Long term information on the risk/benefit ratio of currently available therapies remains crucial for treatment decisions. In the PACS04 phase III trial, patients (pts) with node-positive (N+) breast ...cancer (BC) were double-randomized to concomitant taxane-anthracycline versus standard FEC, as well as 1-year trastuzumab versus nill in the HER2+ subpopulation.
3009 pts (20% HER2+, 12% triple negative (TNBC) BC) were randomly assigned to receive 6 cycles of fluorouracil 500mg/m2, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 (FEC) or epirubicin 75mg/m2 and docetaxel 75mg/m2 (ED). Pts with HER2+ tumors were randomized to either trastuzumab (TRA) for one year, or observation (OBS). The primary endpoint was disease-free survival (DFS).
After a median 115-month follow-up, DFS was not different in the ED compared to the FEC arm (70% vs 68% respectively, HR=0.88 95% CI: 0.77-1.01; p=0.064), nor was OS: 80% with FEC and 81% with ED (HR=0.97 95% CI: 0.81-1.16; p=0.729). Subgroup analysis suggested better DFS with ED in non-TNBC pts HR=0.82 (0.71-9.96) p=0.02. In the 528 pts with HER2+ BC, there was trend for a higher DFS in the TRA arm (68%; 95% CI: 61-74) versus the OBS arm (60%; 95% CI: 54-66); HR=0.77 95% CI:0.57-1.03; p=0.079 (intent to treat population). In the per protocol population, DFS, but not OS, was significantly higher in the TRA arm (HR: 0.69 95%CI: 0.51-0.94; p=0.0156). ED led to more neurological and hematological toxicities (31% vs 11% febrile neutropenia) and led to 5 versus 1 treatment-related deaths. During follow-up, 75 pts developed a second non-breast primary cancer (43 with FEC and 32 with ED); 12 were hematologic malignancies (7 with FEC and 5 with ED). Long term cardiac deaths were rare (3 with FEC and 1 with ED).
This study did not show superiority of the concomitant anthracycline-taxane arm, which was more toxic in high-risk N+ BC pts. Long-term results of the HER2+ subpopulation are in line with the other adjuvant TRA trials but less striking probably due to lack of power. Long term cardiac toxicity and second primary cancer rate are similar to what has been reported by others.
NCT00054587.
UNICANCER. 101 rue Tolbiac, 75013 Paris, France.
Roche, Ligue Nationale Contre le Cancer.
All authors have declared no conflicts of interest.
In ER+ HER2- metastatic breast cancer (MBC), resistance to estrogen deprivation by Aromatase Inhibitors (AI) can stem from activating ESR1 mutations (ESR1mut) or from other less characterized, ...mutually exclusive mechanisms. In this study, we report on factors associated with the onset of ESR1mut during therapy (vs other mechanisms of resistance).
PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection (on cell-free DNA, every 2 months) in ER+ HER2- MBC pts treated first line with AI and palbociclib. Main inclusion criteria are pts with no overt resistance to adjuvant AI and no prior therapy for MBC. This analysis compared pts who experienced a progressive disease with no ESR1mut detected (ESR1wt-PD) with those with a rising ESR1mut detected during therapy.
1017 MBC pts were included in PADA-1 from 04/2017 to 01/2019 and are being followed-up. As of 01/31/2019, 242 pts presented either with an ESR1wt-PD (n=139, 57.4%) or a detectable ESR1mut (n=103, 42.6% (either prior to PD or at time of PD) at any time during AI-palbociclib therapy. During the first 6 months on treatment, ESR1mut (n=17, 18.7%) was less frequent than ESR1wt-PD (n=74, 81.3%); after 6 months, the opposite was true (ESR1mut: n=80, 53.0% vs ESR1wt-PD n=71, 47.0%); this change was highly significant (Chi2 test, p<0.001). Based to a Fine-Gray model adjusted for the number of metastases, a higher risk of ESR1mut during therapy was observed in pts with bone (HR=2.5 1.1; 5.6) or skin (HR=1.9 1.1; 3.7) metastases while liver metastases were associated with a lower risk of ESR1mut (HR=0.5 0.3; 0.8). No other characteristic (including exposure to AI in the adjuvant setting) was associated with the onset of ESR1mut.
ctDNA analysis in PADA-1 suggests that ESR1mut are rarely involved in primary resistance to AI-palbociclib therapy (i.e. PD within 6 months) but may represent the most prevalent mechanism of acquired resistance. The observed association between ESR1mut and metastatic sites might underlie the reported higher efficacy of selective estrogen receptor degraders (such as fulvestrant) in pts with bone metastases.
NCT: 03079011; EudraCT: 2016-004360-18.
UNICANCER.
Pfizer.
F. Bidard: Advisory / Consultancy, lectures fees: Pfizer; Advisory / Consultancy, lectures fees: AstraZeneca. B. Pistilli: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Merus. T. de La Motte Rouge: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. R. Sabatier: Licensing / Royalties: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses, Licensing / Royalties: AstraZeneca; Licensing / Royalties: Tesaro; Research grant / Funding (institution): EISAI; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. F. Clatot: Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. T. Bachelot: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer. S. Delaloge: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.
BackgroundRepeated 5FU infusers’ preparations expose pharmacy technicians to risk of musculoskeletal disorders. To simplify the preparation of infusers in 2 days, the installation of a pump is ...envisaged. To facilitate this new method of production, standardised dose prescription has been initiated in agreement with oncologists.PurposeThe aim of this work is to qualify the pump-preparing infusers after defining standardised doses.Material and methodsAn extraction of prescribed doses of 5FU in infusers was realised over 6 months to define standardised doses. A qualification of the pump IMF is performed in the laboratory with 250 ml water bottles and 250 ml NaCl pockets used as solvent. A measure of infusers’ masses before and after injections by the pump was carried out. Accuracy was measured for four precise volumes by counting recovery rates. Repeatability (RP) was determined for the same four volumes by six repetitions performed on the same day. Finally, the intermediate fidelity (FI) was defined for these four volumes by three repetitions carried out on three consecutive days.ResultsIn the end, four 5FU doses were selected after discussion with oncologists: 3,700, 4,100, 4400 and 4,600 mg with an error of ±5% targeting an interval of patients between 1.5 and 1.9 m². Of the 475 infusers’ doses analysed, dose standardisation accounted for 72% of 5FU infuser production in 2 days. During this study, 36 preparations were created with volumes of water between 74 and 92 ml. Volumes are repeatable and accurate from 74 ml (3,700 mg) to 92 ml (4,600 mg) with a coefficient of variation <2%. The accuracy of filling is included within the limit of +/–2% for each dose.ConclusionThe IMF pump is accurate, repeatable and faithful for preparation of diffuser doses of 5FU between 3700 and 4,600 mg. This H2O2 sterilizable pump can be easily integrated into an isolator. This method qualification must be verified under an isolator with 5FU.Reference and/or Acknowledgements1. Preliminary study for the implementation of standardised rounded doses of cytotoxic druqs. J Pharm Belg 2015 Sep;(3):24–35. French.No conflict of interest
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