Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy.

BACKGROUND: Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies. METHODS: To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3'RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. RESULTS: We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level. CONCLUSIONS: This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.

Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

OBJECTIVE: The aim was to evaluate the impact of local surgery performed during the year after MBC diagnosis on patients' outcomes from a large reallife cohort. SUMMARY BACKGROUND DATA: Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS: Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS: Out of 16,703 patients in the ESME database, 1977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, P < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, P < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, P < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61-0.92] and 0.72 [0.63-0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype, and age. CONCLUSIONS: In the large ESME cohort, surgery within 1 year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

Baseline tumour size is an independent prognostic factor for overall survival in PD-L1 ≥ 50% non-small cell lung cancer patients treated with first-line pembrolizumab.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score ≥ 50% can be treated with pembrolizumab alone. Our aim was to assess the impact of baseline tumour size (BTS) on overall survival (OS) in NSCLC patients treated with pembrolizumab versus chemotherapy. METHODS: This retrospective, multicentre study included all patients with untreated advanced NSCLC receiving either pembrolizumab (PD-L1 ≥ 50%) or platinum-based chemotherapy (any PD-L1). The primary endpoint was the impact of BTS (defined as the sum of the dimensions of baseline target lesions according to RECIST v1.1 criteria) on OS. RESULTS: Between 09-2016 and 06-2020, 188 patients were included, 96 in the pembrolizumab (P-group) and 92 in the chemotherapy group (CT-group). The median follow-up was 26.9 months (range 0.13-37.91) and 44.4 months (range 0.23-48.62), respectively, while the median BTS was similar, 85.5 mm (IQR 57.2-113.2) and 86.0 mm (IQR 53.0-108.5), respectively (p = 0.42). The median P-group OS was 18.2 months [95% CI 12.2-not reached (NR)] for BTS > 86 mm versus NR (95% CI 27.2-NR) for BTS ≤ 86 mm (p = 0.0026). A high BTS was associated with a shorter OS in univariate analyses (p = 0.009) as well as after adjustment on confounding factors (HR 2.16, [95% CI 1.01-4.65], p = 0.048). The CT-group OS was not statistically different between low and high BTS patients, in univariate and multivariate analyses (p = 0.411). CONCLUSIONS: After adjustment on major baseline clinical prognostic factors, BTS was an independent prognostic factor for OS in PD-L1 ≥ 50% advanced NSCLC patients treated first-line with pembrolizumab.

Treatment time interval in breast cancer: A population-based study on the impact of type and number of cancer centres attended.

OBJECTIVES: We studied both the independent and combined effects of the places of biopsy and treatment on the treatment time interval based on a population-based study. METHODS: We analysed the proportion of patients having a treatment time interval higher than the EUSOMA recommendation of 6 weeks, as a function of the number and the type of care centres the patients attended, from a French population-based regional cohort of women treated in 2015 for an incident invasive non-metastatic cancer (n = 505). RESULTS: About 33% [95% CI: 27; 38] of patients had a treatment time interval higher than 6 weeks. About 48% of the patients underwent their biopsy and their initial treatment in the different centres. Results from multivariable analyses supported the impact of the type and number of centres attended on the proportion of time intervals over 6 weeks. This proportion was higher among patients with biopsy and treatment in different centres and among patients treated in a university hospital. CONCLUSION: We pointed out the independent impact of the type and the number of care centres the patients attended, from biopsy to first treatment, on the treatment time interval, which is a well-known prognosis factor.

Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis.

INTRODUCTION: Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial. OBJECTIVE: The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination. METHODS: We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both. RESULTS: LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (p < 0.0001) and were more likely to have only one metastatic site (p < 0.0001) or bone-only metastases (p < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55-0.76, p < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9 months, p < 0.001) and HER2-positive tumors (77.2 vs. 52.6 months, p = 0.008), but not in triple-negative tumors (19 vs. 18.6 months, p = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (p < 0.001). CONCLUSIONS: LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.

Impact of PD-L1 Expression on the Overall Survival of Caucasian Patients with Advanced EGFR-Mutant NSCLC Treated with Frontline Osimertinib.

BACKGROUND: The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI. OBJECTIVE: We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment. METHODS: Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis. RESULTS: Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9). CONCLUSIONS: Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.

[National survey of Advanced Practice Nurses in oncology-haematology: Evaluation of activity and continuing education]. / Enquête nationale auprès des infirmiers en pratique avancée mention oncologie-hématologie : évaluation de l'activité et de la formation continue.

INTRODUCTION: The number of Advanced Practice Nurses (APNs) has significantly increased in France since 2019, with the number of graduates expected to reach 1700 by the end of 2023, up from approximately 60. Fifteen percent of them specialize in oncology-hematology (APN-OH). Data on their activities, access to continuing education, and expectations are limited. METHODS: We conducted an observational study among practicing APN-OHs in France. A questionnaire was distributed from June to September 2023. RESULTS: Of the 55 responding APN-OHs, 78.3% worked in Cancer Centers or within University Hospital Centers. Their primary motivation for becoming APN-OH was to enhance their nursing practice and deepen their medical knowledge, with teaching and research interests remaining marginal. Their level of responsibility generally aligned with their expectations and the medical staff was perceived as supportive. The main challenges were of logistical and material nature. The heterogeneity in APN-OH training was seen as a limiting factor in the attractiveness of the profession. The most significant gaps in their education revolved around the lack of practical cases. CONCLUSION: This study highlights that the primary concern of APN-OHs is to strengthen their practical training. Medical personnel are perceived as supportive, but challenges related to working conditions and education persist. It is essential to consider these factors to support the deployment of APN-OHs across the country and improve ongoing education.

A Multicenter Study Assessing the Real-World Use and Effectiveness of First-Line Chemotherapy Plus Immunotherapy in Advanced Small-Cell Lung Cancer (SCLC) Patients.

BACKGROUND: First-line chemotherapy plus immunotherapy (CT-IO) has recently demonstrated survival benefits over CT alone in extensive-stage small-cell lung cancer (ES-SCLC), based on randomized phase III studies. This retrospective multicenter study assessed the real-world use and effectiveness of CT-IO in ES-SCLC patients. PATIENTS AND METHODS: All newly diagnosed ES-SCLC patients from 4 French hospitals treated with CT alone or CT-IO between May 2020 and December 2021 were included. Overall survival (OS) and real-world progression-free survival (rwPFS) were estimated using the Kaplan-Meier method. Cox proportional hazard models were performed to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs) in univariate and multivariate models. The aim was not to compare efficacy between groups. RESULTS: Among 104 patients, 75 (72.1%) received CT-IO. Brain metastases were diagnosed in 28.3% of patients, and 29.8% were performance status (PS) ≥ 2. At a median follow-up of 16.8 months (95%CI, 14.9-23.4), the median OS was 11.4 months (95%CI, 7.7-14.7) in the CT-IO group, and the 12-month OS rate was 43.6% (95%CI, 33.3-57.2). In the CT group, the median OS was 7.8 months (95%CI, 5.4-11.8) and the 12-month OS rate was 15.3% (95%CI, 5.7-41.0). In multivariate analyses, baseline brain and liver metastases were associated with a shorter OS for patients treated in the CT-IO group (HR, 3.80 [95%CI, 1.90-7.60] and 3.12 [95%CI, 1.60-6.08] respectively; P < 0.001 for both). CONCLUSION: We showed that clinicians have chosen to use IO beyond the specific criteria defined in guidelines. Survival data appeared promising with a median OS comparable to the one previously demonstrated in clinical trials.

Second-line treatment outcomes after first-line chemotherapy plus immunotherapy in Extensive-Stage small cell lung cancer (ES-SCLC) patients: A large French multicenter study.

INTRODUCTION: Chemotherapy combined with immunotherapy (CT-IO) is the standard treatment for patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC). This study evaluates the effectiveness of second-line (2L) following CT-IO. PATIENTS AND METHODS: All patients from 10 centers who received a 2L after a first-line CT-IO were included. They were divided into 3 groups: platinum-based, lurbinectedin or others (topotecan, CAV, taxanes). We assessed overall survival (OS) and 2L progression-free survival (2L-PFS) according to treatment and platinum free-interval (PFI) < or ≥ 90 days. RESULTS: Among 82 patients included, median age was 67.0 years, 29.3 % had a Performans Status ≥ 2, 36.6 % had brain progression, 69.5 % were considered "platine-sensitive" and 30.5 % "platine-resistant" (PFI ≥ or < 90 days, respectively). As 2L, 37/82 patients (45.1 %) received platinum-doublet, 21/82 (25.6 %) lurbinectedin and 24/82 (29.3 %) others. Patients with a PFI ≥ 90 days received mainly platinum-based rechallenge (34/57, 59.6 %). With a median follow-up of 18.5 months, the median OS was 5.0 months (95 %CI, 1.5-7.9) / 6.8 months (95 %CI, 5.5-8.7) for platinum-resistant / sensitive, respectively (log rank p = 0.017). The median 2L-PFS was 1.9 months (95 %CI, 1.2-4.7) / 3.9 months (95 %CI, 2.9-6.0) for platinum-resistant / sensitive, respectively. Median OS was 8.1 (95 %CI, 6.3-12.9) / 4.9 (95 %CI, 3.7-6.8) / 5.1 months (95 %CI, 2.5-7.8) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.017). Median 2L-PFS was 4.6 (95 %CI, 3.9-7.2) / 2.7 (95 %CI, 1.6-3.9) / 2.2 months (95 %CI, 1.5-4.1) with platinum rechallenge / lurbinectedin / others, respectively (p = 0.025). DISCUSSION: Platinum-based rechallenge after a first-line CT-IO showed promising results despite particularly unfavorable characteristics within our real-word population. Lurbinectedin when used after IO demonstrated as low efficacy as other platinum-free regimens.

Prognostic Impact of TP53 Mutations in Metastatic Nonsquamous Non-small-cell Lung Cancer.

BACKGROUND: The prognostic impact of TP53 mutations in advanced or metastatic nonsquamous non-small-cell lung cancer (nsNSCLC) patients treated with chemotherapy and/or immune checkpoint inhibitors (ICI) remains unclear. MATERIALS AND METHODS: We retrospectively collected data from patients with nsNSCLC treated in the first line from January 2018 to May 2021. The patient was separated into 2 groups according to their TP53 mutation status (wt vs. mut). Survival was estimated through the Kaplan-Meier method and compared by log-rank test. RESULTS: Of 220 patients included, 126 were in the mutTP53 group, and 94 were in the wtTP53wt group. Median OS (mOS) was not significantly different between the mutTP53 and wtTP53 groups [17.5 months (95% confidence interval (CI), 11.3-21.5) vs. 9.5 months (95% CI, 7.4-14.2), (P = .051)]. In subgroup analyses, the mutTP53 group treated with ICI had a significantly improved mOS compared to the wtTP53 group [(24.7 months (95% CI, 20.8-not reach) vs. 12.0 months (95% CI, 4.7-not reach), (P = .017)] and mPFS [(9.6 months (95% CI, 5.8-not reach) vs. 3.2 months (95% CI, 1.3-13.8) (P = .048)]. There was no difference in terms of mOS and mPFS between the mutTP53 and the wtTP53 group treated by chemotherapy alone or combined with ICI. CONCLUSION: TP53 mutation had no survival impact in the overall population, but is associated with better outcomes with ICI alone. These results suggest that patients with TP53 mutations could be treated with ICI alone, and wild-type patients could benefit from the addition of chemotherapy.