Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial ...hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10(-4)) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10(-4)). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Precise etch depth control of ultra-thin HfO2 (3.5 nm) films applied as a gate oxide material was investigated by using atomic layer etching (ALET) with an energetic Ar beam and BCl3 gas. A monolayer ...etching condition of 1.2 A/cycle with a low surface roughness and an unchanged surface composition was observed for ultra-thin, ALET-etched HfO2 by supplying BCl3 gas and an Ar beam at higher levels than the critical pressure and dose, respectively. When HfO2-nMOSFET devices were fabricated by ALET, a 70% increase in the drain current and a lower leakage current were observed compared with the device fabricated by conventional reactive ion etching, which was attributed to the decreased structural and electrical damage.
Pluripotent cells, such as embryonic stem cells, are invaluable tools for research and can potentially serve as a source of cell- and tissue-replacement therapy. Rejection after transplantation of ...cells and tissue derived from embryonic stem cells is a significant obstacle to their clinical use. Recently, human somatic cells have been reprogrammed directly to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) to yield induced pluripotent stem (iPS) cells. Human iPS cells are a potential source of patient-specific pluripotent stem cells that would bypass immune rejection. iPS cells can also be used to study diseases for which there are no adequate human in vitro or animal models. In this protocol, we describe how to establish primary human fibroblasts lines and how to derive iPS cells by retroviral transduction of reprogramming factors. Overall, it takes 2 months to complete reprogramming human primary fibroblasts starting from biopsy.
The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes ...occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells.
Abstract
Background: In the MONARCH 3 trial, abemaciclib plus an aromatase inhibitor (AI) significantly improved progression free survival and overall response rate with a generally tolerable safety ...profile compared to placebo plus AI. Here we report patient-reported outcomes (PRO) including health-related quality of life (Qol), functioning, and symptoms.
Methods: MONARCH 3 was a double-blind, randomized phase III study of abemaciclib or placebo plus an AI in 493 post-menopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer with no prior systemic therapy in the advanced setting. Two European Organization for Research and Treatment of Cancer (EORTC) questionnaires were included: Quality of Life Questionnaire (QLQ)-Core 30 (C30) and the EORTC QLQ-Breast 23 (BR23) that were assessed at baseline, every 2 cycles through cycle 19, then every 3 cycles until treatment discontinuation, and at short-term follow up. Higher scores on functional and health status/QoL outcomes indicate higher/better levels of functioning or health; conversely higher scores on symptom outcomes indicate higher/worse levels of symptom burden. Between-arm comparisons of change from baseline were conducted using mixed model methods. Statistical significance was set at 0.05 and clinical meaningfulness was set at ≥10 points on a 0-100 scale1.
Results: PRO completion rates were >91% through cycle 19; duration of treatment was longer for abemaciclib plus AI patients (median number of cycles 19 vs.15). Compared to the placebo arm, diarrhea PRO scores in the abemaciclib arm showed a clinically (18.68 points) and statistically significant (p<0.001) increase/worsening. By-cycle analysis showed group mean diarrhea scores returned to near-baseline levels post-therapy. Other symptom PROs showed statistically significant (<0.05) but not clinically meaningful differences; fatigue (4.96; p=0.004), systemic therapy side effects (4.48, p<0.001), appetite loss (4.03; p=0.034), and nausea/vomiting (2.77; p=0.013). These results were consistent with the investigator-reported treatment emergent adverse events (TEAEs). Several non-symptom results were also statistically significant but not clinically meaningful including global health/health status (-4.36; p=0.003), role function (-4.25; p=0.025), social function (-3.41, p=0.047), and body image (-5.11, p=0.009). No statistically significant between-treatment differences were observed for physical, emotional, and cognitive functioning or for symptoms of pain, dyspnea, insomnia, constipation, or financial difficulties.
Conclusions: The addition of abemaciclib to an AI resulted in clinically and statistically significant changes in diarrhea without clinically meaningful differences in other symptom scores. Increased GI-related symptoms were consistent with the manageable, reversible AE profile; the highest symptom burden was reported during early visits. No clinically meaningful differences in global health status or functional scores were observed.
ClinicalTrials.gov: NCT02246621
Reference:
1. Osoba D et al. J Clin Oncol 2002;20(14):3106-13.
Citation Format: Goetz MP, Johnston S, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Price GL, Boye M, Li L, Forrester T, Gainford C, Gable J, Carter GC, Sood A, DiLeo A. Health-related quality of life in MONARCH 3: Abemaciclib plus an aromatase inhibitor as initial therapy in women with HR+, HER2- advanced breast cancer abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-16-01.
Abstract
Background
The continuum of anti-HER2 agents is regarded as a standard strategy for HER2 positive metastatic breast cancer patients who had progressed disease with anti-HER2 agent- ...containing treatments. However, there has been lack of data on which agents should be continued and how long continuous anti-HER2 therapies would be effective. This study was aimed to evaluate the efficacy of lapatinib plus vinorelbine in HER2 positive metastatic breast cancer patients who had progressed on both trastuzumab and lapatinib treatments.
Methods
A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n=75; laptinib, 1000mg daily ; vinorelbine 20mg/m2 D1,D8 q3w) or vinorelbine alone (V) (n=74; 30mg/m2 D1,D8 q3w). The stratification factors were followings; 1) visceral metastasis, 2) previous response to lapatinib treatment, CR+PR vs. SD ≥ 12 weeks. The primary endpoint was progression free survival (PFS) rate at 18 weeks. The secondary endpoints were objective response rate (ORR), PFS, and overall survival (OS).
Results :
Both arms were well balanced in various clinical factors. The median number of previous anti-HER2 therapies were 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (44.0% vs 36.5%, p=0.44). ORR was 19.7% in LV arm and 16.9% in V arm (p=0.881). PFS and OS did not differ between two arms (LV vs V; median PFS, 16weeks vs 12 weeks, HR= 0.86, 95% CI 0.61-1.22, p=0.41; median OS, 15.0 months vs 18.9 months, HR= 1.07, 95% CI 0.72-1.58, p=0.72). In subgroup analysis, there was no difference in PFS and OS between two arms according to previous response to lapatinib (median PFS, CR+PR vs. SD ≥ 12 weeks, 12.1weeks vs.17.4 weeks; HR= 1.242, 95% CI 0.881-1.751, p=0.215; median OS, 14.9 months vs. 19.4 months; HR= 1.179, 95% CI 0.797-1.744, p=0.41). Most common adverse events in both arms were neutropenia which was more often observed in V arm (55% vs 73%, p=0.03). Overall, the profiles of adverse events were similar in both arms and all were manageable.
Conclusion
Lapatinib plus vinorelbine treatment was tolerable, however, it did not demonstrate the clinical benefits compared to vinorelbine alone in HER2 positive metastatic breast cancer patients after progression on both trastuzumab and lapatinib.
Citation Format: Sim SH, Park IH, Jung KH, Kim S-B, Ahn J-H, Lee K-H, Im S-A, Im Y-H, Park YH, Sohn JH, Kim YJ, Lee S, Kim H-J, Chae YS, Park K-H, Nam B-H, Lee KS, Ro J. Randomized phase II study of lapatinib plus vinorelbine versus vinorelbine in patients with HER2 positive metastatic breast cancer progressed after lapatinib and trastuzumab treatment abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-23.
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