapy before 2020. The ...purpose of this study was to examine the efficacy of pertuzumab retreatment after disease progression following pertuzumab‐containing therapy for HER2‐positive locally advanced or metastatic breast cancer for the first time. This randomized, open‐label, multicenter phase III trial was undertaken in 93 sites in Japan. Eligible patients with HER2‐positive breast cancer who had received pertuzumab, trastuzumab, and chemotherapy as first‐ and/or second‐line therapy were randomly assigned (1:1) to: (i) pertuzumab, trastuzumab, and physician's choice chemotherapy (PTC), or (ii) trastuzumab and physician's choice chemotherapy (TC). The primary end‐point was investigator‐assessed progression‐free survival (PFS). Between August 1, 2015 and December 31, 2018, 219 patients were randomized to PTC (n = 110) or TC (n = 109). Median follow‐up was 14.2 months (interquartile range, 9.0–22.2), and median PFS was 5.3 months (95% confidence interval CI, 4.0–6.6) with PTC and 4.2 months (95% CI, 3.2–4.8) with TC (stratified hazard ratio 0.76 95% CI upper limit 0.967; p = 0.022). Progression‐free survival was improved by adding pertuzumab in all prespecified subgroups. The PTC arm showed a trend towards better overall survival and duration of response, but similar objective response and health‐related quality of life. The incidence of treatment‐related adverse events was similar between groups except for diarrhea. Pertuzumab retreatment contributes to disease control for HER2‐positive locally advanced or metastatic breast cancer previously treated with pertuzumab‐containing regimens.
This randomized, open‐label, multicentre phase 3 trial examined the efficacy of pertuzumab retreatment after disease progression following pertuzumab‐containing therapy for HER2‐positive locally advanced or metastatic breast cancer for the first time. Patients randomly assigned to pertuzumab, trastuzumab and physician #x2019;s choice chemotherapy had improved progression‐free survival compared with those who received trastuzumab and physician #x2019;s choice chemotherapy (5.3 vs 4.2 months; p=0.022). Pertuzumab retreatment also showed a trend towards better overall survival and duration of response, and contributes to disease control for HER2‐positive locally advanced or metastatic breast cancer previously treated with pertuzumab‐containing regimens.
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).
IntroductionAlthough there is a lack of data on health-state utility values (HSUVs) for calculating quality-adjusted life-years in Japan, cost–utility analysis has been introduced by the Japanese ...government to inform decision making in the medical field since 2016.ObjectivesThis study aimed to determine whether the Lloyd model which was a predictive model of HSUVs for metastatic breast cancer (MBC) patients in the UK can accurately predict actual HSUVs for Japanese patients with MBC.DesignThe prospective observational study followed by the validation study of the clinical predictive model.Setting and participantsForty-four Japanese patients with MBC were studied at 336 survey points.MethodsThis study consisted of two phases. In the first phase, we constructed a database of clinical data prospectively and HSUVs for Japanese patients with MBC to evaluate the predictive accuracy of HSUVs calculated using the Lloyd model. In the second phase, Bland-Altman analysis was used to determine how accurately predicted HSUVs (based on the Lloyd model) correlated with actual HSUVs obtained using the EuroQol 5-Dimension 5-Level questionnaire, a preference-based measure of HSUVs in patients with MBC.ResultsIn the Bland-Altman analysis, the mean difference between HSUVs estimated by the Lloyd model and actual HSUVs, or systematic error, was −0.106. The precision was 0.165. The 95% limits of agreement ranged from −0.436 to 0.225. The t value was 4.6972, which was greater than the t value with 2 degrees of freedom at the 5% significance level (p=0.425).ConclusionsThere were acceptable degrees of fixed and proportional errors associated with the prediction of HSUVs based on the Lloyd model for Japanese patients with MBC. We recommend that sensitivity analysis be performed when conducting cost-effectiveness analyses with HSUVs calculated using the Lloyd model.
In the randomised Phase 3 IMpassion130 trial, atezolizumab combined with nab-paclitaxel (atezo + nab-P) in 902 patients with triple-negative breast cancer (TNBC) showed prolonged progression-free ...survival (PFS) in both the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-positive subgroup compared with placebo plus nab-P (plac + nab-P). This study assessed the efficacy and safety of atezo + nab-P in the IMpassion130 Japanese subpopulation.
Eligible patients had unresectable locally advanced or metastatic TNBC previously untreated with chemotherapy for metastatic disease. Patients were randomised 1:1 to receive either atezo + nab-P or plac + nab-P. Co-primary endpoints were investigator-assessed PFS and overall survival (ITT population and PD-L1-positive subgroup). These were also assessed in the Japanese subpopulation.
There were 65 Japanese patients (34 atezo + nab-P; 31 plac + nab-P). The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 plac + nab-P). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio HR, 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35). Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm.
Atezo + nab-P efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population.
Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous ...genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (Pcombined = 4.92 × 10−5 and 5.50 × 10−5, respectively). These data suggest that rs8032978 and rs7406710 could be predictive markers of trastuzumab-induced cardiotoxicity in Japanese and Singaporean populations, and support their potential use in clinical risk assessment. These findings offer a first step toward the development of clinically available markers for the potential risk of trastuzumab-induced cardiotoxicity as well as an improved understanding of the pathogenesis of this complication.
We aimed to determine the dynamic trends in health state utility values (HSUVs) in patients with end-stage breast cancer. We selected 181 patients comprising 137 with primary breast cancer (PBC) and ...44 with metastatic breast cancer (MBC) (28 survivors and 16 patients with MBC death). HSUVs were 0.90 and 0.89 in patients with PBC and 0.83 and 0.80 in those with MBC (survivors) at 6 and 3 months, respectively, before the end of the observation period; these values were 0.73 and 0.66, respectively, in those with MBC (deceased) during the aforementioned period. The root-mean-squared error (RMSE) for the decrease in HSUVs over 3 months was 0.10, 0.096, and 0.175 for patients with PBC, MBC (survivors), and MBC (deceased), respectively. One-way analysis of variance for differences in absolute error among the groups was significant (p = 0.0102). Multiple comparisons indicated a difference of 0.068 in absolute error between patients with PBC and those with MBC (deceased) (p = 0.0082). Patients with end-stage breast cancer had well-controlled HSUVs 3 months before death, with a sharp decline in HSUVs in the 3 months leading up to death.
In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These ...were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).
The Japan Society of Clinical Oncology (JSCO) published the “JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients” in 2017. This ...was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.
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