Patient-reported outcomes are integral in benefit–risk assessments of new treatment regimens. The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of ...life (QOL) for patients with metastatic breast cancer (MBC) receiving first-line endocrine-based therapy (palbociclib plus letrozole and letrozole alone).
Treatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) MBC were randomized 2 : 1 to palbociclib plus letrozole (n=444) or placebo plus letrozole (n=222). Patient-reported outcomes were assessed at baseline, day 1 of cycles 2 and 3, and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions (EQ-5D) questionnaires.
As of 26 February 2016, the median duration of follow-up was 23months. Baseline scores were comparable between the two treatment arms. No significant between-arm differences were observed in change from baseline in FACT-Breast Total, FACT-General Total, or EQ-5D scores. Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm (−0.256 versus −0.098; P=0.0183). In both arms, deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without. No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia.
Overall, women with MBC receiving first-line endocrine therapy have a good QOL. The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2− MBC compared with letrozole alone. Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders.
ClinicalTrials.gov: NCT01740427 (https://clinicaltrials.gov/ct2/show/NCT01740427)
Purpose
In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen ...receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) hazard ratio (HR) 0.58;
P
< 0.001. Herein, we report results overall and by subgroups with extended follow-up.
Methods
In this double-blind, phase 3 study, post-menopausal women with ER+/HER2− ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs).
Results
After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib–letrozole (
n
= 444) and 14.5 months for placebo-letrozole (
n
= 222) (HR 0.563; 1-sided
P
< 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib–letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients’ quality of life was maintained.
Conclusions
With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2− ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427.
In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio HR 0.542 95% confidence interval (CI) 0.413-0.711; P < 0.0001) and improved patient-reported outcomes ...(PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS).
This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments.
A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan–Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses.
In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.
•In BRCA1/2-mutated advanced breast cancer, talazoparib did not significantly improve overall survival (OS) versus chemotherapy.•OS was generally consistent across subgroups including by prior platinum, hormone-receptor status, or line of treatment.•Most patients received subsequent systemic treatments, which may have confounded the survival outcome.•Toxicities were managed by supportive care medication/dose modifications; safety was consistent with previous observations.•Extended follow-up of patient-reported outcomes continued to favor talazoparib over chemotherapy.
Sustainable production of biomass for bioenergy relies on low-input crop production. Inoculation of bioenergy crops with plant growth-promoting endophytes has the potential to reduce fertilizer ...inputs through the enhancement of biological nitrogen fixation (BNF).
Endophytes isolated from native poplar growing in nutrient-poor conditions were selected for a series of glasshouse and field trials designed to test the overall hypothesis that naturally occurring diazotrophic endophytes impart growth promotion of the host plants.
Endophyte inoculations contributed to increased biomass over uninoculated control plants. This growth promotion was more pronounced with multi-strain consortia than with single-strain inocula. Biological nitrogen fixation was estimated through 15N isotope dilution to be 65% nitrogen derived from air (Ndfa).
Phenotypic plasticity in biomass allocation and branch production observed as a result of endophyte inoculations may be useful in bioenergy crop breeding and engineering programs.
In the EMBRACA phase III trial, talazoparib (1mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician’s choice of chemotherapy (PCT; capecitabine, eribulin, ...gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs).
Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model.
Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 95% confidence interval (CI) 1.2, 4.8 versus −5.4 95% CI −8.8, −2.0; between arms, P<0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3months, respectively; P<0.0001). A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms.
Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL.
NCT01945775.
Using data from 50 long-term permanent plots from across Venezuelan forests in northern South America, we explored large-scale patterns of stem turnover, aboveground biomass (AGB) and woody ...productivity (AGWP), and the relationships between them and with potential climatic drivers. We used principal component analysis coupled with generalized least squares models to analyze the relationship between climate, forest structure and stem dynamics. Two major axes associated with orthogonal temperature and moisture gradients effectively described more than 90% of the environmental variability in the dataset. Average turnover was 1.91 ± 0.10% year-1 with mortality and recruitment being almost identical, and close to average rates for other mature tropical forests. Turnover rates were significantly different among regions (p < 0.001), with the lowland forests in Western alluvial plains being the most dynamic, and Guiana Shield forests showing the lowest turnover rates. We found a weak positive relationship between AGB and AGWP, with Guiana Shield forests having the highest values for both variables (204.8 ± 14.3 Mg C ha-1 and 3.27 ± 0.27 Mg C ha-1 year-1 respectively), but AGB was much more strongly and negatively related to stem turnover. Our data suggest that moisture is a key driver of turnover, with longer dry seasons favoring greater rates of tree turnover and thus lower biomass, having important implications in the context of climate change, given the increases in drought frequency in many tropical forests. Regional variation in AGWP among Venezuelan forests strongly reflects the effects of climate, with greatest woody productivity where both precipitation and temperatures are high. Overall, forests in wet, low elevation sites and with slow turnover stored the greatest amounts of biomass. Although faster stand dynamics are closely associated with lower carbon storage, stem-level turnover rates and woody productivity did not show any correlation, indicating that stem dynamics and carbon dynamics are largely decoupled from one another.
This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast ...cancer (ABC) with or without visceral metastases.
Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement.
Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2months with palbociclib plus fulvestrant versus 3.4months with placebo plus fulvestrant hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61, and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3months with palbociclib plus letrozole versus 12.9months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC.
Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy.
NCT01942135, NCT01740427
Zusammenfassung
Mammakarzinome werden längst nicht mehr ausschließlich anhand der klassischen klinikopathologischen Parameter Tumorgröße, Hormonrezeptorstatus, Grading und Nodalstatus klassifiziert, ...sondern auch anhand spezifischer Veränderungen im Genexpressionsmuster. Unterschiedliche molekulare Subtypen bedingen unterschiedliche Krankheitsverläufe, bezogen auf progressionsfreies Überleben und Gesamtüberleben. Auf dieser Grundlage haben verschiedene Genexpressionstests in die klinische Routine beim frühen Mammakarzinom Einzug gehalten. In Deutschland sind zurzeit 3 solcher Tests mit dem Evidenzgrad (LoE) IB kommerziell erhältlich: Oncotype DX® (Genomic Health), Endopredict® (Sividon) und Prosigna® (NanoString); sie werden im Beitrag vorgestellt. Gemeinsamkeiten und Unterschiede u. a. hinsichtlich der Auswirkung auf die klinische Therapieentscheidung, der Prädiktion des Benefits durch eine Chemotherapie und der Vorhersagbarkeit von Spätmetastasen werden aufgezeigt und im klinischen Kontext diskutiert.
A stationary response of tree radial growth to climatic variables is assumed as a basis for climatic reconstructions and future growth projections in response to climate change. Mountain hemlock ...(Tsuga mertensiana (Bong.) Carrière) trees on the western slopes of the North Cascade Range (Washington, USA) were examined for stability in growth response to climatic influences at a small spatial scale. Moving correlation functions demonstrate that climateâgrowth interactions are nonstationary over time, alternating between periods of significant and nonsignificant responses. Correlations between growth and winter precipitation have weakened, becoming statistically insignificant in the last decade, but correlations with spring temperature and previous-year summer temperature have strengthened, becoming statistically significant. The Pacific Decadal Oscillation influences patterns in climateâgrowth correlations but does not seem to account for the most recent changes in correlation strength. At an interannual scale, growth differs between El Niño Southern Oscillation phases, specifically between El Niño and La Niña years and between La Niña and neutral phase years. The variability in growth response to climate at interannual and interdecadal time frames, especially with the climate changes emerging in recent decades, will challenge the reliability and accuracy of reconstruction and predictive models.
Increased frequency of droughts and degraded edaphic conditions decreases the success of many reforestation efforts in the Pacific Northwest. Microbial endophyte consortia have been demonstrated to ...contribute to plant growth promotion and protection from abiotic and biotic stresses - specifically drought conditions - across a number of food crops but for limited tree species. Our research aimed to investigate the potential to improve establishment of economically and ecologically important conifers through a series of
field trials and
simulations. Microbial endophyte consortia from Salicaceae, previously shown to confer drought tolerance, and conifer endophyte strains with potentially symbiotic traits were selected for trials with Douglas-fir (
) and western redcedar (
). Reductive experimentation was used to subject seedlings to a spectrum of simulated drought levels or presence/absence of fertilizer, testing hypotheses that endophyte consortia impart improved drought resistance and growth promotion, respectively. Inoculation from Salicaceae consortia significantly (
≤ 0.05) improved survival among seedlings of both species subject to increasing drought stress, with
seedlings surviving at twofold higher rates in extreme drought conditions. Both species demonstrated improved growth 540 days after inoculation of seed with conifer derived consortia. In the carefully controlled greenhouse experiments with both species, seedling Fv/Fm and SPAD values remained significantly (
≤ 0.05) more stable in inoculated treatment groups as stress increased. Our findings confirm that multi-strain consortia may be applied as seed or field amendment to conifers, and the approach is efficient in garnering a positive growth response and can mitigate abiotic stressors.
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