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Chemotherapy; Non–small cell lung cancer; RET inhibitors Quimioteràpia; Càncer de pulmó de cèl·lules no petites; Inhibidors de RET Quimioterapia; Cáncer de pulmón de células no pequeñas; Inhibidores de RET Introduction Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. Methods This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. Results For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). Conclusions Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients. Writing assistance was provided by Mrs. Sarah Mackenzie. Dr. Marinello was the recipient for the grant for DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie). Dr. Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health); Ayuda de la Acción Estratégica en Salud-ISCIII FIS 2021 (PI21/01653); Ayuda SEOM-Juan Rodés 2020. Dr. Cortellini acknowledges the support from the National Institute for Health Research Imperial Biomedical Research Centre. Dr. Pinato acknowledges the support from the Wellcome Trust Strategic Fund (PS3416), Associazione Italiana per la Ricerca sul Cancro (Associazione Italiana per la Ricerca sul Cancro MFAG Grant ID 25697), National Institute for Health Research Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and the Imperial College Tissue Bank.

International audience; No abstract available

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). Results: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design:We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis).Results:We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001).Conclusions:As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Supplementary Figure 1: Graphical Abstract Supplementary Figure 2: Overall Survival in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to EGFR mutation Supplementary Figure 3: Recursive partitioning identified classical monocytes and NK as the main immune populations whose frequency splits patients into distinct patterns of overall survival Supplementary Figure 4: Classical monocytes, NK cells and ICOS+ CD4+ T cells are associated with improved pembrolizumab efficacy in advanced NSCLC patients. Supplementary Figure 5: Gating strategy of the 3 main immune populations associated with pembrolizumab efficacy. Supplementary Figure 6: Comparison side by side of Maxstat cut-offs with cut-off from Younden index for overall survival in the 3 populations of interest. Supplementary Figure 7: Survival outcomes in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to blood baseline frequency of classical monocytes. Supplementary Figure 8: Baseline immune peripheral score is also associated with PFS in melanoma patients treated with PD-1 inhibitors.

Introduction Thyroid dysfunction is the most frequent endocrine immune related adverse event (irAE) in non-small cell lung cancer (NSCLC), typically arising 3–6 months into immune checkpoint inhibitor (ICI) therapy, but arising after ICI cessation, in some cases. Due to limited post-treatment adverse event reporting requirements on ICI trials, the incidence of ICI-induced thyroid dysfunction arising after therapy is unclear. We investigated ICI-induced thyroid dysfunction in a cohort of 294 NSCLC patients, with a specific focus on the post-treatment setting. Methods Retrospective analysis of ICI-induced thyroid dysfunction (clinically acted upon or laboratory only) was performed in 294 UCLA NSCLC patients treated 2012–2018. Clinically acted upon thyroid dysfunction was defined as thyroid diagnosis documentation and/or thyroid medication administration. Laboratory only dysfunction was defined as abnormal thyroid labs in the absence of clinical action. Timing of thyroid dysfunction relative to ICI treatment and thyroid monitoring patterns were also assessed. Results 82% (241/294) of ICI treated NSCLC patients had thyroid labs during treatment. Of these 241 patients, 13% (31/241) had clinically acted upon thyroid dysfunction prior to, 8% (18/241) during, and 4% (9/241) after ICI. Most patients, 66% (159/241), did not have thyroid labs after ICI, but in the 53 patients with labs and no prior clinical dysfunction, 17% (9/53) developed clinical dysfunction after ICI. In these 9 patients, median time from ICI initiation to dysfunction was 253 days. Two patients with post-treatment laboratory only dysfunction were observed. Conclusions ICI-induced thyroid dysfunction arising post-treatment appears more common than previously appreciated, warranting additional evaluation.

research support, non-u.s. gov't letter 2023 Mar 2022 12 07 imported

Background: PD-1 blockade (αPD-1) has shown limited efficacy in breast & gynecologic cancers. In other types of solid tumor, regulatory T cells (Tregs) harbouring markers of highly suppressive effector Tregs (eTregs) correlates with poor responses to PD-1 blockade, prompting combination therapy based on eTregs depletion. Yet, subsets of Tregs remain to be determined in breast & gynecologic cancers, in order to: (i) evaluate the role of eTregs in resistances to PD-1 blockade, (ii) identify the most selective target for eTregs depletion tailored to tumors context and combination strategy. Methods: We collected public single-cell RNA/TCR-sequencing data from primary tumors and metastases of Triple-Negative Breast Cancer patients (TNBC, N = 28) biopsied before and after αPD-1 (pembrolizumab). Microarray data from primary TNBC (N = 124) biopsied before and after αPD-1 were quired for association with clinical responses. Deep phenotyping of Tregs from normal breast tissues (N = 4) and primary breast tumors (N = 8) or gynecologic tumors (N = 17) was performed by mass cytometry. ALD2510 (αCD25NIB, Alderaan Biotechnology) is a novel non-IL-2 blocking Fc-optimized anti-CD25 mAb (1). αPD-1 and αCD25NIB combination was evaluated using: (i) a humanized αCD25NIB in CD34+ humanized NSG mice grafted with human TNBC cell lines, (ii) a murine surrogate of αCD25NIB in a syngeneic TNBC mouse model. Results: CD25high Tregs were accumulating in breast & gynecologic tumor tissues. In TNBC patients treated with αPD-1, fractions of CD25high Tregs were further increased. CD25high Tregs highly expressed eTregs-related molecules in primary tumors, invaded tumor-draining lymph nodes and distant metastases. Amongst the potential therapeutic targets for Treg depletion, only CD25, 4-1BB and CCR8 were largely restricted to intratumoral CD25high eTregs. Yet, CD25 was the best candidate for CD25high eTregs depletion with limited on-target off-Treg effects, as: (i) CCR8 marked a small fractions of CD25high eTregs in primary tumors and was not detected in metastasis, (ii) 4-1BB marked antigen-experienced αβCD8 T cell revigorated by PD-1 blockade, (iii) only CD25high eTregs expressed 4-1BB and CCR8, yet TCR clonotype analysis revealed that CD25high eTregs originate in part from activated CD25+ Tregs, suggesting that anti-CCR8/-4-1BB mAbs may be ineffective due to CD25high eTregs replenishment in tumors. In murine models resistant to αPD-1 alone, αCD25NIB effectively depleted intratumoral CD25high eTregs, with limited effects on peripheral Tregs, and synergized with αPD-1 by restoring a positive effector αβCD8 T cells/Tregs ratio, leading to tumor clearance without adverse effects. Conclusions: This study supports clinical evaluation of CD25high effector Tregs depletion by ALD2510 in patients with breast or gynecologic cancers resistant to PD-1 blockade. Citation Format: Stéphane FATTORI, Aude Le Roy, Jemila Houacine, Lucie Robert, Riad Abes, Laurent Gorvel, Samuel Granjeaud, Marie-Sarah Rouvière, Amira Ben Amara, Nicolas Boucherit, Carole Tarpin, Jihane Pakradouni, Emmanuelle Charafe-Jauffret, Julien Barrou, Gilles Houvenaeghel, Eric Lambaudie, François Bertucci, Philippe Rochigneux, Anthony Gonçalves, Arnaud Foussat, Anne-Sophie Chrétien, Daniel Olive. Selective depletion of regulatory T cells by ALD2510, a novel IL-2-sparing anti-CD25 antibody, synergizes with PD-1 blockade in breast and gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3239.

International audience; Background: Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate. Methods: This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021. Discussion: The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.

Significance This work provides a report of accumulation of unconventional CD56−CD16+ NK cells in nonvirally induced malignancies. Increased frequency of CD56−CD16+ NK cells is associated with adverse clinical outcome in AML, as well as other maturation defects, and might contribute to a defective control of AML progression. Pseudotime analysis highlights a disruption in the maturation process of conventional NK cells in AML patients, leading to a bifurcation point absent in healthy subjects. This analysis, combined with the reduced frequency of conventional NK cells observed in AML patients, suggests that unconventional CD56−CD16+ NK cells derive from an aberrant maturation of conventional NK cells. Overall, accumulation of CD56−CD16+ NK cells could be an important feature of immune escape from innate immunity., Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56−CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (n = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects (n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56−CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56−CD16+ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56−CD16+ NK cells. Overall, our data suggest that the accumulation of CD56−CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.

Simple Summary The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. Immunotherapy enables the immune defense of the organism to target liver cancer cells. Recent technologies enable engineering of immune cells, and notably T lymphocytes, to make them more efficient against the tumor. These technics (called TCR engineered T cells and CAR-T cells) are promising and are actually tested in clinical trials. This review explains the concept of TCR modified and CAR-T cells in liver cancer (targets and mechanisms of action) and reports the results from recent clinical trials. Abstract The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials.

Simple Summary Vδ2+ γδ T cells have potent antitumor properties both in vitro and in murine preclinical models of breast cancers. However, in the context of human breast cancer, there is a lack of information for potential phenotypic alterations of this crucial immune cell subset. This is partly due to Vδ2+ γδ T cells scarcity in surgical specimens. To break this deadlock, we assessed Vδ2+ γδ T cell phenotypes using untreated breast cancer patients’ peripheral blood, so-called minimally invasive “liquid biopsy”. We show that circulating Vδ2+ γδ T cell phenotypic alterations are already established at diagnosis and related to tumor progression. Notably, terminally differentiated Vδ2+ γδ T cells expressing canonical markers of replicative senescence and exhaustion were significantly associated with tumor-draining lymph node invasion. Our results shed light on the interest of using liquid biopsy to monitor rare events and support Vδ2+ γδ T cell involvement in breast cancer pathogenesis and progression. Abstract The rationale for therapeutic targeting of Vδ2+ γδ T cells in breast cancer is strongly supported by in vitro and murine preclinical investigations, characterizing them as potent breast tumor cell killers and source of Th1-related cytokines, backing cytotoxic αβ T cells. Nonetheless, insights regarding Vδ2+ γδ T cell phenotypic alterations in human breast cancers are still lacking. This paucity of information is partly due to the challenging scarcity of these cells in surgical specimens. αβ T cell phenotypic alterations occurring in the tumor bed are detectable in the periphery and correlate with adverse clinical outcomes. Thus, we sought to determine through an exploratory study whether Vδ2+ γδ T cells phenotypic changes can be detected within breast cancer patients’ peripheral blood, along with association with tumor progression. By using mass cytometry, we quantified 130 immune variables from untreated breast cancer patients’ peripheral blood. Supervised analyses and dimensionality reduction algorithms evidenced circulating Vδ2+ γδ T cell phenotypic alterations already established at diagnosis. Foremost, terminally differentiated Vδ2+ γδ T cells displaying phenotypes of exhausted senescent T cells associated with lymph node involvement. Thereby, our results support Vδ2+ γδ T cells implication in breast cancer pathogenesis and progression, besides shedding light on liquid biopsies to monitor surrogate markers of tumor-infiltrating Vδ2+ γδ T cell antitumor activity.

International audience; Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.

Natural killer (NK) cells are major anti-leukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the present work, we highlight an accumulation of CD56-CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly-diagnosed AML (N=48, HEMATOBIO cohort, NCT02320656) and healthy subjects (N=18) by mass cytometry. We evidenced a moderate to drastic accumulation of CD56- CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30, and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56-CD16+ NK cells at diagnosis was associated with an adverse clinical outcome, with decreased overall survival (HR=0.13; P=.0002) and event-free survival (HR=0.33; P=.018), and retained statistical significance in multivariate analysis. Pseudo-time analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56-CD16+ NK cells. Overall, our data suggest that the accumulation of CD56-CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.SignificanceThis work provides the first report of accumulation of unconventional CD56-CD16+ NK cells in non-virally induced malignancies. Pseudotime analysis highlights a bifurcation point occurring during the course of NK cell maturation, providing elements regarding the possible origin of CD56-CD16+ NK cells. Increased frequency of CD56-CD16+ NK cells is associated with adverse clinical outcome in AML and might contribute, as well as other maturation defects, to a defective control of AML progression. Overall, accumulation of CD56-CD16+ NK cells could be an important feature of immune escape from innate immunity.Graphical abstractKey pointsA disruption in the maturation process of NK cells leads to accumulation of unconventional CD56- CD16+ NK cells in patients with AMLHigh frequency of CD56-CD16+ NK cells is associated with adverse clinical outcome

International audience; No abstract available

Docetaxel is an antimicrotubules cytotoxic agent prescribed widely by medical oncologists in multiple tumor types (breast, lung, prostate, stomach, head, and neck). However, the side effects of docetaxel are numerous (cytopenia, peripheral edema, myalgia, arthralgia, alopecia, and sensitive neuropathy) and recent concerns have been raised about neutropenic enterocolitis in France. Here, we report the case of a 57-year-old patient with metastatic prostatic cancer, who developed a severe myositis and fasciitis grade IV 1 week after his second docetaxel infusion. We reviewed the five cases of docetaxel-related myositis described in the literature, and found that most of them occurred in patients with diabetes (n=5/5) or hypertension (n=4/5). A vascular toxicity may explain this severe complication, and patients with diabetes or hypertension should be monitored closely in the context of a docetaxel chemotherapy.

Background Early integration of palliative care for patients with metastatic lung cancer improves their quality of life and survival and reduces the aggressiveness of care near the end of life. This study examined the association between the timing of palliative care needs reporting and the aggressiveness of end-of-life care. Methods This retrospective cohort study used the French National Hospital Registry to identify all hospitalized adults (≥20 years old) who died of metastatic lung cancer in France between 2010 and 2013. It compared the use of care and treatments near the end of life as a function of the timing of the first reporting of palliative care needs. The use of chemotherapy and the use of invasive ventilation were defined as primary outcomes. Propensity score weighting was used to control for potential confounders. Results Among a total of 64,950 deceased patients with metastatic lung cancer, the reporting of palliative care needs was characterized as timely (from 91 to 31 days before death) for 26.3%, late (from 30 to 8 days before death) for 31.5%, and very late (from 7 to 0 days before death) for 12.8%. Palliative care needs were not reported for 19,106 patients (29.4%). Patients with timely reporting of palliative care needs had the earliest and most progressive decrease in the use of anticancer therapy. The use of invasive ventilation also increased with a delay in palliative care needs reporting. Conclusions There is a clear association between the timing of palliative care needs reporting and the aggressiveness of care near the end of life. Cancer 2018;124:3044-51. © 2018 American Cancer Society.

Resume L’utilisation de biomarqueurs en oncologie permet de selectionner des populations pouvant beneficier de traitements anticancereux plus efficaces et moins toxiques, et suscitent ainsi l’espoir d’une medecine de precision. L’essor de la biologie moleculaire a provoque un bouleversement du developpement des therapies moleculaires ciblees, permettant d’observer des signaux d’efficacite des les essais de phase 1 et d’accelerer ainsi l’obtention d’autorisations de mise sur le marche. A ce jour, plusieurs essais academiques, dont SHIVA, SAFIR-01 et MOSCATO-01, ont evalue l’interet de fonder le traitement oncologique sur les seules anomalies moleculaires de la tumeur, avec l’ambition a terme de supplanter les classifications anatomopathologiques et cliniques historiques. L’administration de traitements cibles a egalement permis une amelioration du pronostic de nombreux cancers, et leur recours est de plus en plus envisage en situation palliative avancee. Franchir ces frontieres permettra de tendre vers une medecine de precision en oncologie, dont l’integration en pratique clinique est desormais une attente forte des praticiens et des patients.

Background: This nationwide prospective cohort reports on the outcome of patients with cancer presenting COVID-19 symptoms with or without detectable SARS-COV2 on RT-PCR and/or specific CT-scan imaging. Methods: This prospective study was conducted in 23 Cancer Centers and hospitals. Inclusion criteria were :1) confirmed diagnosis of solid or hematologic cancer in treatment and 2) clinical symptoms of COVID-19. COVID-19 infection was defined as: 1) detectable SARS-CoV2 on RT-PCR (repeated twice if negative first) and/or specific CT-scan imaging if undocumented SARS-COV-2 on RT-PCR. The primary endpoint was death at day-28 after COVID-19 test, in patients with (COVID-19 positive group) or without (COVID-19 negative group) documented COVID-19. Findings: From March 1st 2020 to May 21st 2020, 1230 cancer patients with suspicion of COVID-19, including 1162 (94·5%) matching inclusion criteria were included. 425 (36·6%) [including 155 [13·3%] with diagnosis on CT-scan only], and 737 (63·4%) were in the COVID-19+ and COVID-19- groups respectively. Deaths within 28 days after COVID-19 diagnosis occurred in 116/425 (27·8%) of COVID-19+ patients, and in 118/737 (16·3%) of COVID-19 negative patients (p 100 mg/L vs 35/203 (17·4%) of other patients died before day 28 (p

Background: Percutaneous radiofrequency ablation (RFA) is one of the main treatments of small hepatocellular carcinoma (HCC). However, it remains unclear whether this local treatment can induce systemic immune variations. Methods: We conducted a prospective study in a tertiary center including consecutive cirrhotic patients with unifocal HCC

Recently, Biton et al . published in Clinical Cancer Research the article “TP53, STK11 and EGFR Mutations Predict Tumor Immune Profile and the Response to anti-PD-1 in Lung Adenocarcinoma” (1). This article points out the challenging question of the interplay between tumoral mutations in lung adenocarcinoma (localized and metastatic) and the composition of immune microenvironment.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours of the digestive tract, derived from Cajal interstitial cells. Bone metastases are very rare, and there is no consensus regarding their treatment. Here, we present the unusual case of a 66-year-old man with a gastric GIST with synchronous bone and liver metastases, fully documented at the pathological and molecular levels with a KIT exon 11 mutation. After 9 months of imatinib, the scanner showed a 33% partial response of target lesions. We also review the literature and describe the characteristics, treatment, and outcome of all cases previously reported.

9561 Background: Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune biomarkers of efficacy are still lacking. Preliminary data in leukemia and pancreatic cancer showed that soluble immune checkpoints are associated with a reduced overall survival (OS). This led us to explore the prognostic and predictive value of soluble immune checkpoints in non-small cell lung cancer (NSCLC) patients treated with chemotherapy or ICI. Methods: We analyzed 90 advanced NSCLC patients. The pilot cohort (Rennes University Hospital, France), included 48 patients treated with platinum doublets (n = 33) or ICI (n = 15) (LOC/11-16 protocol). The confirmation cohort (Paoli-Calmettes Institute) included 42 patients treated with ICI (nivolumab or pembrolizumab) in a longitudinal prospective setting (Immunosup trial, NCT03595813). In both cohorts, enzyme-linked immunosorbent assays (ELISA) were performed in baseline plasma samples for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3-A1 and BTN2A1. Soluble ICI levels were linked to clinical data using Kaplan-Meier, log-rank and Cox proportional-hazards models. Cut-points were determined using maxstat package for survival, R software R 3.6.2. Results: Five soluble immune checkpoints correlated and clustered together in unsupervised analysis (PD-1, PD-L1, global BTN3, BTLA, BTN3-A1), but were not associated with ICI efficacy. In patients treated with ICI, in the pilot and confirmation cohort, a high baseline plasmatic concentration of soluble BTN2A1 was significantly associated with an improved OS (confirmation cohort with a BTN2A1 cut-point of 3.55 ng/ml: HR = 0.30, 95%CI = 0.12-0.74, p = 0.0057, median OS in BTN2A1low = 7.6 months and median OS in BTN2A1hi = 19.5 months). On the contrary, in patients treated with chemotherapy, soluble BTN2A1 concentration was not associated with overall survival. Conclusions: In advanced NSCLC patients, a high baseline plasmatic concentration of soluble BTN2A1 was correlated with improved outcomes for ICI, but not for chemotherapy, suggesting that baseline soluble BTN2A1 level is a potential predictive biomarker of ICI efficacy. Additional studies are ongoing to confirm this finding.

e16527 Background: Gastric cancer (GC) occurs in 50% of case after 70 years old (y/o). Radical surgery or perioperative treatments have to be balanced with safety management in those potential frail patients. Methods: We perfomed a retrospective review of our single institution database to address the outcome of patient (pts) > 70y/o who underwent radical surgery for GC with or without neoadjuvant and adjuvant treatment. Results: From 2005 to 2019, 60 eligible patients (pts) have undergone radical surgery for resectable GC. Median age at diagnosis was 74.2y/o [70.3-92.8] and 82% were male. Initial echoendoscopy staged 12% of T1/T2 tumor versus 70% of T3/T4, whereas 60% were found with lymph node spreading (N+). 80% of pts were given neoadjuvant treatment: chemoradiation (58%), chemotherapy (45%) or radiation alone (1%). 1/4 pt received perioperative chemotherapy. Only one patient had post-operative radiation with FOLFOX and none had adjuvant radiation alone. Surgery procedure was total (27%) or sub-total (5%) gastrectomy, polar-oesogastrectomy with thoracotomy (18%) or without thoracotomy (50%). Post-operative mortality within 3 months was 5% (n = 3) including 2 pts in the first 30 days. For the global cohort, median overall survival (mOS) was 44.75 months and median progression free survival (mPFS) was 21.2 months. Patients who frontly underwent radical surgery (n = 15, 25%) had small disease with 13% pT0 and 60% of pT1 on final pathology. Only 27% had pT2/T3 but all had vascular and/or peri-nervous emboli. Two of them (13%) were pN+. The mOS was 60 months and mPFS 60 months in this cohort and 33% of pts end/was lost of follow up. Only one metastatic relapse was identifies and no local relapse. Six pts died (40%): 2 in the 30-days post surgery (13%), 3 (30%) from other cause than GC and 1 (7.5%) because of GC distant relapse. The cohort treated with neoadjuvant chemotherapy (n = 45, 75%) was given platinum and anthracycline-based regimen in 73% and 16% of cases, respectively. 1% received fluoropyrimidine +/- irinotecan. 53% associated radiation to neoadjuvant chemotherapy. After neoadjuvant treatment completion, 47% of downstaging (including 18% of pCR), 33% of stable stage and 15.5% of upstaging was observed and 40% of initial usN+ was pN0. After perioperative treatment, mOS was 31 months and mPFS was 18.9 months. Overall 44% experienced local and/or distant relapse. Conclusions: Age above 70y/o should not systematically exclude patient from neoadjuvant or perioperative treatment and radical surgery, which is feasible in selected population displaying long term result in focal and distant disease control.

ObjectiveTo investigate patterns of care during the last months of life of hospitalised patients who died from different haematological malignancies.MethodsNationwide register-based study, including all hospitalised adults ≥20 years who died from haematological malignancies in France in 2010–2013. Outcomes included use of invasive cancer treatments and referral to palliative care. Percentages are adjusted for sex and age using direct standardisation.ResultsOf 46 629 inpatients who died with haematological malignancies, 24.5% received chemotherapy during the last month before death, 48.5% received blood transfusion, 12.3% were under invasive ventilation and 18.1% died in intensive care units. We found important variations between haematological malignancies. The use of chemotherapy during the last month of life varied from 8.6% among patients with chronic myeloid leukaemia up to 30.1% among those with non-Hodgkin’s lymphoma (PConclusionA high proportion of patients who died from haematological malignancies receive specific treatments near the end of life. There is a need for a better and earlier integration of the palliative care approach in the standard practice of haematology. However, substantial variation according to the type of haematological malignancy suggests that the patients should not be considered as one homogeneous group. Implementation of palliative care should account for differences across haematological malignancies.

Background Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments. Case presentation We report the case of a 51 year old man with a metastatic pRCC (hepatic dome and left colonic peritoneal carcinomatosis) progressive after sunitinib, with a MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSé crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months’ clinical efficacy. Conclusions In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.

Early integration of palliative care for patients with metastatic lung cancer improves their quality of life and survival and reduces the aggressiveness of care near the end of life. This study examined the association between the timing of palliative care needs reporting and the aggressiveness of end-of-life care.This retrospective cohort study used the French National Hospital Registry to identify all hospitalized adults (≥20 years old) who died of metastatic lung cancer in France between 2010 and 2013. It compared the use of care and treatments near the end of life as a function of the timing of the first reporting of palliative care needs. The use of chemotherapy and the use of invasive ventilation were defined as primary outcomes. Propensity score weighting was used to control for potential confounders.Among a total of 64,950 deceased patients with metastatic lung cancer, the reporting of palliative care needs was characterized as timely (from 91 to 31 days before death) for 26.3%, late (from 30 to 8 days before death) for 31.5%, and very late (from 7 to 0 days before death) for 12.8%. Palliative care needs were not reported for 19,106 patients (29.4%). Patients with timely reporting of palliative care needs had the earliest and most progressive decrease in the use of anticancer therapy. The use of invasive ventilation also increased with a delay in palliative care needs reporting.There is a clear association between the timing of palliative care needs reporting and the aggressiveness of care near the end of life. Cancer 2018;124:3044-51. © 2018 American Cancer Society.

To evaluate the frequency and the factors associated with the use of chemotherapy and artificial nutrition near the end of life in hospitalised patients with metastatic oesophageal or gastric cancer.Nationwide, register-based study, including all hospitalised adults (≥20 years) who died with metastatic oesophageal or gastric cancer between 2010 and 2013, in France. Chemotherapy and artificial nutrition during the final weeks of life were considered as primary outcomes.A total of 4031 patients with oesophageal cancer and 10,423 patients with gastric cancer were included. While the proportion of patients receiving chemotherapy decreased from 35.9% during the 3rd month before death to 7.9% in the final week (p 0.001 for trend), the use of artificial nutrition rose from 9.6% to 16.0% of patients. During the last week before death, patients with stomach cancer were more likely to receive chemotherapy (adjusted odds ratio (aOR) = 1.35, 95% CI = 1.17-1.56) but less likely to receive artificial nutrition (aOR = 0.80, 95%CI = 0.73-0.88) than patients with cancer of the oesophagus. The adjusted rates of chemotherapy use during the last week of life varied from 1.6% in rural hospitals to 11.2% in comprehensive cancer centres, while the adjusted probability to receive artificial nutrition varied from 12.1% in private for-profit clinics up to 19.9% in rehabilitation care facilities (p 0.001).Our study shows that in hospitalised patients with metastatic oesophageal or gastric cancer, the use of chemotherapy decreases while the use of artificial nutrition increases as death approaches. This raises important questions, as clinical guidelines clearly recommend to limit the use of artificial nutrition in contexts of limited life expectancy.

The development of personalized medicine in oncology is based on biomarkers that help select populations for more efficient and less toxic therapies. The onset of molecular biology led to new paradigms in drug development, with efficacy data reported in early clinical trials and accelerated approvals. Multiple clinical trials, including SHIVA, SAFIR-01 and MOSCATO-01, have been developed to evaluate the interest of treatment decision-making based on tumor molecular profiling, with the ambition to replace historical clinical and pathological classifications. Targeted molecular therapies have also drastically enhanced the prognosis of patients in several cancer subtypes, with increased use in the context of advanced palliative care. Breaking through those boundaries might lead to a true precision medicine in oncology, which implementation in clinical routine is now expected by patients and physicians.

International audience; Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

Background Use of chemotherapy near the end of life in patients with metastatic cancer is often ineffective and toxic. Data about the factors associated with its use remain scarce, especially in Europe. Methods Nationwide, register-based study including all hospitalized patients aged ≥20 years who died from metastatic solid tumors in France between 2010 and 2013. Results A total of 279 846 hospitalized patients who died from metastatic cancer were included. During the last month before death, 19.5% received chemotherapy (including 11.3% during the last 2 weeks). Female sex (OR= 0.96, 95% CI= 0.93–0.98), older age (OR= 0.70, 95% CI= 0.69–0.71 for each 10-year increase) and higher number of chronic comorbidities (OR= 0.83, 95% CI= 0.82–0.84) were independently associated with lower rates of chemotherapy. Although patients with chemosensitive tumors were statistically more likely to receive chemotherapy during the last month before death (OR= 1.21, 1.18–1.25), this association was mostly fueled by testis and ovary tumors and we found no obvious pattern between the expected chemosensitivity of different cancers and the rates of chemotherapy use close to death. Compared with university hospitals, patients who died in for-profit clinics/hospital (OR= 1.40, 95% CI= 1.34–1.45), or comprehensive cancer centers (OR= 1.43, 95% CI= 1.36–1.50) were more likely to receive chemotherapy. Finally, high-volume centers and hospitals without palliative care units reported greater-than-average rates of chemotherapy near the end of life. Conclusion among hospitalized patients with cancer, young individuals, treated in comprehensive cancer centers or in high-volume centers without palliative care units were the most likely to receive chemotherapy near the end of life. We found no evident pattern between the expected chemosensitivity of different cancers and the probability for patients to receive chemotherapy close to death.

SummaryBackground Although the aggressiveness of end-of-life cancer care has come under great scrutiny over the past two decades, little is known about the intensity of care and treatments in the last months of life of patients with metastatic melanoma. Objectives To measure the prevalence of aggressive cancer care use, and to assess the frequency of palliative care referral over the course of the last 3 months of life of hospitalized patients who died from metastatic melanoma. Methods A nationwide register-based study in France was carried out, including all hospitalized adults aged ≥ 20 years who died from metastatic melanoma in metropolitan France between 2010 and 2013. Results Of 3889 patients who died from metastatic melanoma, 51·9% received chemotherapy in the last 3 months before death, 25·9% in the last month, 12·9% in the last 2 weeks and 7·6% in the last week. On average, patients were hospitalized for 31·7 days over the course of their last 3 months of life. During the final month before death, 12·0% of patients received radiation therapy, 14·0% received blood transfusion, 12·1% were transferred into an intensive care unit and 19·7% remained hospitalized continuously. Palliative care needs were identified in 78·4% of patients, with variations according to the type of facility. In total 17% of all patients died in palliative care inpatient units. Conclusions Treatment intensity near the end of life of patients with metastatic melanoma raises concerns for the quality of care. There is a need for clinical guidelines and adequate support to facilitate patient–physician communication and to improve access to palliative care services.

9527 Background: Over the past decades, dramatic changes in the treatment of advanced cancer have raised concerns regarding the quality of end-of-life care in terminally-ill patients. However, Earl...

4150 Background: Pancreatic ductal adenocarcinoma (PDAC) has poor outcome and surgical resection remains the only curative treatment. Post-operative (Post-Op) chemotherapy (CT) improves survival and FOLFIRINOX (FFX) regimen is the standard of care. Increasing number of patients with borderline resectable (BL) or locally advanced (LA) disease are treated with pre-operative (Pre-Op) CT with FFX. However, the benefit of Post-Op CT after Pre-Op FFX remains unclear. The aim of this study was to analyze the impact on survival of Post-Op CT in patients with resected BL or LA PDAC after Pre-Op FFX CT. Methods: 116 consecutive patients treated at the Institut Paoli-Calmettes comprehensive cancer center between 2014 and 2020 were retrospectively analyzed. All patients underwent pancreatectomy after Pre-Op FFX for a BL or LA PDAC. Patients who progressed or died within 3 months after surgery were excluded from the analysis. We compared median relapse-free survival (mRFS) and median overall survival (mOS) defined by time from surgery to relapse or death in patients who received or not Post-Op CT. Results: 116 patients (80% BL, 20% LA) were included: 82 received Post-Op CT (CT+) and 34 did not (CT-). The median number of Pre-Op FFX cycles was 4 in the CT+ group vs 6 in the CT- group. 24 (29.3%) patients received Post-Op FFX, 37 (45.1%) received Gemcitabine, 9 (11%) received Gemcitabine + Capecitabine, and 9 (11%) received a 5FU-based CT. Median time between surgery and first Post-Op CT cycle was 63 days. No difference in mRFS nor in mOS were found between CT+ and CT- groups: mRFS 15.0 vs 13.6 months, HR 1.1 [IC95% 0.69–1.77] and mOS 33.8 vs 36.1 months, HR 0.94 [IC95% 0.55–1.60]. Among patients with pathologic node positive disease (N+) (n = 79), mRFS was 13.9 months in the CT+ group vs 6.9 months in the CT- group (HR 0.68 [IC 0.35 – 1.19]), and mOS was 31.8 months in the CT+ group vs 16.5 months in the CT- group (HR 0.96 [IC95% 0.51-1.81]). Patients who received peri-operative (Peri-Op) FFX (n = 24) experienced longer mOS compared to patients who received Gemcitabine Post-Op CT: NR vs 33.8 months, HR 0.45 [IC95% 0.25-1.02]. Patients who received Peri-Op CT for a total of six months or more (n = 31) had increased mOS (55 vs 32 months, HR 0.61 [IC 95% 0.37- 1.11] and mRFS (16 vs 14 months HR 0.80, [IC95% 0.50 -1.31]) than patients receiving less than 6 months Peri-Op CT (n = 85) Conclusions: Post-Op CT does not clearly impact survival in BL or LA pancreatic cancer pretreated with Pre-Op FFX. We observed a trend in the N+ population for a survival benefit. Peri-Op FFX was associated with longer survival than Gemcitabine Post-Op regimen. Further randomized data are needed to assess the impact of Peri-Op FFX for these patients

Contexte : le traitement médical des cancers solides a radicalement changé depuis le développement des inhibiteurs de checkpoint immunitaire (ICI). Cependant, les effets indésirables (EI) immuno-induits sont un défi dans la pratique courante. La dysthyroïdie est l’EI endocrinien le plus fréquent et certaines séries suggèrent que la dysthyroïdie pourrait être associée à l'efficacité des ICI. Ceci nous a conduit à explorer l'association entre la dysthyroïdie induite par les ICI et la survie globale (SG) dans une grande cohorte de patients atteints de tumeurs solides en utilisant l'exploration des données des dossiers patients informatisés (DPI).Patients et méthodes : ConSoRe est un outil d'analyse de données de nouvelle génération utilisant le Traitement Automatique du Langage (TAL) pour rechercher des données agrégées et effectuer une exploration de données avancée. Cet outil a été utilisé pour extraire des DPI les données des patients traités par ICI pour un cancer solide à l'Institut Paoli-Calmettes (Centre anticancéreux de Marseille, France). Les analyses de survie ont été réalisées par la méthode de Kaplan-Meier et comparées à l'aide du test log-rank (package R survminer). Une analyse landmark a été utilisée pour prendre en compte le biais d’immortalité. Dans l'analyse univariée et multivariée, un modèle de Cox à risques proportionnels a été utilisé pour estimer les variables associées à la SG. Le hazard Ratio (HR) a été estimé avec un intervalle de confiance à 95%. Deux modèles ont été réalisés, un modèle de Cox dit dépendant du temps et un modèle de Cox dit indépendant du temps. Résultats : l'extraction des données a permis d'identifier 1 385 patients traités par ICI entre 2011 et 2021. La survenue d’une dysthyroïdie a été observée chez 90 pts (7%). La dysthyroïdie a été associée à une meilleure SG (HR=0,46, 95%CI 0,33-0,65, p