Introduction
Oral targeted therapies (OTTs) are widely used for cancer management. However, there is no consensus on OTT dose adaptation in older patients with cancer.
Methods
This noninterventional, ...retrospective study was a real‐life assessment of dose adaptation for six OTTs (afatinib, everolimus, palbociclib, pazopanib, sorafenib and sunitinib), at baseline and during treatment, and the reasons for the changes, in ≥70‐year‐old patients treated between February 2016 and August 2019. Data were compared with univariate models fitted with all variables.
Results
Among the 986 patients treated with OTT, the group of ≥70‐year‐old patients (n = 122) received afatinib (15.6%), everolimus (14.8%), palbociclib (50.8%), pazopanib (9.8%), sorafenib (5.8%) or sunitinib (3.2%). At baseline, the prescribed OTT dose was adapted (reduction) in 29% of ≥70‐year‐old patients (35/122). These 35 patients were significantly older (mean age 80 vs 74 years, P < .001), and more frequently had a performance status score ≥2 (P < .01) than the other patients (n = 87). In the standard dose group, higher toxicity grades (P = .18) and subsequent dose reduction (41% of patients, 36/87) tended to be more frequent compared with the baseline adapted dose group (26%, 9/35, P = .1). At the study end, 53% of patients in the whole cohort (65/122) were taking a lower dose than the recommended one.
Conclusion
At OTT initiation, dose was adapted in 29% of older adults with cancer, rarely after a formal oncogeriatric evaluation (6.5% of all patients). In the absence of recommendations, clinical studies are needed to evaluate the efficacy and safety of baseline OTT dose reduction in older adults with cancer.
Background
Breast cancer (BC) is one of the solid tumors most commonly associated with leptomeningeal disease (LMD). LMD carries a devastating prognosis; however, disease presentation and prognostic ...factors are uncertain.
Subjects, Materials, and Methods
In order to describe patient characteristics, treatment patterns, and factors associated with survival in a contemporary multicentric cohort, 153 consecutive BC patients diagnosed with LMD at two European institutions (2002–2017) were included. Time to LMD and overall survival (OS) after LMD diagnosis were evaluated using the Kaplan‐Meier method and Cox proportional hazards models.
Results
Median age at LMD diagnosis was 58 years (25–84). Tumor phenotype distribution was as follows: hormone receptor (HR) positive (HR+)/human epidermal growth receptor 2 (HER2) negative 51.0%, triple‐negative 15.0%, HR+/HER2 positive (HER2+) 13.1% and HR negative/HER2+ 7.2%. Most patients received active anticancer treatments (radiation therapy RT n = 42, systemic therapy n = 110, intrathecal treatment n = 103).
Median OS was 3.9 months (95% confidence interval CI 2.4–5.5). Eastern Cooperative Oncology Group performance status (ECOG PS) >2, high white blood cells count, low glucose, and high protein in cerebrospinal fluid (CSF) were poor prognostic factors. Having received RT or systemic treatment was associated with better prognosis. In multivariate analysis, ECOG PS (hazard ratio 2.22, 95% CI 1.25–3.94), CSF glucose levels (hazard ratio 1.74, 95% CI 1.05–2.88), and having received systemic treatment (hazard ratio 0.17, 95% CI 0.09–0.32) were confirmed as independent prognostic factors. In HER2+ BC patients, having received systemic HER2‐targeted therapy was the only factor maintaining independent prognostication (hazard ratio 0.12, 95% CI 0.02–0.67) in multivariate analysis.
Conclusion
Despite being limited by their retrospective nature, these results highlight the need for clinical trials in BC LMD, stratified on tumor biology.
Implications for Practice
Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC), and its optimal therapy is still not defined. Here, patient characteristics, treatment patterns, and prognostic factors from a contemporary cohort of 153 BC‐related LMD patients are reported. In multivariate analysis, Eastern Cooperative Oncology Group performance status, cerebrospinal fluid glucose levels, and having received systemic treatment were confirmed as independent prognostic factors in the overall population, whereas in human epidermal growth receptor 2 (HER2) positive BC patients, having received systemic HER2‐targeted therapy was the only factor maintaining independent prognostication in multivariate analysis. These results highlight the need to consider stratification on tumor biology in the treatment of BC LMD.
This article presents data regarding patient characteristics, treatment patterns, and prognostic factors from a contemporary cohort of 153 patients with breast cancer‐related leptomeningeal disease. It reports on the different prognostic effects of clinical characteristics and treatments according to tumor biology, thus highlighting the need to consider stratification on tumor biology in the treatment of breast cancer related leptomeningeal disease.
Abstract
Background
Data regarding the prognostic value of programmed cell death ligand 1 (PD-L1) expression on circulating tumor cells (CTCs) are lacking. However, CTCs could represent an ...alternative approach to serial biopsies, allowing real-time monitoring of cancer phenotype.
Methods
We evaluated, in a dedicated prospective clinical trial, the clinicopathological correlations and prognostic value of PD-L1(+)-CTCs in 72 patients with metastatic breast cancer (MBC).
Results
Eighteen of 56 patients with available archival tissue presented at least one positive (≥1%) PD-L1 tumor sample. Baseline CTCs and PD-L1(+)-CTCs were detected in 57 (79.2%) and 26 (36.1%) patients. No significant correlation was found between PD-L1 tumors and CTC expression. In univariate analysis, triple negative (TN) phenotype, number of metastatic treatments, >2 metastatic sites, ≥5 CTCs and PD-L1(+)-CTCs were significantly associated with progression-free survival, while tissue PD-L1 expression was not. In multivariate analysis, TN phenotype, number of metastatic treatments and of metastatic sites were the only 3 variables independently associated with progression-free survival. Progesterone receptor negativity, TN phenotype, >2 metastatic sites and ≥5 CTCs were significantly associated with overall survival in univariate analysis. In multivariable analysis, TN phenotype and >2 metastatic sites were the only 2 independent variables.
Conclusions
Unlike PD-L1(+)-tumor, PD-L1(+)-CTCs correlate to survival in MBC. Reappraisal of the role of PD-L1 expression by tumor tissue and by CTCs under anti-PD-1/PD-L1 treatment is necessary to evaluate its predictive value and potential role as a stratifying factor in strategies and trials for MBC patients with MBC.
Clinical trial registration
NCT02866149
Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict ...prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients.
Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay.
At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1
sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1
sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1
sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001).
CTCs and high PD-L1
sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS.
NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 .
What is known and Objective
Sunitinib pharmacokinetics can be influenced by the physio‐pathological conditions of individual patients. Therapeutic drug monitoring (TDM) helps to optimize efficacy and ...reduce the risk of adverse effects. We report on the use of Bayesian analysis to optimize sunitinib blood levels.
Case Summary
We describe two patients with risk of sunitinib pharmacokinetic variability due to gastrectomy and ongoing haemodialysis, respectively. TDM and Bayesian estimation allowed maintaining their sunitinib pharmacokinetic profiles within the usual limits.
What is new and conclusion
Our analysis showed that Bayesian analysis can be successfully applied for real‐time TDM to optimize sunitinib blood levels in patients with major comorbidities.
Few data exist concerning genotype-phenotype relationships in left ventricular noncompaction (LVNC).
From a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients ...with LVNC, and their genotype-phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate.
Ion channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.
Summary
In oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing ...how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot capture the duration or the evolution of adverse events induced by extended treatment durations. Many authors have highlighted this issue and argue that the analysis of safety data from clinical trials should be modernized by considering the dimension of time and the recurrent nature of adverse events. This paper aims to illustrate the limitations of current methods and discusses the value of alternative approaches such as the prevalence function, Q-TWiST, the ToxT and the recurrent event approaches. The rationale and design of the MOTIVATE trial, which aims to model the evolution of toxicities over time using the prevalence function in patients treated by immunotherapy, is also presented (
ClinicalTrials.gov
Identifier: NCT03447483; Date of registration: 27 February 2018).
Purpose
Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes ...insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2− pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination.
Method
This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical–pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient’s outcome (relapse-free survival, RFS, and overall survival, OS).
Result
Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS.
Conclusion
The personalization of the patients’ treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.
PDF
