Beyond EGFR Targeting in SCCHN: Angiogenesis, PI3K, and Other Molecular Targets

Although the molecular landscape of squamous cell carcinoma of the head and neck (SCCHN) has been largely deciphered, only one targeted therapy has been approved to date without any molecular selection, namely cetuximab. Cetuximab is a monoclonal antibody targeting EGFR. It has been shown to improve overall survival in the locally advanced setting in combination with radiotherapy and the recurrent and/or metastatic setting in combination with a platinum compound and 5FU. Beside EGFR targeting agents, antiangiogenic agents have been shown to produce antitumor activity but were associated with substantial toxicity. Buparlisib that targets PI3K was also shown to improve survival in combination with paclitaxel in an unselected patient population. Several other targeted therapies have been developed in SCCHN, most of time in all comers, potentially explaining the limited efficacy reported with them. The recent emergence of clinical trials of targeted therapies in enriched patient populations and precision medicine trials such as umbrella trials might boost the clinical development of targeted therapy in SCCHN

Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02-3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34-2.57, p < 0.001), liver metastases (OR = 3.33, 2.07-5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96-5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36-0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors.

peer reviewed[en] BACKGROUND: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. MATERIALS AND METHODS: In this expansion cohort of NCT02517398-a global, open-label, phase I trial-adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. RESULTS: Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. CONCLUSION: Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy

Determinants of the access to remote specialised services provided by national sarcoma reference centres

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis

Étude génomique et fonctionnelle de la dérégulation du gène HMGA2 dans les tumeurs adipocytaires

Benign adipocytic tumors (AT) are mainly represented by lipomas whereas most malignant AT are Atypical Lipomatous Tumors/Well-differentiated liposarcomas (ALT/WDLPS) and dedifferentiated liposarcomas (DDLPS). HMGA2 gene (High Mobility Group A2) is rearranged in some lipomas and amplified in ALT/WDLPS and DDLPS. Thus, we hypothesized that HMGA2 played a fundamental role in benign and malignant AT genesis. In favor of this hypothesis, we observed a constant overexpression of HMGA2 in amplified ALT/WDLPS and DDLPS, and in rearranged lipomas. In a case of lipomatosis, that is a pathological proliferation of the adipocytic tissu without rearrrangement of HMGA2, the overexpression of HMGA2 was asssociated with an inhibition of the expression of several let-7 microRNAs. However, we did not find a leading role of let-7 microRNAs in the deregulation of HMGA2 expression in AT. We also studied partner fusion genes of HMGA2 in lipomas and have specifically identified a new fusion involving PPAP2B (Phosphatidic Acid Phosphatase type 2B) which is located in 1p32. We also confirmed the role of NFIB gene (9p22) in lipomas. Finally, we have established prognostic correlations in a series of 116 ALT/WDLPS and DDLPS: HMGA2 amplification was associated with ALT/WDLPS histotype and a longer survival whereas respective CDK4 and JUN amplification were associated with DDLPS and shorter survival. Thus, our data support the hypothesis of an early and major role of HMGA2 in the genesis well differentiated AT.Les tumeurs adipocytaires (TA) bénignes sont majoritairement constituées par les lipomes, alors que les TA malignes sont principalement des Tumeurs Lipomateuses Atypiques (TLA)/ liposarcome (LPS) bien différenciés (LBD) et les LPS dédifférenciés (LDD). Le gène HMGA2 (High Mobility Group A2) est remanié dans certains lipomes et amplifié dans les TLA/LBD et LDD. Ainsi, nous avons émis l’hypothèse que HMGA2 jouait un rôle fondamental dans la genèse des TA bénignes et malignes. En faveur de cette hypothèse, nous avons observé une surexpression constante de HMGA2 dans les TLA/LBD et LDD avec amplification de HMGA2 et les lipomes avec remaniement de HMGA2. Dans un cas de lipomatose, hypertrophie pathologique du tissu adipeux sans anomalie du gène HMGA2, une surexpression de HMGA2 était associée à une inhibition de l’expression de plusieurs microARN let-7. En revanche, nos travaux ne sont pas en faveur d’un rôle prépondérant des microARN let7 dans la surexpression de HMGA2 dans les TA. Nous nous sommes également intéressés aux gènes partenaires de fusion avec HMGA2 dans les lipomes et avons notamment identifié une nouvelle fusion impliquant PPAP2B (Phosphatidic Acid Phosphatase type 2B) localisé en 1p32. Nous avons aussi confirmé le rôle du gène NFIB (9p22) dans les lipomes. Enfin, nous avons établi des corrélations pronostiques dans une grande série de 116 TLA/LBD et LDD : l’amplification de HMGA2 était associée à l’histotype TLA/LBD et à une survie longue alors que les amplifications de CDK4 et JUN sont associées au type LDD et une survie courte. Ainsi, nos données confortent l’hypothèse d’un rôle précoce et majeur de HMGA2 dans la genèse des TA bien différenciées

Genomic and functional study of HMGA2 deregulation in adipocytic tumors

Les tumeurs adipocytaires (TA) bénignes sont majoritairement constituées par les lipomes, alors que les TA malignes sont principalement des Tumeurs Lipomateuses Atypiques (TLA)/ liposarcome (LPS) bien différenciés (LBD) et les LPS dédifférenciés (LDD). Le gène HMGA2 (High Mobility Group A2) est remanié dans certains lipomes et amplifié dans les TLA/LBD et LDD. Ainsi, nous avons émis l’hypothèse que HMGA2 jouait un rôle fondamental dans la genèse des TA bénignes et malignes. En faveur de cette hypothèse, nous avons observé une surexpression constante de HMGA2 dans les TLA/LBD et LDD avec amplification de HMGA2 et les lipomes avec remaniement de HMGA2. Dans un cas de lipomatose, hypertrophie pathologique du tissu adipeux sans anomalie du gène HMGA2, une surexpression de HMGA2 était associée à une inhibition de l’expression de plusieurs microARN let-7. En revanche, nos travaux ne sont pas en faveur d’un rôle prépondérant des microARN let7 dans la surexpression de HMGA2 dans les TA. Nous nous sommes également intéressés aux gènes partenaires de fusion avec HMGA2 dans les lipomes et avons notamment identifié une nouvelle fusion impliquant PPAP2B (Phosphatidic Acid Phosphatase type 2B) localisé en 1p32. Nous avons aussi confirmé le rôle du gène NFIB (9p22) dans les lipomes. Enfin, nous avons établi des corrélations pronostiques dans une grande série de 116 TLA/LBD et LDD : l’amplification de HMGA2 était associée à l’histotype TLA/LBD et à une survie longue alors que les amplifications de CDK4 et JUN sont associées au type LDD et une survie courte. Ainsi, nos données confortent l’hypothèse d’un rôle précoce et majeur de HMGA2 dans la genèse des TA bien différenciées.Benign adipocytic tumors (AT) are mainly represented by lipomas whereas most malignant AT are Atypical Lipomatous Tumors/Well-differentiated liposarcomas (ALT/WDLPS) and dedifferentiated liposarcomas (DDLPS). HMGA2 gene (High Mobility Group A2) is rearranged in some lipomas and amplified in ALT/WDLPS and DDLPS. Thus, we hypothesized that HMGA2 played a fundamental role in benign and malignant AT genesis. In favor of this hypothesis, we observed a constant overexpression of HMGA2 in amplified ALT/WDLPS and DDLPS, and in rearranged lipomas. In a case of lipomatosis, that is a pathological proliferation of the adipocytic tissu without rearrrangement of HMGA2, the overexpression of HMGA2 was asssociated with an inhibition of the expression of several let-7 microRNAs. However, we did not find a leading role of let-7 microRNAs in the deregulation of HMGA2 expression in AT. We also studied partner fusion genes of HMGA2 in lipomas and have specifically identified a new fusion involving PPAP2B (Phosphatidic Acid Phosphatase type 2B) which is located in 1p32. We also confirmed the role of NFIB gene (9p22) in lipomas. Finally, we have established prognostic correlations in a series of 116 ALT/WDLPS and DDLPS: HMGA2 amplification was associated with ALT/WDLPS histotype and a longer survival whereas respective CDK4 and JUN amplification were associated with DDLPS and shorter survival. Thus, our data support the hypothesis of an early and major role of HMGA2 in the genesis well differentiated AT

Recheche de facteurs prédictifs de la réponse à une chimiothérapie à base de sels de platine dans les carcinomes épidermoïdes de la tête et du cou de l'adulte (étude de l'expression des protéines ERCC1, HIF-1-alpha, E-cadhérine, REGF et VEGFR2)

NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

HODGKIN LYMPHOMA IN OLDER PATIENTS: AN ORPHAN DISEASE?

Hodgkin Lymphoma HL ica be  cured in the large majority of younger patients, but prognosis for older patients, especially those with advanced-stage disease, has not improved substantially. The percentage of HL patients aged over 60 ranges between 15% and 35%.A minority of them is enrolled into clinical trials. HL in the elderly have some specificities: more frequent male sex, B-symptoms, advanced stage, sub diaphragmatic presentation, higher percentage of mixed cellularity, up to 50% of advanced cases associated to EBV. Very old age (>70) and comorbidities are factor of further worsening prognosis. Like in younger patients, ABVD is the most used protocol, but treatment outcome remains much inferior with more frequent, severe and sometimes specific toxicities. Few prospective studies with specific protocols are available. The main data have been published by the Italian Lymphoma Group with the VEPEMB schedule and the German Hodgkin Study Group with the PVAG regimen. Recently, the Scotland and Newcastle Lymphoma Study Group published the SHIELD program associating a prospective phase 2 trial with VEPEMB and a prospective registration of others patients. Patients over 60y with early-stage disease received three cycles plus radiotherapy and had 81% of 3-year overall survival (OS).Those with advanced-stage disease received six cycles, with 3-year OS of 66%.The role of geriatric and comorbidity assessment in the treatment’s choice for HL in the elderly is a major challenge. The combination of loss of activities of daily living combined with the age stratification more or less 70y has been shown as a simple and effective survival model. Hopes come from promising new agents like brentuximab-vedotin (BV) a novel antibody-drug conjugate. The use of TEP to adapt the combination of chemotherapy and radiotherapy according to the metabolic response could also be way for prospective studies

HMGA2-NFIB fusion in a pediatric intramuscular lipoma: a novel case of NFIB alteration in a large deep-seated adipocytic tumor.

International audienceLipomas are frequently characterized by aberrations of the 12q13 approximately q15 chromosomal region and often by rearrangements of the HMGA2 gene. These rearrangements include the formation of chimeric genes that fuse the 5' region of HMGA2 with a variety of partners, such as LPP (3q28) or NFIB (9p22). We describe here the fourth reported case of lipoma showing a HMGA2-NFIB fusion, and the first one in a child. We found a translocation t(9;12)(p22;q14) in a deep-seated intramuscular lipoma occurring in the buttock of a 5-year-old boy. By fluorescence in situ hybridization and reverse-transcription polymerase chain reaction, we have shown that the translocation t(9;12) resulted in an in-frame fusion of the first four exons of HMGA2 with the last exon of NFIB. Intramuscular lipomas are very rare in childhood. Our results confirm that lipomas containing NFIB rearrangements may be related to peculiar clinicohistologic features, including large size, deep situation, infiltration of surrounding muscles, or precocious occurrence. Both the truncation of HMGA2 and the nature of its fusion partner gene might be relevant in the adipose tissue tumorigenesis