Among patients with breast cancer and germline mutations in the
BRCA
DNA repair pathway genes, the poly(adenosine diphosphate–ribose) inhibitor talazoparib provided a significant benefit over ...standard chemotherapy with respect to progression-free survival.
Purpose
Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human ...epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748;
P
= 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results.
Methods
Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety.
Results
A total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623–1.294;
P
= 0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%).
Conclusions
Palbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS.
Pfizer Inc (NCT00721409)
Summary Background Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen ...receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. Methods In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 ( CCND1 ), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2·5 mg daily or continuous oral letrozole 2·5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov , number NCT00721409. Findings Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29·6 months 95% CI 27·9–36·0 for the palbociclib plus letrozole group and 27·9 months 25·5–31·1 for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10·2 months (95% CI 5·7–12·6) for the letrozole group and 20·2 months (13·8–27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 0·319–0·748; one-sided p=0·0004). In cohort 1 (n=66), median progression-free survival was 5·7 months (2·6–10·5) for the letrozole group and 26·1 months (11·2–not estimable) for the palbociclib plus letrozole group (HR 0·299, 0·156–0·572; one-sided p<0·0001); in cohort 2 (n=99), median progression-free survival was 11·1 months (7·1–16·4) for the letrozole group and 18·1 months (13·1–27·5) for the palbociclib plus letrozole group (HR 0·508, 0·303–0·853; one-sided p=0·0046). Grade 3–4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three 4% patients), back pain (two 2%), and diarrhoea (two 2%). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. Interpretation The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. Funding Pfizer.
Palbociclib improves outcomes for women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). Dose reductions are recommended for ...the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3.
This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant.
A total of 311 (35.5%) patients with HR+/HER2- ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction.
A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management.
These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.
The real driving emissions of an EU stage IV forest harvester were measured four times within five years to monitor long-time emission behaviour. In this period, the harvester worked 7650 h in total, ...thereof 6300 h with pure rapeseed oil fuel DIN 51605 (R100) and 1350 h with conventional diesel fuel initially. Data analysis according to relevant EU regulation 2017/655 shows that the emission behaviour complies with the legal requirements of exhaust gas stage IV within the five years under consideration. According to EU regulation 2016/1628 the achieved 7650 operating hours nearly correspond to the emission durability period of 8000 h. However, between the single measurements some differences in emission results are clear evident. They are primarily caused by different working profiles, and unavoidable random events. Detailed analysis of the results showed that the measured nitrogen oxides (NO
X
), carbon monoxide, and hydrocarbons remain at the same level over time at comparable operation conditions. Thus, the operation time had no major impact on the emission behaviour of the harvester. During cold start and non-working events higher nitrogen oxides (NO
X
) concentrations are observed in the exhaust since the exhaust aftertreatment system is not within its operation temperature. When the exhaust gas aftertreatment is within its operating range, exhaust emissions are at a very low level indicating an efficient, clean combustion. It can be concluded that the operation of the harvester with R100 did not affect the emission behaviour and functionality of the exhaust gas aftertreatment system.
Article Highlights
Real driving emission measurements were performed four-times in five years
Exhaust gas aftertreatment system still works reliably in practice after 7650 operating hours
Rapeseed oil fuel does not impair the functionality and emission behaviour of the harvester
Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival ...gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.
Adjuvant chemotherapy decision in patients with hormone receptor positive, HER2 negative breast cancer (BC) is challenging. Ki-67 is widely used for adjuvant therapy decision in BC. The multigene ...assay EndoPredict (EP) has shown to provide valid and additional information about the risk of recurrence compared to traditional pathological factors. In this study, we compared Ki-67 with EP assay generated risk groups.
We analyzed the results from prospective EP testing (n = 373) and tumor proliferation assessed by Ki-67 staining in luminal breast cancer. We statistically investigated the association of both parameters and probed for equivalence in risk stratification.
Evaluation of Ki-67 was feasible in 307 (82%) BC specimens with known EP test results. The EPscore (now called 12-gene molecular score) delineated 140 low and 167 high scores. After combining the EPscore with pathological tumor stage and nodal status, we received 203 EPclin low-risk and 104 EPclin high-risk classifications. EPscore and EPclin were significantly associated with Ki-67 indices and tumor grade (p < 0.001). Overall, we observed a moderate correlation between Ki-67 and the EPscore (r = 0.63) as well as the EPclin score (r = 0.59).
Ki-67 values above 25% partly overlap with EP test results and therefore indicate a high-risk profile. In these cases, the additional prognostic information from EP testing might be rather low. However, low and intermediate Ki-67 values (less than 25%) alone were not reliable in predicting a low risk EP profile, indicating that EP testing is useful in this subgroup.
•Comparison of prospective EndoPredict tests with Ki-67 in a large breast cancer cohort.•EPscore and EPclin were significantly associated with Ki-67 indices.•Ki-67 values above 25% partly overlap with high-risk EP test results.•Ki-67 less than 25% was not reliable in predicting a low-risk EP profile.•EP testing is useful, particularly in breast cancer with low and intermediate Ki-67 levels.
Purpose
Prospectively collected outcome data of patients (pts) whose adjuvant systemic therapy recommendation was based on the clinico-molecular test EndoPredict
®
(EP) are presented.
Methods
Pts ...with ER-positive, HER2-negative early breast cancer with 0–3 positive lymph nodes were enrolled. The EP was carried out on all tumor samples. Pts were evaluated for treatment compliance, local recurrence, distant metastases and overall survival. Censored time-to-event outcomes were analysed by Cox proportional hazards models. Additional estimates of the event-free-survival were calculated by the Kaplan–Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels.
Results
373 consecutive pts were enrolled. EP classified 238 pts (63.8%) as low risk and 135 pts (36.2%) as high risk. Median follow-up was 41.6 months. Risk for disease recurrence or death in EPclin high-risk patients was twofold higher in comparison with EPclin low-risk patients (hazard ratio (HR) 2.05 (95% CI 0.85–4.96;
p
= 0.110). Patients with EPclin high risk were at significant higher risk of distant metastases than patients with EPclin low risk (HR 5.18; 95% CI 1.04–25.74;
p
= 0.0443). EPclin high-risk patients who actually underwent adjuvant CTX had a 3-year-DFS of 96.3% (95% CI 92.2–100) in contrast to EPclin high-risk patients without CTX (3-year-DFS: 91.5% (95% CI 82.7–100%); HR 0.32; 95% CI 0.10–1.05;
p
= 0.061).
Conclusion
These first prospective outcome results show that EP, in clinical routine, is a valid clinico-molecular test, to predict DFS and to guide decision of adjuvant CTX use in ER-positive, HER2-negative early breast cancer pts with 0–3 positive lymph nodes. Adjuvant CTX seems to be beneficial for EPclin high-risk patients.
Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that has progressed on ...endocrine therapy. Metronomic administration may offer a better balance of efficacy and safety than standard regimens, but data from previous trials are scarce.
In this open-label, multicenter, phase II trial, patients were randomized to oral vinorelbine administered on a metronomic (50 mg three times weekly) or weekly (60 mg/m2 in cycle 1, increasing to 80 mg/m2 if well tolerated) schedule. Treatment was continued until disease progression or intolerance. The primary endpoint was disease control rate (DCR, the proportion of patients with a best overall confirmed response of CR, PR, or stable disease lasting 6 months or more).
One-hundred sixty-three patients were randomized and treated. The DCR was 63.4% (95% confidence interval CI: 52.0–73.8) with metronomic vinorelbine and 72.8% (95% CI: 61.8–82.1) with weekly vinorelbine. Weekly vinorelbine was also associated with longer progression-free survival (5.6 vs 4.0 months) and overall survival (26.7 vs 22.3 months) than metronomic vinorelbine, but was associated with more adverse events.
In this randomized phase II trial, single-agent metronomic oral vinorelbine was effective and well tolerated as first-line chemotherapy for patients with HR-positive/HER2-negative ABC. Formal comparisons are not done in this phase II study and one can simply observe that confidence intervals of all endpoints overlap. When deciding for a chemotherapy after failure of endocrine therapy and CDK 4/6 inhibitors, oral vinorelbine might be an option to be given with either schedule.
EudraCT 2014-003860-19.
•This is a randomized phase II of weekly versus metronomic vinorelbine therapy in HR+/HER2-breast cancer.•Patients received metronomic or weekly vinorelbine until disease progression.•Longer progression-free and overall survival was observed with weekly vinorelbine.•Metronomic vinorelbine produced fewer adverse events than weekly vinorelbine.•Metronomic vinorelbine is efficacious/tolerable in HR+/HER2– breast cancer patients.
Adjuvant therapy decisions in early breast cancer are based on accurate risk assessment. Urokinase plasminogen activator (uPA) and plaminogen activator inhibitor-1 (PAI-1) have been the first ...biomarkers in hormone receptor (HR) positive breast cancer to reach highest level of evidence. The EndoPredict test (EPclin) combines gene expression information with nodal status and tumor size. The aim of this prospective study was to compare uPA/PAI-1 and EPclin as prognostic biomarkers with regard to feasibility, risk stratification and impact on adjuvant therapy recommendation.
395 patients with HR positive, HER2 negative, intermediate risk breast cancer were enrolled. Relations and concordance of histologic grading as well as EPclin and uPA/PAI-1 values were assessed by Spearman's rank correlation coefficient and Cohen's Kappa. To compare decision impact of EPclin and uPA/PAI-1 three independent case discussions were held: One with known uPA/PAI-1 and EPclin results, one blinded to EPclin alone and another one blinded to both EPclin and uPA/PAI-1.
EPclin could be determined in all 395 (100%), uPA/PAI-1 in 190 (48%) of the tumor samples. EPclin allocated 250 patients (63%) to the low-risk group and 145 patients (37%) to the high-risk group, whereas uPA/PAI-1 allocated 88 patients (46%) to the low-risk group and 102 patients (54%) to the high-risk group. In 59% of cases, both tests showed concordant results. EPclin resulted more frequently in a change of therapy recommendation than the uPA/PAI-1 test (46% vs 24%). Recommendation of adjuvant chemotherapy (CTX) was abandoned twice as often by EPclin (45%) compared to uPA/PAI-1 (22%).
In this first prospective comparison of EPclin and uPA/PAI-1 we found, that EPclin is superior to uPA/PAI-1 with respect to feasibility and decision impact. This leads to substantial avoidance of adjuvant CTX in endocrine-sensitive, HER2-negative breast cancer. Data collection for patients´ clinical outcome is ongoing.
PDF
