This study was designed to demonstrate that efficacy progression-free survival (PFS) of CAELYX pegylated liposomal doxorubicin HCl (PLD) is non-inferior to doxorubicin with significantly less ...cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC).
Women (n=509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m2 (every 4 weeks) or doxorubicin 60 mg/m2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose.
PLD and doxorubicin were comparable with respect to PFS 6.9 versus 7.8 months, respectively; hazard ratio (HR)=1.00; 95% confidence interval (CI) 0.82-1.22. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR=3.16; 95%CI 1.58-6.31; P<0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin.
In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a ...first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer.
Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS).
From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules.
Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.
•Multicenter double-blind phase II MADONNA trial evaluated antitumor activity and toxicity of docetaxel and sorafenib or matching placebo as a 1st line treatment in metastatic/locally advanced HER-2 negative breast cancer.•Increased hematological and skin toxicity led to slow patient accrual and early trail termination.•The trial failed to demonstrate improved PFS under addition of sorafenib to taxane-based chemotherapy in metastatic breast cancer.
In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant ...progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC.
Eligible patients no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay population, and then in the ITT population. OS was a secondary endpoint.
Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug.
Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone.
NCT03125902.
•The phase III IMpassion131 trial evaluated atezolizumab combined with paclitaxel as first-line therapy for aTNBC.•The primary endpoint was investigator-assessed PFS, tested hierarchically in the PD-L1+ and then ITT populations.•Neither PFS nor OS was improved with the combination of atezolizumab plus paclitaxel in either population.•These findings may result from imbalances in prognostic features or chance findings in a relatively small trial.•IMpassion131 results highlight the need for further research into immunotherapy for TNBC.
Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs).
ABRAZO is a ...two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 C1, n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 C2, n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23.
Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval CI) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1–3.1 months and 4.2–5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6–4.0 months and 4.2–5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: −2.6 95% CI, −7.8, 2.5; C2: 1.2 95% CI, −5.5, 8.0). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2).
Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.
•ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in advanced breast cancer/germline BRCA mutation.•Patient-reported global health status/quality of life (GHS/QoL) was maintained from baseline among talazoparib patients.•These findings are the first-ever detailed patient-reported outcomes for talazoparib in advanced breast cancer patients.•The encouraging efficacy achieved with talazoparib is accompanied by maintaining patient-reported GHS/QoL.
Objective
A challenge in the management of breast cancer is development of brain metastases (BM) with limited survival. In primary breast cancer, ER/PR/HER2 are important prognostic markers and are ...important for making effective treatment decisions. Changes in immunohistochemical markers of metastases are with unclear clinical significance, and mechanisms of resistance to endocrine therapy are an additional challenge. The aim of this retrospective study is to detect changes in immunohistochemical markers of primary and BM and to recognize if receptor change has prognostic impact.
Methods
Twenty-four consecutive primary breast cancer patients who developed BM and got surgical resection of BM were enrolled. Matched pair analyses of primary and BM were done with evaluation by immunostaining (ER/PR/HER2).
Results
A small tumor size, ductal histology and HER2+ tumors were associated with BM. Loss of ER/PR receptor positivity was observed in BM compared to primary (ER: 50.0 %/22.7 %;
p
= 0.004; PR: 45.8 %/9.1 %;
p
= n.s), respectively, and almost no change in HER2 status (>80 %;
p
= 0.012). Patients with ER-/PR-negative or HER2-positive primary had shorter time to recurrence than ER-/PR-positive and HER2-negative patients. Receptor change has negative prognostic impact.
Conclusion
With the observed loss of receptor positivity, therapeutic options are diminished. Identification of patients with a high risk for BM is warranted to evaluate preventive strategies.
Purpose
A challenge in management of breast cancer is the development of brain metastases (BM). Because of improvements in systemic therapy with longer survival of patients with advanced cancer, BM ...can appear at a time when extra-BM disease is under control. Development of potential preventive strategies are considered, and new developments in systemic approaches to treatment of BM, (cytotoxic/targeted therapy), are explored. In primary breast cancer, ER/PR, HER2 are important biological markers for predicting prognosis and making effective treatment decisions. Known are changes in markers due to metastases, but clinical significance is still unclear. Aim of this retrospective study is to detect changes in immunohistochemical markers of primary and BM, to recognize concordance and impact on prognosis.
Methods
Twenty-one consecutive primary breast cancer patients who developed BM and got surgical resection of BM were enrolled in this study. Matched-pair analyses of primary and BM were done with evaluation by immunostaining (ER, PR, HER2).
Results
Loss of ER/PR receptor positivity was seen in BM compared to primary (ER: 47.6 %/9.0 %; PR: 42.9 %/0 %), respectively. High concordance exists for HER2 status in primary and BM (>80 %). HER2-positive breast cancer had a shorter median interval until appearance of metastases than HER2-negative patients (32.1/39 months; p = n.s.).
Conclusion
With loss of receptor positivity (ER/PR) in BM treatment, decisions are very difficult. High concordance of HER2 status was seen in matched-pair analysis. Further studies had to investigate whether HER3/4 is a possible target for further therapy.
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