In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to ...fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.
We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1–21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.
From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2–41·4) from inclusion and 26·0 months (13·8–34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1–13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9–7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43–0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 70·3% of 1017 patients), lymphopenia (66 6·5%), and thrombocytopenia (20 2·0%). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 41·7% of 84 patients in the aromatase inhibitor and palbociclib group vs 39 44·3% of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three 3·6% vs four 4·5%). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.
PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.
Pfizer.
The benefit of taxanes in the adjuvant setting for node-negative (N0) early breast cancer (EBC) has not yet been established. We conducted a meta-analysis of randomized adjuvant trials comparing ...docetaxel-containing versus non-taxane-containing regimens. The purpose of this study was to determine whether the incorporation of docetaxel improves disease-free survival (DFS) and overall survival (OS) in early stage breast cancer. Studies were retrieved by searching major databases and the proceedings of leading breast cancer conferences. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for DFS and OS and obtained pooled estimates using an inverse-variance model. Fourteen randomized phase III studies were included (25,067 patients). The pooled HR estimate was 0.84 (95% CI 0.78–0.89;
P
< 0.001) favoring docetaxel for DFS and 0.86 (0.78–0.94;
P
< 0
.
001) for OS. In N0 patients (4,274 patients), the pooled HR estimate for DFS was 0.86 (0.73–1.00;
P
= 0.05). The HR for OS was equal to 1 (0.75–1.34). The improvement in DFS with docetaxel-containing regimens was observed across all subgroups (age, under or over 50; number of involved nodes; hormone receptor or HER2 status (including triple negative status), or administration schedule (sequential or concomitant). The addition of docetaxel to a non-taxane-containing regimen improves DFS and OS in high risk EBC patients. The benefit in DFS was seen across all subgroups regardless of nodal status, age, hormone receptor or HER2 status (including triple negative status), or administration schedule.
To develop and test the feasibility of a tailored therapeutic educational program, with the aim of improving adherence to oral endocrine adjuvant chemotherapy in women with breast cancer. .
A ...qualitative study to identify educational needs and a feasibility study assessing the efficacy of the program. .
A comprehensive cancer center, the Lucien Neuwirth Cancer Institute in Saint-Priest-en-Jarez, France. .
Two consecutive samples (N = 11, N = 6) of women taking adjuvant oral endocrine chemotherapy for breast cancer. .
A mixed qualitative and quantitative method was used. The participants' representations of disease and treatment were explored through one-on-one interviews and then translated into educational needs, which were used to develop a tailored therapeutic education program. The pilot study evaluated the reach and efficacy using before-and-after comparisons. .
Educational objectives, knowledge, trust in the treatment, and anxiety. .
Five educational objectives (acquiring knowledge, improving communication skills, managing anxiety, managing side effects, and improving adherence) were identified through 11 interviews. A three-session program was developed. Eight of the 23 patients invited to participate in a pilot study accepted, and six completed the intervention. Knowledge improved from 38.9 of 100 preintervention to 69.4 of 100 postintervention (p = 0.045). Trust in treatment showed a trend to improvement from 5.5 of 10 to 8 of 10 (p = 0.14), but anxiety did not change significantly; anxiety went from 6 to 7 (p = 0.88). .
Results from the feasibility study showed promising efficacy for the educational objectives and provided information about how the program could be improved. .
Tailored educational programs conducted by trained nurses may help patients to adhere to and live with the effects of endocrine therapy.
Cognitive dysfunction is common in multiple sclerosis (MS). Deficits can affect attention, concentration, planning, and memory. They can have severe functional consequences in many domains. Cognitive ...complaints are frequently associated with other confounding factors (fatigue, anxiety, depression, or treatment side effects). In most cases, cognitive assessment is proposed after a spontaneous complaint, but determining the extent of discomfort perceived by the patient, the influence of coexisting factors, or the optimal timing for a more complete neuropsychological assessment is difficult.
The objective of this work was to evaluate the feasibility and relevance of a fast global assessment of both objective and subjective cognitive dysfunction in MS.
MS patients underwent a brief cognitive assessment including 7 visual analogue scales (VASs) asking about the patient's subjective level of discomfort in various domains, a memory test (Barbizet's lion story), a commonly used test of information processing speed (Symbol Digit Modalities Test SDMT) and self-reporting questionnaires for fatigue and mood (Fatigue Severity Scale FSS and Hospital Anxiety and Depression Scale HADS). Spearman correlation coefficients among scores were estimated.
The mean age of the 73 patients included was 48.3 (SD 11.1) years; 78% were females and 52.8% had the remittent-recurrent MS form, 8.3% the primary progressive form, and 38.9% the secondary progressive form. In less than 20min, this brief cognitive assessment was able to identify symptoms and quantify discomfort level. Symptoms of fatigue and anxiety frequently coexisted with cognitive complaints. We found modest correlations between scores on the VAS fatigue and the FSS and between scores on the VAS mood and the HADS. Analytical evaluation revealed that most patients had similar SDMT and recall profiles; however, a small proportion showed a dissociation between these 2 tests, which validated the inclusion of both tests in the assessment. Accounting for coexisting factors (e.g., anxiety and fatigue) and their functional repercussions is essential for prioritizing these problems within the context of multidisciplinary patient treatment.
Considering the possible multifactorial character of cognitive dysfunction in MS, it is essential to ask patients about their experiences and to take into account cognitive complaints in the follow-up of patients. The assessment tool we propose is simple and easy to use in a clinical setting and provides the information necessary for requesting (or not) a more complete neuropsychological assessment.
Purpose
In first-line metastatic breast cancer, both paclitaxel (P)-doxorubicin (A) and docetaxel (D)-doxorubicin (A) combinations have shown superiority over treatments without taxane. The aim of ...this study was to compare the two combinations.
Patients and methods
Chemotherapy-naive (except for adjuvant therapy) metastatic breast cancer patients were randomly assigned to intravenous AD (arm D) or AP (arm P) every 3 weeks for a maximum of four cycles, then four cycles of single agent docetaxel (arm D) or paclitaxel (arm P). Primary endpoint was overall quality of life (QoL) measured by EORTC QLQ-C30 after four courses of doxorubicin–taxane combination. Secondary endpoints were toxicity, overall survival (OS), progression-free survival (PFS), and QoL sub-scores.
Results
Between March 2000 and April 2004, 210 patients were randomized: 103 to arm P and 107 to arm D. Patient characteristics were well balanced between arms. After four courses, QoL score differences between groups or compared to baseline scores were not significant. Response rate was 39.6% for AD and 41.8% for AP. After a median follow-up of 50.2 months, median PFS and median OS were 8.7 and 21.4 months in arm D and 8.0 and 27.3 months in arm P (
p
= 0.977 and 0.081, respectively). Hematological toxicity was significantly more frequent in arm D than in arm P (
p
< 10
−6
), as well as grades 3–4 asthenia (
p
= 0.03). Neuropathy occurred more frequently in arm P (
p
= 0.03).
Conclusion
In this study, paclitaxel or docetaxel combined with doxorubicin were not significantly different in terms of QoL scores and efficacy, but had different toxicity profiles.
To evaluate the duration and dose intensity of epirubicin-based regimens in premenopausal patients with lymph node-positive breast cancer.
Between 1986 and 1990, 621 patients with operable breast ...cancer were randomly assigned to receive fluorouracil (Roche SA, Basel, Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days (FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All patients in the three arms received chest wall irradiation at the end of the third cycle.
After a 131-month median follow-up, the 10-year disease-free survival (DFS) was 53.4%, 42.5%, and 43.6% (P =.05) in the three arms, respectively. Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P =.02) and to 3 FEC 75 (P =.05). The 10-year overall survival (OS) for the 6 FEC 50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm, it was 59.7% (P =.25), respectively. Pairwise comparisons demonstrate that 6 FEC 50 was more effective than 3 FEC 50 (P =.10). Cox regression analysis demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC 50 arm (P =.046). No severe infections (grade 3 to 4), acute cardiac toxicity, or deaths from toxicity have been observed. Only five patients developed delayed cardiac dysfunctions, and three patients developed acute myeloblastic leukemia.
After a long-term follow-up in an adjuvant setting, the benefit of six cycles of FEC 50 compared with three cycles, whatever the dose, is highly significant in terms of DFS. As regards OS, the group receiving six cycles of FEC 50 has significantly better results than the group receiving three cycles of FEC 50.
Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 ...status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.
Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC).
We report a single-center retrospective analysis ...of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients.
From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%).
Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients.
Sarcoma of vulva, vagina and ovary Magné, Nicolas, MD, PhD; Pacaut, Cécile, MD; Auberdiac, Pierre, MD ...
Best practice & research. Clinical obstetrics & gynaecology,
12/2011, Letnik:
25, Številka:
6
Journal Article
Recenzirano
Less than 5% of vulvar, vaginal and ovarian malignant diseases are sarcomas. Adequate knowledge of these particular malignant diseases is essential for accurate diagnosis and for choice of surgical ...treatment, adjuvant therapy and efficient medical treatment in relapse. A crucial aspect in the management of women with these diseases is a multidisciplinary approach. Globally, presenting signs and symptoms of these sarcomas are non-specific of histological type but linked to initial location. In view of this, management should be undertaken by clinicians experienced in these particular malignancies. Long-term side-effects, particularly in children with sarcoma, adversely affect quality of life. New treatment strategies require special attention.
BackgroundEftilagimod alpha (efti; IMP321) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by CD8 ...T-cells. Weekly paclitaxel is a standard of care chemo-regimen after failure of endocrine-based therapy for metastatic breast carcinoma (MBC). AIPAC (Active Immunotherapy PAClitaxel) investigated the addition of efti to weekly paclitaxel in these patients (pts).MethodsThis placebo-controlled, double-blinded, 1:1 randomized phase IIb trial enrolled pts with measurable disease, HR+ HER2- MBC after endocrine-based therapy. Pts received paclitaxel (80 mg/m² IV on D1, D8, D15) + efti (30 mg) or placebo on D2, D16 (every 2 weeks) for up to 24 weeks following efti/placebo for up to 52 weeks. The primary endpoint (EP) was progression-free survival (RECIST1.1) by BICR. Secondary EPs included overall survival (OS), PFS (local read), overall response rate (ORR), biomarker, quality of life. Exploratory EPs included univariate/multivariate analyses.Results227 pts were randomized (Jan2017-Jul2019). All except 1 received ≥1 treatment and were included in the full analysis set efti (n=114); placebo (n=112). Data cut-off was 14May2021 (min. follow-up= 22 months). Median age was 60 yrs with ECOG 0 in 61.5%. 91.6% had visceral disease. Pts were mostly endocrine resistant (84%) and partially pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Median OS was 20.4 (95% CI: 14.3-25.1) months in the efti group vs. 17.5 (95% CI: 12.9-21.9) in the placebo group. HR was 0.88 (95%CI: 0.64-1.19; p=0.197). In predefined univariate analyses, younger pts, low baseline monocytes and luminal B showed significant/clinically meaningful improvement in OS (table 1).Efti increased PBMC/T cell (CD4/CD8) count vs. placebo, correlating with improved OS (Spearman Rho=0.6, p=0.02 for CD8 T cells). In a whole population multivariate cox regression model, increasing BMI and prior treatment with CDK4/6 were independent significant poor prognostic markers for PFS and OS.TEAEs leading to discontinuation were similar at 5.3%(efti) & 6.3%(placebo). PFS (Primary EP) and safety were reported at SABCS 2020 (Abstract#132).Abstract 948 Table 1Overall survival by subgroups at final analysisConclusionsEfti added to paclitaxel led to a non-significant 2.9 months median OS increase in HR+ HER2- MBC pts after endocrine-based therapy. Effects were significant in pts <65yrs, with low monocytes and more aggressive disease (luminal B). Efti increased circulating CD4/CD8 T cells, which significantly correlated to improved OS. Weekly paclitaxel + efti should be further investigated in MBC.Trial RegistrationThe trial identifiers are IMP321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833 (ClinicalTrials.gov).Ethics ApprovalThe study was approved by relevant ethic committees and institutional review boards.
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