Publications by authors named "Gérard Zalcman"

140 Publications

Does Very Poor Performance Status Systematically Preclude Single Agent Anti-PD-1 Immunotherapy? A Multicenter Study of 35 Consecutive Patients.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Department of Thoracic Oncology, Bichat Claude Bernard Hospital, APHP, CIC Inserm 1425, Université de Paris, 75018 Paris, France.

Anti-PD-1 antibodies prolong survival of performance status (PS) 0-1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3-4 patients is unknown. Conse- cutive PS 3-4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3-4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1-7) as first- ( = 6) or second-line ( = 29) therapy. At a median of 52-month follow-up (95%CI, 41-63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1-3.2). Median OS was 4.4 months (95%CI, 0.5-8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9-14.3, = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7-13.8, = 0.003) predicted worse survival. PS improvement from 3-4 to 0-1 ( = 9) led to a median 43-month (95%CI, 0-102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.
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http://dx.doi.org/10.3390/cancers13051040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958129PMC
March 2021

National early access programs and clinical trials: What opportunities for early access to therapeutic innovations for patients with malignant melanoma?

Cancer 2021 Mar 31. Epub 2021 Mar 31.

Université de Paris, AP-HP Dermatology, INSERM U976, Saint Louis Hospital, Paris, France.

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http://dx.doi.org/10.1002/cncr.33495DOI Listing
March 2021

Apoptosis mapping in space and time of 3D tumor ecosystems reveals transmissibility of cytotoxic cancer death.

PLoS Comput Biol 2021 Mar 30;17(3):e1008870. Epub 2021 Mar 30.

Department of Electronic Engineering, University of Rome Tor Vergata, Rome, Italy.

The emerging tumor-on-chip (ToC) approaches allow to address biomedical questions out of reach with classical cell culture techniques: in biomimetic 3D hydrogels they partially reconstitute ex vivo the complexity of the tumor microenvironment and the cellular dynamics involving multiple cell types (cancer cells, immune cells, fibroblasts, etc.). However, a clear bottleneck is the extraction and interpretation of the rich biological information contained, sometime hidden, in the cell co-culture videos. In this work, we develop and apply novel video analysis algorithms to automatically measure the cytotoxic effects on human cancer cells (lung and breast) induced either by doxorubicin chemotherapy drug or by autologous tumor-infiltrating cytotoxic T lymphocytes (CTL). A live fluorescent dye (red) is used to selectively pre-stain the cancer cells before co-cultures and a live fluorescent reporter for caspase activity (green) is used to monitor apoptotic cell death. The here described open-source computational method, named STAMP (spatiotemporal apoptosis mapper), extracts the temporal kinetics and the spatial maps of cancer death, by localizing and tracking cancer cells in the red channel, and by counting the red to green transition signals, over 2-3 days. The robustness and versatility of the method is demonstrated by its application to different cell models and co-culture combinations. Noteworthy, this approach reveals the strong contribution of primary cancer-associated fibroblasts (CAFs) to breast cancer chemo-resistance, proving to be a powerful strategy to investigate intercellular cross-talks and drug resistance mechanisms. Moreover, we defined a new parameter, the 'potential of death induction', which is computed in time and in space to quantify the impact of dying cells on neighbor cells. We found that, contrary to natural death, cancer death induced by chemotherapy or by CTL is transmissible, in that it promotes the death of nearby cancer cells, suggesting the release of diffusible factors which amplify the initial cytotoxic stimulus.
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http://dx.doi.org/10.1371/journal.pcbi.1008870DOI Listing
March 2021

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody.

Biomark Res 2021 Mar 23;9(1):21. Epub 2021 Mar 23.

Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Background: The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data.

Methods: Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman's rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation.

Results: Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells.

Conclusions: Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.
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http://dx.doi.org/10.1186/s40364-021-00273-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989014PMC
March 2021

[Lung cancer in non smokers].

Rev Prat 2020 Oct;70(8):851

Service d'oncologie thoracique, université Paris-Diderot, hôpital Bichat-Claude-Bernard, AP-HP, Paris, France.

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October 2020

[Different histological subtypes of lung cancer, mutations and rearrangements].

Rev Prat 2020 Oct;70(8):849-850

Service d'oncologie thoracique, université Paris-Diderot, hôpital Bichat-Claude-Bernard, AP-HP, Paris, France.

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October 2020

[Epidemiology of lung cancer in France and in the world].

Rev Prat 2020 Oct;70(8):844-848

Service d'oncologie thoracique, université Paris-Diderot, hôpital Bichat-Claude-Bernard, AP-HP, Paris, France.

Epidemiology of lung cancer in france and in the world. Lung cancer is the leading cause of death from cancer worldwide. In France, lung cancer is the second most common cancer in men (after prostate cancer), and the third in women (after breast and colon cancer). However, it ranks first among the deadliest cancers in men and second among women (after breast cancer). In the United States, mortality from lung cancer in women has exceeded mortality from breast cancer, and it is likely that this will be the case in France in a few years. The main risk factor is smoking. Although the incidence and mortality rates continue to increase in women, they remain twice higher in men compared to women. The development since the 1990s is marked by a clear increase in the incidence of adenocarcinomas in both sexes, probably linked to differences in smoking behavior.
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October 2020

[Does lung cancer patients' survival increase?]

Rev Prat 2020 Oct;70(8):827-833

Service d'oncologue thoracique, CIC Inserm 1425, hôpital Bichat-Claude Bernard, AP-HP, université de Paris, Paris, France.

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October 2020

[Initial assessment of lung cancer].

Rev Prat 2020 Dec;70(10):1111-1120

Service d'oncologie thoracique, université Paris-Diderot, hôpital Bichat-Claude-Bernard, AP-HP, Paris, France.

Initial assessment of lung cancer. Lung cancer is frequent with a high mortality rate. Improvement of diagnosis tools provide better staging and tumor characterization enhancing prognosis. We explain in this review the diagnosis procedures emphasizing the most im¬portant techniques and their goals. Clinicians define a target to sample with different means considering general condition and extension of the disease. Staging needs CT-Scan of thorax and abdomen, cerebral imaging, PET-CT, bronchoscopy in order to assess endobronchial invasion especially for localized or locally advanced cancer. New tools are emerging such as EBUS-TBNA or EUS-FNA for mediastinal staging. Transthoracic biopsy and Radial-EBUS or Electromagnetic navigation diagnostic bronchoscopy can be used for small peripheral lung lesions diagnosis. Conse¬quently, patients can benefit from individualized and precise therapeutic approach.
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December 2020

Treatment strategies and safety of rechallenge in the setting of immune checkpoint inhibitors-related myositis: A national multicenter study.

Rheumatology (Oxford) 2021 Mar 16. Epub 2021 Mar 16.

Department of Dermatology, Hôpital Bichat, AP-HP, Université de Paris, Paris, France.

Objectives: The occurrence of immune-related myositis (irM) is increasing, yet there are no therapeutic guidelines. We sought to analyze the current therapeutic strategies of irM and evaluate the outcomes of immune checkpoint inhibitors (ICI) rechallenge.

Methods: We conducted a nationwide retrospective study between April 2018 and March 2020 including irM without myocardial involvement. Depending on the presence of cutaneous signs or unusual histopathological features, patients were classified into two groups: typical or atypical irM. Therapeutic strategies were analyzed in both groups. The modalities and outcomes of ICI rechallenge were reviewed.

Results: Among the 20 patients, 16 presented typical irM. Regardless of severity, most typical irM were treated with steroid monotherapy (n = 14/16) and all had a complete response within ≤ 3 weeks. The efficacy of oral steroids for non-severe typical irM (n = 10) was the same with low-dose (≤ 0.5 mg/kg/day) or high-dose (1 mg/kg/day). Severe typical irM were successfully treated with intravenous methylprednisolone. Atypical irM (n = 4) had a less favorable evolution, including one irM-related death, and required heavy immunosuppression. ICI were safely reintroduced in 9 patients presenting a moderate (n = 6) or a severe (n = 3) irM.

Conclusion: Our data highlight that steroid monotherapy is an effective treatment for typical irM, either with prednisone or with intravenous methylprednisone pulses depending on the severity. The identification of unusual features is important in determining the initial therapeutic strategy. The outcomes of rechallenged patients are in favor of a safe reintroduction of ICI following symptom resolution and CK normalization in moderate and severe forms of irM.
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http://dx.doi.org/10.1093/rheumatology/keab249DOI Listing
March 2021

[The French regulatory system facing the development of antitumor immunotherapy: Issues related to patient access to new therapies according to the French society of ImmunoTherapy against Cancer (FITC)].

Bull Cancer 2021 Apr 11;108(4):343-349. Epub 2021 Mar 11.

Société française d'immunothérapie contre le cancer (FITC), Centre Léon-Bérard, 28, rue Laennec, 69008 Lyon, France; Université de Paris, AP-HP, hôpital Bichat-Claude-Bernard, département d'oncologie thoracique et CIC1425-CLIP(2) Paris-Nord, 46, rue Henri-Huchard, 75018 Paris, France.

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http://dx.doi.org/10.1016/j.bulcan.2020.12.008DOI Listing
April 2021

Intergroupe francophone de cancérologie thoracique, Société de pneumologie de langue française, and Société d'imagerie thoracique statement paper on lung cancer screening.

Diagn Interv Imaging 2021 Apr 26;102(4):199-211. Epub 2021 Feb 26.

Université de Paris, F-75006 Paris, France; Department of Radiology, Groupe Hospitalier Bichat-Claude-Bernard, Assistance publique-Hôpitaux de Paris, 75018 Paris, France.

Following the American National Lung Screening Trial results in 2011 a consortium of French experts met to edit a statement. Recent results of other randomized trials gave the opportunity for our group to meet again in order to edit updated guidelines. After literature review, we provide here a new update on lung cancer screening in France. Notably, in accordance with all international guidelines, the experts renew their recommendation in favor of individual screening for lung cancer in France as per the conditions laid out in this document. In addition, the experts recommend the very rapid organization and funding of prospective studies, which, if conclusive, will enable the deployment of lung cancer screening organized at the national level.
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http://dx.doi.org/10.1016/j.diii.2021.01.012DOI Listing
April 2021

Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Université de Paris, Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), 92110 Clichy, France.

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rb) or the absence of very intense p53 staining (p53) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, = 0.040; LCNEC vs. SCNEC, < 0.001). The ORR was significantly higher in NEN presenting with Rb (63% vs. 42%, = 0.025) and p16 (66% vs. 35%, = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11-15.53, = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.
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http://dx.doi.org/10.3390/cancers13040643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915900PMC
February 2021

Immune checkpoint blockade for patients with lung cancer and idiopathic pulmonary fibrosis.

Eur J Cancer 2021 Mar 22;145:179-182. Epub 2021 Jan 22.

Université Paris Sorbonne Nord, UFR Santé, Médecine et Biologie Humaine, Bobigny, France; Department of Pneumology, Avicenne Hospital, AP-HP, Bobigny, France.

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http://dx.doi.org/10.1016/j.ejca.2020.12.016DOI Listing
March 2021

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Lancet 2021 01 21;397(10272):375-386. Epub 2021 Jan 21.

Bichat-Claude Bernard University Hospital, AP-HP, Université de Paris, Paris, France.

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.

Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m intravenously] plus cisplatin [75 mg/m intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.

Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).

Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S0140-6736(20)32714-8DOI Listing
January 2021

In vitro bone metastasis dwelling in a 3D bioengineered niche.

Biomaterials 2021 Feb 24;269:120624. Epub 2020 Dec 24.

Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, 75005, Paris, France; ART Group, Inserm U830, 75005, Paris, France. Electronic address:

Bone is the most frequent metastasis site for breast cancer. As well as dramatically increasing disease burden, bone metastases are also an indicator of poor prognosis. One of the main challenges in investigating bone metastasis in breast cancer is engineering in vitro models that replicate the features of in vivo bone environments. Such in vitro models ideally enable the biology of the metastatic cells to mimic their in vivo behavior as closely as possible. Here, taking benefit of cutting-edge technologies both in microfabrication and cancer cell biology, we have developed an in vitro breast cancer bone-metastasis model. To do so we first 3D printed a bone scaffold that reproduces the trabecular architecture and that can be conditioned with osteoblast-like cells, a collagen matrix, and mineralized calcium. We thus demonstrated that this device offers an adequate soil to seed primary breast cancer bone metastatic cells. In particular, patient-derived xenografts being considered as a better approach than cell lines to achieve clinically relevant results, we demonstrate the ability of this biomimetic bone niche model to host patient-derived xenografted metastatic breast cancer cells. These patient-derived xenograft cells show a long-term survival in the bone model and maintain their cycling propensity, and exhibit the same modulated drug response as in vivo. This experimental system enables access to the idiosyncratic features of the bone microenvironment and cancer bone metastasis, which has implications for drug testing.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120624DOI Listing
February 2021

Glucocorticoids with low-dose anti-IL1 anakinra rescue in severe non-ICU COVID-19 infection: A cohort study.

PLoS One 2020 16;15(12):e0243961. Epub 2020 Dec 16.

Pulmonology and Thoracic Oncology Department, University Hospital Bichat-Claude Bernard, AP-HP, Université de Paris, Paris, France.

Background: The optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated.

Material And Methods: A cohort study was designed to evaluate whether a therapeutic algorithm using steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects.

Results: Of 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI [0.80-1.01], p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%).

Conclusion: In COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743937PMC
December 2020

Epidermal growth factor receptor-mutant non-small cell lung Cancer and Choroidal metastases: long-term outcome and response to epidermal growth factor receptor tyrosine kinase inhibitors.

BMC Cancer 2020 Dec 3;20(1):1186. Epub 2020 Dec 3.

Thoracic Oncology Department & CIC1425-CLIP2 Early Phase Cancer Clinical Trials Unit, University Hospital Bichat-Claude Bernard, Medical Faculty, Université de Paris, Hôpital Bichat, APHP, 46 Rue Henri Huchard, 75018, Paris, France.

Background: Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis.

Methods: We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics' files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010.

Results: Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2-47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1-51.4]) versus 27.9 mo (95%CI [16.9-38.9]) in the non-choroidal metastasis group (p = 0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset.

Conclusions: Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.
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http://dx.doi.org/10.1186/s12885-020-07630-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712981PMC
December 2020

The STK38-XPO1 axis, a new actor in physiology and cancer.

Cell Mol Life Sci 2021 Mar 3;78(5):1943-1955. Epub 2020 Nov 3.

Inserm U830, Institut Curie, Centre de Recherche, Paris Sciences Et Lettres Research University, Paris, France.

The Hippo signal transduction pathway is an essential regulator of organ size during developmental growth by controlling multiple cellular processes such as cell proliferation, cell death, differentiation, and stemness. Dysfunctional Hippo signaling pathway leads to dramatic tissue overgrowth. Here, we will briefly introduce the Hippo tumor suppressor pathway before focusing on one of its members and the unexpected twists that followed our quest of its functions in its multifarious actions beside the Hippo pathway: the STK38 kinase. In this review, we will precisely discuss the newly identified role of STK38 on regulating the nuclear export machinery by phosphorylating and activating, the major nuclear export receptor XPO1. Finally, we will phrase STK38's role on regulating the subcellular distribution of crucial cellular regulators such as Beclin1 and YAP1 with its implication in cancer.
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http://dx.doi.org/10.1007/s00018-020-03690-wDOI Listing
March 2021

Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19).

Eur J Cancer 2020 12 8;141:62-81. Epub 2020 Oct 8.

Department of Gastroenterology, Saint Louis Hospital, APHP, Université de Paris, Paris, FFCD, France.

Background: Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated.

Patients And Methods: In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and 11th June 2020. The primary end-point was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary end-points.

Results: From April 4 to 11th June 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), The Eastern Cooperative Oncology Group Performance Scale (ECOG PS) ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except for cytotoxic chemotherapy in the subgroup of patients with detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcriptase polymerase chain reaction (RT-PCR), which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment (such as chemotherapy, targeted or immune therapy) interrupted or stopped following diagnosis of COVID-19.

Conclusions: Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.
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http://dx.doi.org/10.1016/j.ejca.2020.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543792PMC
December 2020

Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer.

Cancer Discov 2020 Sep 20;10(9):1330-1351. Epub 2020 May 20.

Institut Curie, Stress and Cancer Laboratory, Equipe labélisée par la Ligue Nationale contre le Cancer, PSL Research University, Paris, France.

A subset of cancer-associated fibroblasts (FAP/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance. SIGNIFICANCE: Our work provides a significant advance in characterizing and understanding FAP CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1384DOI Listing
September 2020

Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study.

Eur J Cancer 2020 05 8;131:27-36. Epub 2020 Apr 8.

Cancer Medecine Department, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France. Electronic address:

Purpose: Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer (nsNSCLC).

Methods: In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671.

Results: One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44-0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8-30·3) and 5·5% (95% CI: 0·0-11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group).

Conclusion: Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population.

Clinical Trials Registration Number: ClinicalTrials.gov Identifier: NCT01763671.
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http://dx.doi.org/10.1016/j.ejca.2020.02.022DOI Listing
May 2020

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis.

J Thorac Oncol 2020 07 12;15(7):1147-1159. Epub 2020 Mar 12.

Da Volterra, Paris, France. Electronic address:

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan-Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13-1.90) for PFS and 1.69 (95% CI: 1.25-2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1-8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [-60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.
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http://dx.doi.org/10.1016/j.jtho.2020.03.002DOI Listing
July 2020

Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial.

Clin Cancer Res 2020 07 6;26(13):3172-3181. Epub 2020 Mar 6.

Intergroupe Francophone de Cancérologie Thoracique (IFCT), Paris, France.

Purpose: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI.

Patients And Methods: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR patients.

Results: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR and EGFR-WT cohorts. In the EGFR cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death.

Conclusions: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3056DOI Listing
July 2020

Antiangiogeneic Strategies in Mesothelioma.

Front Oncol 2020 18;10:126. Epub 2020 Feb 18.

Thoracic Oncology Department & CIC1425-CLIP2 Early Phase Cancer Clinical Trials Unit, University Hospital Bichat-Claude Bernard, Medical Faculty, University Paris-Diderot, Paris, France.

There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.
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http://dx.doi.org/10.3389/fonc.2020.00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040194PMC
February 2020

Unmet needs in clinical nutrition in oncology: a multinational analysis of real-world evidence.

Ther Adv Med Oncol 2020 14;12:1758835919899852. Epub 2020 Feb 14.

Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Pavia, Italy.

Background: Knowledge about cancer-related malnutrition and the use of clinical nutrition (CN) in the real-world setting are lacking. We investigated diagnosis and treatment frequency of malnutrition in a multinational survey to identify unmet needs in cancer patients' care.

Methods: Retrospective analyses were conducted on data from three administrative healthcare datasets from France ( = 570,727), Germany ( = 4642) and Italy ( = 58,468). Data from France described frequency and timing of malnutrition diagnosis in hospitalized gastrointestinal cancer patients. The German data detailed home parenteral nutrition (HPN) use in cancer patients with stage III/IV cancers. The Italian data analysed three cohorts: metastatic with CN, metastatic without CN, and patients without metastatic disease.

Results: In France, malnutrition diagnosis at first hospitalization occurred in 10% of patients, 13% were subsequently diagnosed, and 77% had no malnutrition diagnosis. In Germany, 16% of patients received HPN. Patients started HPN around 3 months before death. In Italy, 8.4% of metastatic cancer patients received CN; average time between metastasis diagnosis and first CN prescription was 6.6 months. Average time between first CN prescription and death was 3.5 months.

Conclusions: These data indicate that in the real-world clinical practice, cancer-related malnutrition is under-recognized and undertreated. CN often appears to be prescribed as an end-of-life intervention or is not prescribed at all.Appropriate CN use remains challenging, and current practice may not allow optimal oncologic outcomes for patients at nutritional risk. Improving awareness of malnutrition and generating further evidence on clinical and economic benefits of CN are critical priorities in oncology.
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http://dx.doi.org/10.1177/1758835919899852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025419PMC
February 2020

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

Neuroendocrinology 2021 3;111(1-2):158-169. Epub 2020 Feb 3.

Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France.

Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity.

Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity).

Results: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations.

Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.
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http://dx.doi.org/10.1159/000506292DOI Listing
February 2020

RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis-an updated review.

Cell Death Dis 2019 12 5;10(12):928. Epub 2019 Dec 5.

Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, Caen, France.

The Ras association domain family protein1 isoform A (RASSF1A) is a well-known tumor-suppressor protein frequently inactivated in various human cancers. Consistent with its function as a molecular scaffold protein, referred to in many studies, RASSF1A prevents initiation of tumorigenesis, growth, and dissemination through different biological functions, including cell cycle arrest, migration/metastasis inhibition, microtubular stabilization, and apoptosis promotion. As a regulator of key cancer pathways, namely Ras/Rho GTPases and Hippo signaling without ignoring strong interaction with microtubules, RASSF1A is indeed one of the guardians of cell homeostasis. To date, as we approach the two decade anniversary of RASSF1A's discovery, this review will summarize our current knowledge on the RASSF1A key interactions as a tumor suppressor and discuss their impact on cell fate during carcinogenesis. This could facilitate a deeper understanding of tumor development and provide us with new strategies in cancer treatment by targeting the RASSF1A pathway.
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http://dx.doi.org/10.1038/s41419-019-2169-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895193PMC
December 2019

Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial.

Cancers (Basel) 2019 Nov 21;11(12). Epub 2019 Nov 21.

Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, 14074 Caen, France.

gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.
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http://dx.doi.org/10.3390/cancers11121835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966477PMC
November 2019