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Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-01.

Although hexagonal boron nitride (hBN) is a thermally conductive and electrically insulating filler in composite materials, surface modification remains difficult, which limits its dispersibility and functionalization. In this study, carbon layer formation on hBN particles by plasma processing in hydroquinone aqueous solution was investigated as a surface modification technique. Carbon components with features of polymeric hydrogenated amorphous carbon were found to be uniformly distributed on the hydroquinone-aided plasma-modified hBN (HQpBN) particles. Electron spin resonance measurements revealed abundant unpaired electrons in HQpBN, indicating that defects were formed on hBN by plasma processing and that the carbon layer contained dangling bonds. The defects on hBN could help in the attachment of the carbon layer, whereas the dangling bonds could act as reactive sites for further functionalization. The carbon layer on HQpBN was successfully functionalized with isocyanate groups, thus confirming the ability of this carbon layer to facilitate surface modification. These results demonstrate that the carbon layer formed on hBN can provide a designable interface in organic/inorganic composite materials.

Purpose:In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2− advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease.Patients and Methods:Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed.Results:The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45–0.73; second-line, HR, 0.48; 95% CI, 0.36–0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64–1.14; second-line, HR, 0.66; 95% CI, 0.46–0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26–0.63; OS, HR, 0.58; 95% CI, 0.35–0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39–0.73; OS, HR, 0.82; 95% CI, 0.58–1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27–0.57; OS, HR, 0.51; 95% CI, 0.33–0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups.Conclusions:Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.

Treatment Discontinuation, Drug Exposure, and Dose Adjustment

[Purpose] It is important to make early decisions about treatment changes in treatment-resistant groups. The aim of this study is to extract non-responders among preoperative chemotherapy using 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) in primary breast cancer. We hypothesized that early evaluation of FDG PET after the first course of docetaxel (DTX) would predict treatment resistant group by the relationship between changes on FDG accumulation and tumor diameter on magnetic resonance imaging (MRI). [Patients and Methods] Thirty-seven of 41 patients were evaluated. Clinical stage was T1-4, N0-3, and M0 between August 2007 and December 2010. Four courses of DTX were administered followed by 4 courses of fluorouracil/epirubicin/cyclophosphamide (FEC) followed by surgery. FDG-PET evaluation was performed by the maximum standardized uptake value (SUVmax). FDG-PET scans were performed at baseline, at 15 days after the first course of DTX (C1D15), and at 15 days after 4 courses of DTX (C4D15). Tumor reduction rate was measured on MRI at baseline and at C4D15 according to Response Evaluation Criteria in Solid Tumors (RECIST). ROC analysis was performed by between SUVmax of C1D15 and MRI of C4D15. Changes of SUVmax C1D15 were divided into high and low group by ROC analysis. Core needle biopsy (CNB) was performed to evaluate the treatment effect pathologically after 4 courses of DTX (C4CNB). The pathological treatment effect of surgical specimens after 4 courses of FEC (C4FEC) was also examined. The difference in progression-free survival (PFS) rate or overall survival (OS) rate between the low and high SUVmax of C1D15 change rate was calculated using Kaplan-Meier survival curves and compared by log-rank test. The protocol of the study was approved by the Ethics Committee of the Gunma Prefectural Cancer Center (ECGPCC), and all patients gave their written informed consent before enrollment (No. 19011). The observational study was also approved by ECGPCC (No. 30087). [Results] There were ER+HER2-:17, ER+HER2+:4, ER-HER2-:11, and ER-HER2+:5 cases. SUVmax change rate C1D15 correlated with the SUVmax change rate C4D15 and tumor shrinkage rate on MRI C4D15 in univariate (SUVmax C4D15: γ=.567, p Citation Format: Tomoko Hirakata, Yasuhiro Yanagita, Tomomi Fujisawa, Teruhiko Kinoshita, Hiroyuki Horikoshi, Nariyuki Oya, Tsukasa Akiyoshi, Misa Iijima, Takeshi Miyamoto, Keiko Yanai, Hiroshi Matsumoto, Kenichi Inoue, Rie Horii, Takaaki Fujii, Ken Shirabe. Changes in 18F-FDG-PET uptake after the first course of DTX reflect response to preoperative chemotherapy and prognosis in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-23.

Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin-based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double-blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide (AC/EC) chemotherapy.Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (55 vs ≥55 years) and study site. The primary end point was the incidence of treatment-related adverse events (TRAEs) with FosNTP.Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%-34.7%) and FosAPR (22.0%; 95% CI, 11.5%-36.0%), with any-cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment-related ISRs observed in 0% and 10.0%, respectively. The overall (0-120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR.FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.

Excitatory spiny stellate neurons are prominently featured in the cortical circuits of sensory modalities that provide high salience and high acuity representations of the environment. These specialized neurons are considered developmentally linked to bottom-up inputs from the thalamus, however, the molecular mechanisms underlying their diversification and function are unknown. Here, we investigated this in mouse somatosensory cortex, where spiny stellate neurons and pyramidal neurons have distinct roles in processing whisker-evoked signals. Utilizing spatial transcriptomics, we identified reciprocal patterns of gene expression which correlated with these cell-types and were linked to innervation by specific thalamic inputs during development. Genetic manipulation that prevents the acquisition of spiny stellate fate highlighted an important role for these neurons in processing distinct whisker signals within functional cortical columns, and as a key driver in the formation of specific whisker-related circuits in the cortex.

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.

Purpose: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR+), HER2− advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease. Patients and Methods: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed. Results: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45–0.73; second-line, HR, 0.48; 95% CI, 0.36–0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64–1.14; second-line, HR, 0.66; 95% CI, 0.46–0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, n = 265; placebo arm, n = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26–0.63; OS, HR, 0.58; 95% CI, 0.35–0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39–0.73; OS, HR, 0.82; 95% CI, 0.58–1.20). In second-line patients (abemaciclib arm, n = 170; placebo arm, n = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27–0.57; OS, HR, 0.51; 95% CI, 0.33–0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups. Conclusions: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.

Objective Monitoring quality of life (QoL) in patients with cancer can provide insight into functional, psychological and social consequences associated with illness and its treatment. The primary objective of this study is to examine the influence of cultural factors on the communication between the patient and the health care provider and the perceived QoL in women with breast cancer in Japan and the Netherlands. Methods In Japanese and Dutch women with early breast cancer, the number, content and frequency of QoL-related issues discussed at the medical encounter were studied. Patients completed questionnaires regarding QoL and evaluation of communication with the CareNoteBook. Results The total number, frequency and content of QoL-related issues discussed differed between the two countries. Japanese women (n = 134) were significantly more reticent in discussing QoL-issues than the Dutch women (n = 70) (p < .001). Furthermore, Dutch patients perceived the CareNoteBook methodology significantly more positively than the Japanese patients (p < .001). Both groups supported the regular assessment via a CareNoteBook methodology. Conclusions Japanese women are more reluctant in expressing their problems with the illness, its treatment and patient-physician communication than Dutch women.

CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild-type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1−/− mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1−/− neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioural test battery, adult CHAMP1 heterozygous knockout mice showed mild memory defects, altered social interaction, and depression-like behaviours. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1−/− brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double‐blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent‐to‐treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression‐free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P, Abemaciclib in combination with endocrine therapy (ET) in the East Asian populations of MONARCH 2 and MONARCH 3 improved efficacy for patients with HR+, HER2− advanced breast cancer.

Background It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin. Methods This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan–Meier method, with the cut-off value of 1500/μL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3. Results The median OS was longer in patients with an ALC of ≥ 1500/μL than in those with an ALC of Conclusions Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.

Background Abemaciclib is approved for patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) with progression on prior endocrine therapy (ET). The MONARCH 2 trial showed a statistically significantly benefit in progression-free survival (PFS) (hazard ratio [HR]: 0.553; 95% CI: 0.449-0.681; p < 0.001), overall survival (OS) (HR: 0.757; 95% CI: 0.606-0.945; p = 0.01) and a manageable safety profile for abemaciclib plus fulvestrant compared with fulvestrant alone. Here we report the pre-specified final overall survival (OS) analysis from the MONARCH 2 trial (NCT02107703). Methods MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib or placebo, plus fulvestrant for treatment of pre-, peri- or postmenopausal women with CDK 4 & 6 inhibitor naïve HR+, HER2- ABC that progressed during ET. Pts were randomized 2:1 to receive abemaciclib or placebo, 150 mg twice daily, plus fulvestrant. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary versus secondary). OS and safety were key secondary endpoints, and chemotherapy-free survival was an exploratory endpoint defined as the time from randomization to initiation of chemotherapy or death, whichever occurs the earliest. Kaplan-Meier (KM) method was used to analyze time-to-event variables. A stratified Cox proportional hazards model was used to estimate treatment effect hazard ratio (HR). The prespecified final analysis was planned to occur based on approximately 441 OS events. Data cutoff was March 18, 2022. Results 669 women were randomized 2:1 to receive abemaciclib (n = 446) or placebo (n = 223), plus fulvestrant. Baseline characteristics have been previously reported (Sledge et. al., Jama Oncol 2020). The median follow-up time was approximately 80 months and at the time of the data cutoff, 11% of pts were still receiving study drug in the abemaciclib arm versus 2% in the placebo arm. 440 OS events were observed in the ITT population (abemaciclib arm: 283 events; placebo arm: 157 events). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR: 0.784; 95% CI: 0.644-0.955). The maintained separation of the KM curves beyond the medians is illustrated by the differences in the estimated 5- and 6-year OS rates between arms (5-year: 41.2% versus 29.2%; 6-year: 34.7% versus 23.7%; abemaciclib versus placebo respectively). While OS benefit was generally consistent across subgroups, a more pronounced benefit is noted in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI: 0.499-0.829), primary resistance to ET (HR: 0.634; 95% CI: 0.436-0.922) or negative progesterone receptor status (HR: 0.623; 95% CI: 0.405-0.959). Moreover, the addition of abemaciclib to fulvestrant deferred the initiation of chemotherapy (HR: 0.674; 95% CI: 0.562-0.809), with substantial difference in yearly chemotherapy-free survival rates (3 year: 42% vs 29.3%; 4 year: 37% vs 18.6%; 5 year: 32.4% vs 14.7%). Notably with longer exposure to abemaciclib, no new additional safety risks or cumulative toxicities were identified. Conclusions At the prespecified final OS analysis of the MONARCH 2 trial, with a median follow-up of 6.5 years, the statistically significant benefit previously demonstrated was confirmed and maintained. OS benefit was generally consistent across subgroups, with numerically greater effect size observed among patients with poorer prognosis. Importantly, the survival benefit came with a substantial extension of the chemotherapy-free survival time, which is an important consideration for pts with ABC. The results also provide assurance of the safety of abemaciclib with longer-term use. Citation Format: Antonio Llombart-Cussac, George Sledge, Masakazu Toi, Patrick Neven, Joo Hyuk Sohn, Kenichi Inoue, Xavier Pivot, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Valerie Andre, Yuanyuan Bian, Ashwin Shahir, Gertjan van Hal. PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-11.

Background: Brain metastases (BM) occur in 20%-50% of patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC), and their presence is a poor prognostic factor. Leptomeningeal carcinomatosis (LMC) occurs in 12%–43% of pts with MBC. Therapeutic options for BC pts with BM and/or LMC are limited. Results of the DESTINY-Breast01 and DESTINY-Breast03 studies have shown the clinical benefit of trastuzumab deruxtecan (T-DXd) in HER2+ MBC pts with stable BM; however, the study populations were small and did not include pts with active BM (untreated or progressive) and/or LMC. This data gap is addressed in the present study. Methods: ROSET-BM (UMIN000044995) is a multicenter, retrospective chart review study of pts who received T-DXd for HER2+ MBC with BM and LMC between May 25, 2020, and April 30, 2021, in a standard-of-care setting. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Additionally, in the pts with brain imaging data, intracranial (IC)-ORR and IC-PFS were evaluated by independent radiologists to provide central review according to RECIST v1.1. Active BM were determined by independent central review (ICR). Pts whose baseline and pre-baseline brain imaging data were compared and confirmed increased tumor size, or pts with new lesions were classified as active BM. LMC was determined by ICR using brain imaging. Results: In the study period, 62 sites participated, enrolling 113 pts with HER2+ MBC and BM were treated with T-DXd. After exclusion of data from 9 who did not meet the criteria for inclusion, 104 pts were included in the analysis. In the 104 pts, 70.2% (n=73) were active BM, 16.3% (n=17) were active BM with LMC, 5.8% (n=6) were stable BM, 1.9% (n=2) were only LMC, and 5.8% (n=6) were not classified. Symptomatic BM were observed in 30.8% (n=32). Median number of prior lines of therapy was 4 (range, 1–15). Median duration of follow up from first T-DXd treatment was 11.2 months. ORR assessed by investigator was 55.7% (complete response [CR], 5.2%) in all pts, 51.7% (CR, 6.9%) in symptomatic BM pts (n=29), and 57.4% (CR, 4.4%) in asymptomatic BM pts (n=68). Among all pts, median PFS was 16.1 months (95%CI, 12.0–n/a), and median OS was not reached (OS at 1 year was 74.9%). In the 19 pts with LMC, 1-year PFS and OS were 60.7% (95%CI, 34.5–79.1) and 87.1% (95%CI, 57.3–96.6), respectively (neither reached the median). Of the 89 pts with brain lesion imaging data (at both baseline and follow-up), IC-ORR was 62.7% (CR, 0.0%). IC-PD was observed in 5.9% (n=3) of pts. Median IC-PFS was 16.1 months (95%CI, 12.2–n/a). In all pts, the most common event and adverse event leading to discontinuation of T-DXd were PD (27 pts, 26.0%) and interstitial lung disease (19 pts,18.3%), respectively. Conclusion: The results of this retrospective chart review show that T-DXd has promising efficacy in HER2+ MBC pts with active BM and LMC. This study was funded by Daiichi Sankyo Co., Ltd. Citation Format: Takashi Yamanaka, Naoki Niikura, Hironori Nomura, Hiroki Kusama, Mitsugu Yamamoto, Kazuo Matsuura, Kenichi Inoue, Sachiko Takahara, Shosuke Kita, Miki Yamaguchi, Tomoyuki Aruga, Nobuhiro Shibata, Akihiko Shimomura, Yuri Ozaki, Kazuhiro Shiraishi, Shuji Sakai, Yoko Kiga, Tadahiro Izutani, Kazuhito Shiosakai, Junji Tsurutani. Trastuzumab deruxtecan for the treatment of patients with HER2-positive breast cancer with brain and/or leptomeningeal metastases: A multicenter retrospective study (ROSET-BM study) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-01.

Introduction: U3-1402 is a novel, investigational ADC directed against HER3, which is widely expressed in breast cancer. Safety and preliminary antitumor activity of U3-1402 was previously reported in this ongoing, phase 1/2 clinical trial (NCT02980341/JapicCTI-163401). Here we report updated safety data from the dose escalation/dose finding (DE/DF) and phase 2 dose expansion parts, and we present for the first time efficacy data for patients in the expansion part with HR+/HER2− MBC with high or low levels of HER3 expression. Methods: In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2− MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg). Primary objectives included safety and efficacy of U3-1402; secondary objectives included correlative biomarker and pharmacokinetics analyses. Archival or pretreatment tissue obtained in the 6 months prior to U3-1402 treatment was analyzed by IHC for HER3 expression. Results: As of March 2020, all 4 expansion cohorts had completed enrollment. In the DE/DF and expansion parts combined, 172 patients received ≥1 dose of U3-1402 (114 [66%] had HR+/HER2− MBC). Median age was 56 y (range, 30-83 y); 123 (72%) and 49 (28%) patients had an ECOG PS of 0 or 1, respectively. Patients received a median of 6 (range, 1-14) prior systemic therapies. Median treatment duration of U3-1402 was 5 mo (range, 1-30 mo). 101 patients (59%) discontinued because of progressive disease, and 15 (9%) discontinued because of an AE. The most common grade ≥3 treatment-emergent AEs reported were decreased neutrophil count (43 patients [25%]), decreased platelet count (39 patients [23%]), decreased white blood cell count (28 patients [16%]), and anemia (31 patients [18%]). Nine patients (5%) experienced treatment-related interstitial lung disease according to central adjudication, including one grade 5 event. At data cutoff, 85 patients in the HR+/HER2− expansion part were evaluable for efficacy by blinded independent central review. Among 33 patients with HR+/HER2− HER3-high MBC treated with 4.8 mg/kg, 10 (30%) had a response (all partial responses [PRs]), with a clinical benefit rate (CBR; complete response + PR + stable disease for ≥6 mo) of 45% (15/33). Among 31 patients with HER3-high MBC treated with 6.4 mg/kg, 3 (10%) had a response (all PR) with a CBR of 16% (5/31). Among 21 patients with HER3-low MBC treated with 6.4 mg/kg, 6 (29%) had a response (all PRs) with a CBR of 33% (7/21). TNBC data are immature at the time of abstract data cutoff; efficacy by HR status will be provided in the presentation. Membrane HER3 expression levels were dynamic; they varied between archival and pretreatment biopsies and decreased on treatment with U3-1402. Across the doses evaluated, the U3-1402 AUC and Cmax of the total antibody, intact ADC, and released payload were approximately dose proportional, with minimal accumulation after multiple doses; the released payload Cmax was highest in cycle 1 and decreased in later cycles. Conclusions: In this heavily pretreated MBC population, U3-1402 demonstrated clinically meaningful antitumor activity in HR+/HER2− MBC with high or low levels of HER3 expression. The safety profile of U3-1402 was consistent with that previously reported, with 9% of patients discontinuing because of AEs. Clinical data pertaining to patients with TNBC and correlative analyses (including association of HER3 expression with response) will be presented. Citation Format: Ian Krop, Kan Yonemori, Shunji Takahashi, Kenichi Inoue, Takahiro Nakayama, Hiroji Iwata, Tatsuya Toyama, Yutaka Yamamoto, Masato Takahashi, Akihiko Osaki, Shigehira Saji, Yasuaki Sagara, Joyce O’Shaughnessy, Tiffany Traina, Shoichi Ohwada, Zhenhao Qi, Yang Qiu, Hiroshi Onuma, Om Sharma, Sabeen Mekan, Norikazu Masuda. Safety and efficacy results from the phase 1/2 study of U3-1402, a human epidermal growth factor receptor 3 (HER3)-directed antibody drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-09.

In this study, soft X-ray emission spectroscopy of an aqueous colloidal dispersion of multi-walled carbon nanotubes modified via the plasma process in an aqueous solution was performed for investigating the electronic state of water molecules on the colloidal particles. In the aqueous dispersion, reconstruction of the hydrogen-bonded network was implied by the O 1s spectral changes in the 1b1' and 1b1'' peaks. Furthermore, the O 1s spectral intensity around the 3a1 state was enhanced to an unusually broad energy range in comparison with previous studies. This unusual spectral change might be attributed to the hybridization of the electronic states of oxygen-containing functional groups on the surface of the plasma-modified multi-walled carbon nanotubes and that of the surrounding water molecules. Our observation indicates not only reconstruction of the hydrogen-bonded network in the aqueous dispersion but also a significant interaction of the electronic states between the water molecules and the plasma-modified multi-walled carbon nanotubes.

BACKGROUND In the field of breast screening using mammography, announcing to the examinees whether they are dense or not has not been deprecated in Japan. One of the reasons is a shortage of objectivity estimating their dense breast. Our aim is to build a system with deep learning algorithm to calculate and quantify objective breast density automatically. MATERIAL AND METHOD Mammography images taken in our institute that were diagnosed as category 1 were collected. Each processed image was transformed into eight-bit grayscale, with the size of 2294 pixels by 1914 pixels. The "base pixel value" was calculated from the fatty area within the breast for each image. The "relative density" was calculated by dividing each pixel value by the base pixel value. Semantic segmentation algorithm was used to automatically segment the area of breast tissue within the mammography image, which was resized to 144 pixels by 120 pixels. By aggregating the relative density within the breast tissue area, the "breast density" was obtained automatically. RESULT From each but one mammography image, the breast density was successfully calculated automatically. By defining a dense breast as the breast density being greater than or equal to 30%, the evaluation of the dense breast was consistent with that by a computer and human (76.6%). CONCLUSION Deep learning provides an excellent estimation of quantification of breast density. This system could contribute to improve the efficiency of mammography screening system.

BackgroundIn the double-blind, phase 3 PALOMA-2 and PALOMA-3 studies, palbociclib plus endocrine therapy (ET) demonstrated significant improvement in progression-free survival versus placebo plus ET in patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer. This analysis assessed subsequent treatment patterns after palbociclib therapy in Japanese patients enrolled in the PALOMA-2 and PALOMA-3 studies.MethodsPALOMA-2 included postmenopausal women who had not received prior systemic therapy for advanced disease. PALOMA-3 included pre- or postmenopausal women who had progressed on previous ET. Types of subsequent therapy were assessed, and treatment durations of subsequent therapy were estimated using the Kaplan–Meier method.ResultsJapanese patients were enrolled in PALOMA-2 (n = 46) and PALOMA-3 (n = 35). In both studies, the most common first subsequent therapy was ET (PALOMA-2, 77% in the palbociclib group and 75% in the placebo group; PALOMA-3, 55% and 43%, respectively), followed by chemotherapy (PALOMA-2, 18% and 8%; PALOMA-3, 32% and 57%). The median (95% CI) duration of first subsequent therapy was 6.4 (2.3‒13.9) months with palbociclib plus letrozole and 6.7 (2.8‒13.0) months with placebo plus letrozole in PALOMA-2 and 3.8 (2.4‒5.7) months with palbociclib plus fulvestrant and 9.7 (1.0‒not estimable) months with placebo plus fulvestrant in PALOMA-3.ConclusionsThe types of first subsequent therapy received by Japanese patients in the palbociclib plus ET and placebo plus ET groups were similar. Further evaluation of subsequent therapy data in the real-world setting is warranted considering the small sample size of this analysis.

Palbociclib is a highly selective, reversible, oral inhibitor of cyclin‐dependent kinases 4 and 6 that is approved to treat hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. An open‐label, single‐arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in 42 postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. The probability of progression‐free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3‐84.4), but median progression‐free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow‐up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8‐49.2). The probability of progression‐free survival at 1 year was 75.6% (90% confidence interval, 62.4‐84.7). Median progression‐free survival was 35.7 months (95% confidence interval, 21.7‐46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0‐63.6) and 85.7% (95% confidence interval, 71.5‐94.6), respectively. Common treatment‐related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment‐related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health‐related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer in this updated analysis., With longer follow‐up of an open‐label, single‐arm, Japanese phase 2 study conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer, median progression‐free survival was 35.7 months (95% CI, 21.7‐46.7). Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer.

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in germinal BRCA1- or BRCA2-mutation carriers. Since tumors with the phenotype have defects in the DNA damage repair pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who underwent diagnostic core-needle biopsy and received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. They had a tumor size of T1, T2, T3, or T4, a lymph node status of N0, N1, N2, or N3, and no distant metastasis (M0) at diagnosis, and were enrolled as subjects in this study. The methylation and/or loss or UPD of BRCA1 (termed BRCA1 alterations) and the loss or UPD of BRCA2 (termed BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, out of 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P Citation Format: Mamoru Takada, Yasuhiko Kaneko, Masayuki Haruta, Shigenori Nagai, Kenichi Inoue, Katsunori Toduka, Masafumi Kurozumi, Hiroyuki Takei, Seishi Ogawa, Takeshi Nagashima, Takafumi Sangai, Hiroshi Fujimoto, Junta Sakakibara, Ryotaro Teranaka. BRCA1 alterations with additional defects in DNA damage repair genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-15.

Background: In MONARCH 2 (M2), abemaciclib, an oral selective cyclin dependent kinase 4 & 6 inhibitor, demonstrated significant progression-free survival (PFS) improvement in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer when added to fulvestrant. Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median overall survival (OS) benefit of 9.4 months (hazard ratio 0.757; 95% confidence interval, 0.606, 0.945; p=0.0137).1 High grade tumors, progesterone receptor (PgR) negativity, liver metastases, and absence of bone-only disease were identified as independent poor prognostic disease characteristics.2 In a retrospective analysis of M2, among subgroups analyzed, patients within those poor prognostic subgroups numerically received the largest improvement from the addition of abemaciclib to endocrine therapy (ET) with PFS hazard ratios in the range of 0.4 to 0.5.2 Methods: M2 (NCT02107703) was a global, randomized, double-blind Phase 3 trial of abemaciclib + fulvestrant (N=446) or placebo + fulvestrant (N=223) in women with ET resistant HR+, HER2- advanced breast cancer. Investigator-assessed PFS was the primary objective and OS was a key secondary endpoint. Here, we present exploratory OS results conducted within the previously described prognostic subgroups.2 Hazard ratios were estimated using Cox models with a test of interactions of subgroups with treatment performed. Results: As of the data cut-off (20 June 2019), OS prolongation was consistent across all subgroups; a numerically greater OS effect was observed in patients with previously identified negative prognostic factors including patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases, relative to their complementary subgroups (Table). However, no statistically significant interaction between these prognostic factors and treatment effect were observed. Similar to OS, a more pronounced effect for abemaciclib plus fulvestrant for patients with high tumor grade, PgR negativity, baseline liver metastases, and absence of bone-only metastases was also observed when examining the time to chemotherapy or death, whichever is earlier (chemotherapy free survival [CFS]). Conclusions: Consistent with the statistically significant and clinically meaningful benefit observed in the overall study population, abemaciclib plus fulvestrant improved OS across all exploratory subgroups, with the largest OS effects observed in patients with poor prognostic factors, consistent with previously reported PFS data. Refernces: 1. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer. Abstract to be presented at: European Society for Medical Oncology 2019; Barcelona, Spain. 2. Di Leo A, O’Shaughnessy J, Sledge GW Jr, et al. Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy. NPJ Breast Cancer. 2018;4:41. Abbreviations: CFS, chemotherapy free survival; HR, hazards ratio; N, number in overall study population; n, number in specified subgroup; OS, overall survival; PgR, progesterone receptor. n (%) N=669Overall Survival Hazard Ratio (95% CI)Chemotherapy Free Survival Hazard Ratio (95% CI)Tumor gradeHigh169 (25.26)0.66 (0.44, 1.01)0.52 (0.36, 0.75)Low/intermediate345 (51.57)0.79 (0.58, 1.08)0.78 (0.60, 1.02)Unknown155 (23.17)0.83 (0.52, 1.31)0.50 (0.34, 0.76)PgR statusNegative141 (21.08)0.66 (0.41, 1.05)0.59 (0.39, 0.89)Positive509 (76.08)0.79 (0.61, 1.01)0.68 (0.55, 0.85)Baseline liver metastasesYes174 (26.01)0.73 (0.49, 1.08)0.60 (0.42, 0.85)No495 (73.99)0.76 (0.58, 0.99)0.64 (0.51, 0.81)Bone-only metastasesYes180 (26.91)0.91 (0.56, 1.46)0.69 (0.46, 1.01)No486 (72.65)0.72 (0.57, 0.93)0.64 (0.52, 0.80) Citation Format: Patrick Neven, Stephen Johnston, Masakazu Toi, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Yi Lu, Nadine Haddad, Karla Hurt, Antonio Llombart-Cussac, George W Sledge. MONARCH 2: Interim analysis of overall survival in patients with poor prognostic factors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-01.

markdownabstract__Purpose:__ Examine illness perceptions, functional health and quality of life of lung cancer patients throughout chemotherapy treatment. __Patients and Methods:__ Longitudinal design with baseline measure 12 days after the first chemotherapy and follow-up measure 3 months later, where illness perceptions (BIPQ), functional health, and quality of life (EORTC QLQ-C-30) were measured. A total of 21 patients with non-small-cell lung cancer took part. Non-parametric testing was performed given the pilot nature of the study and the associated relatively small sample size. __Results:__ Small to medium changes in illness perceptions and functional health between the two measurement points were detected, with both becoming more positive. More negative illness perceptions at the beginning of the treatment were associated with less functioning and lower quality of life at both beginning and end of treatment. __Conclusion:__ Addressing illness perceptions seems a clinically relevant approach in improving functioning and quality of life of patients with non-small-cell lung cancer.

Purpose The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. Methods Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2‐positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). Results Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER− (67–76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. Conclusion In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.

Hiroyuki Kondo, Takafumi Matsumura, Mari Kaneko, Kenichi Inoue, Hidetaka Kosako, Masahito Ikawa, Yousuke Takahama, Izumi Ohigashi, PITHD1 is a proteasome-interacting protein essential for male fertilization, Journal of Biological Chemistry, Volume 295, Issue 6, 2020, Pages 1658-1672, ISSN 0021-9258, https://doi.org/10.1074/jbc.RA119.011144., The proteasome is a protein-degrading molecular complex that is necessary for protein homeostasis and various biological functions, including cell cycle regulation, signal transduction, and immune response. Proteasome activity is finely regulated by a variety of proteasome-interacting molecules. PITHD1 is a recently described molecule that has a domain putatively capable of interacting with the proteasome. However, it is unknown whether PITHD1 can actually bind to proteasomes and what it does in vivo. Here we report that PITHD1 is detected specifically in the spermatids in the testis and the cortical thymic epithelium in the thymus. Interestingly, PITHD1 associates with immunoproteasomes in the testis, but not with thymoproteasomes in the thymus. Mice deficient in PITHD1 exhibit severe male infertility accompanied with morphological abnormalities and impaired motility of spermatozoa. Furthermore, PITHD1 deficiency reduces proteasome activity in the testis and alters the amount of proteins that are important for fertilization capability by the sperm. However, the PITHD1-deficient mice demonstrate no detectable defects in the thymus, including T cell development. Collectively, our results identifyPITHD1as a proteasome- interacting protein that plays a nonredundant role in the male reproductive system.

SummaryBackground Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8–17.6), 22.8 (17.3–31.0), 16.3 (12.4–19.9), and 12.6 (11.2–15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7–4.4), 5.2 (3.7–5.9), 4.2 (3.7–5.1), and 3.8 (3.5–4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.

Covid-19 pandemic waves have been hitting us again and again in the past couple years in many countries, while the reason why they come in such repetitive manners remains unexplained, which have brought us with lingering anxieties and economic stagnations.We proposed a mathematical model to describe the mechanism of the repetitive appearance of the number of new cases based upon the SIQR model in which Q (quarantined infectors) were distinguished from I (un-quarantined ones). The repetitive behavior of the pandemic was simulated by an activator-inhibitor system around a fixed point in a phase space as a kind of self-organized oscillations. Periods between each wave were confirmed to be approximately similar. Repetitive behaviors were also observed in actual Covid-19 data.Practical policies and actions were discussed on the ways to effectively control the repetition of pandemic, and proactive PCR test especially after the peak-out stage is highly recommended.

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.