Exploration du rôle pronostique du ratio neutrophiles/lymphocytes sanguin et analyse du microenvironnement tumoral dans les tumeurs neuroendocrines pancréatiques bien différenciées

Médecine (oncologie médicale)Nous avons réalisé une étude rétrospective explorant le rôle pronostique du ratio neutrophiles/lymphocytes (RNL) sanguin chez les patients suivis pour des TNEp bien différenciées de grade 1 et 2. L'objectif de cette étude était de déterminer le meilleur seuil du RNL sanguin au diagnostic permettant de prédire le risque de survie globale. Nous avons ensuite analysé le microenvironnement tumoral via la déconvolution des cellules immunes à partir des données des transcriptomes de 83 tumeurs primaires de TNEp et 30 métastases hépatiques disponibles publiquement. Un RNL sanguin supérieur à 4 a été retrouvé comme un facteur indépendant de survie globale dans la cohorte (HR=2,85 lC=[1,17-6,94], P=0,02). L'élévation du RNL sanguin était associée à la présence de métastases hépatiques synchrones (p=0,05). La déconvolution des transcriptomes et I'analyse de la distribution des cellules immunes ont montré une augmentation des neutrophiles dans les métastases hépatiques en comparaison avec les tumeurs primaires (p=0,03). En outre, l'analyse des enrichissements de l'ensemble de gènes (GSEA) a révélé l'activation de la voie du complément dans ces métastases (p-0,001). Ces données peuvent suggérer l'importance de l'immunité innée dans le potentiel métastatique des TNEp.We have evaluated the best prognostic value of neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR-=4 was associated with worse overall survival, in univariate analysis (HR=3.53; lC95%=LsG 8.31; p=0.004) and in multivariate analysis, (HR=2.850,IC95%=1.170-6.94, p=0.02).The surgery had a protective role (HR=0.157 lC=0.063-0.391,p-0.001). We inferred the distribution of immune cells from transcriptome of 83 primary tumors and 30 liver metastasis. The neutrophils score was higher in metastasis versus primary tumors (p=0.005). We observed an up-regulation of complement pathway in metastasis versus primary tumors (NES=1.84, p-0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identitied two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. The earlier one characterized by neutrophils infiltration and activation of the complement pathway was highly enriched for metastatic liver samples as compared to the latter one (p-0.0001). These data suggest the possible link between metastasis, complement pathway activation and neutrophils infiltration

Exploration du rôle pronostique du ratio neutrophiles/lymphocytes sanguin et analyse du microenvironnement tumoral dans les tumeurs neuroendocrines pancréatiques bien différenciées

Médecine. Oncologie médicaleNous avons réalisé une étude rétrospective explorant le rôle pronostique du ratio neutrophiles/lymphocytes (RNL) sanguin chez les patients suivis pour des TNEp bien différenciées de grade 1 et 2. L'objectif de cette étude était de déterminer le meilleur seuil du RNL sanguin au diagnostic permettant de prédire le risque de survie globale. Nous avons ensuite analysé le microenvironnement tumoral via la déconvolution des cellules immunes à partir des données des transcriptomes de 83 tumeurs primaires de TNEp et 30 métastases hépatiques disponibles publiquement. Un RNL sanguin supérieur à 4 a été retrouvé comme un facteur indépendant de survie globale dans la cohorte (HR=2,85 lC=[1,17-6,94], P=0,02). L'élévation du RNL sanguin était associée à la présence de métastases hépatiques synchrones (p=0,05). La déconvolution des transcriptomes et I'analyse de la distribution des cellules immunes ont montré une augmentation des neutrophiles dans les métastases hépatiques en comparaison avec les tumeurs primaires (p=0,03). En outre, l'analyse des enrichissements de l'ensemble de gènes (GSEA) a révélé l'activation de la voie du complément dans ces métastases (p-0,001). Ces données peuvent suggérer l'importance de l'immunité innée dans le potentiel métastatique des TNEp.We have evaluated the best prognostic value of neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR-=4 was associated with worse overall survival, in univariate analysis (HR=3.53; lC95%=LsG 8.31; p=0.004) and in multivariate analysis, (HR=2.850,IC95%=1.170-6.94, p=0.02).The surgery had a protective role (HR=0.157 lC=0.063-0.391,p-0.001). We inferred the distribution of immune cells from transcriptome of 83 primary tumors and 30 liver metastasis. The neutrophils score was higher in metastasis versus primary tumors (p=0.005). We observed an up-regulation of complement pathway in metastasis versus primary tumors (NES=1.84, p-0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identitied two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. The earlier one characterized by neutrophils infiltration and activation of the complement pathway was highly enriched for metastatic liver samples as compared to the latter one (p-0.0001). These data suggest the possible link between metastasis, complement pathway activation and neutrophils infiltration

Exploration du rôle pronostique du ratio neutrophiles/lymphocytes sanguin et analyse du microenvironnement tumoral dans les tumeurs neuroendocrines pancréatiques bien différenciées

Médecine (oncologie médicale)Nous avons réalisé une étude rétrospective explorant le rôle pronostique du ratio neutrophiles/lymphocytes (RNL) sanguin chez les patients suivis pour des TNEp bien différenciées de grade 1 et 2. L'objectif de cette étude était de déterminer le meilleur seuil du RNL sanguin au diagnostic permettant de prédire le risque de survie globale. Nous avons ensuite analysé le microenvironnement tumoral via la déconvolution des cellules immunes à partir des données des transcriptomes de 83 tumeurs primaires de TNEp et 30 métastases hépatiques disponibles publiquement. Un RNL sanguin supérieur à 4 a été retrouvé comme un facteur indépendant de survie globale dans la cohorte (HR=2,85 lC=[1,17-6,94], P=0,02). L'élévation du RNL sanguin était associée à la présence de métastases hépatiques synchrones (p=0,05). La déconvolution des transcriptomes et I'analyse de la distribution des cellules immunes ont montré une augmentation des neutrophiles dans les métastases hépatiques en comparaison avec les tumeurs primaires (p=0,03). En outre, l'analyse des enrichissements de l'ensemble de gènes (GSEA) a révélé l'activation de la voie du complément dans ces métastases (p-0,001). Ces données peuvent suggérer l'importance de l'immunité innée dans le potentiel métastatique des TNEp.We have evaluated the best prognostic value of neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR-=4 was associated with worse overall survival, in univariate analysis (HR=3.53; lC95%=LsG 8.31; p=0.004) and in multivariate analysis, (HR=2.850,IC95%=1.170-6.94, p=0.02).The surgery had a protective role (HR=0.157 lC=0.063-0.391,p-0.001). We inferred the distribution of immune cells from transcriptome of 83 primary tumors and 30 liver metastasis. The neutrophils score was higher in metastasis versus primary tumors (p=0.005). We observed an up-regulation of complement pathway in metastasis versus primary tumors (NES=1.84, p-0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identitied two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. The earlier one characterized by neutrophils infiltration and activation of the complement pathway was highly enriched for metastatic liver samples as compared to the latter one (p-0.0001). These data suggest the possible link between metastasis, complement pathway activation and neutrophils infiltration

Sarcomatoid Dedifferentiation in Renal Cell Carcinoma: From Novel Molecular Insights to New Clinical Opportunities

Sarcomatoid features in renal cell carcinoma (RCC) have long been associated with dismal prognosis and poor response to therapy, while biological mechanisms underpinning sarcomatoid dedifferentiation remained obscure. Several efforts have been conducted to break down the molecular profile of sarcomatoid RCC and investigate different targeted therapeutic approaches. Mutations enriched for in sarcomatoid RCC involve, notably, TP53, BAP1, cell cycle, and chromatin-remodeling genes. The immunological landscape of these tumors is also gradually being uncovered, showing frequent expression of programmed cell death ligand-1 (PD-L1) and high levels of tumor-infiltrating lymphocytes. These features may be major determinants for the activity of immune checkpoint inhibitors in this population, which has been confirmed by retrospective studies and subgroup analyses of large randomized phase 3 trials. Combinations based on PD-1/PD-L1 inhibition have demonstrated response rates and complete responses in >50% and >10% of patients in the first-line metastatic setting, respectively, with median overall survival exceeding two years. This remarkable improvement in outcomes effectively establishes immune checkpoint inhibitor combinations as a new standard of care in patients with sarcomatoid RCC. New research fields, including epigenetic regulations and tumor–microenvironment interactions, may further sharpen understanding of sarcomatoid RCC and advance therapeutic developments

Immunotherapy in breast cancer: an overview of current strategies and perspectives

Abstract Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials

Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment

Antibody–drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these ‘off-target effects’, such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes. Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR−)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS)). Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR−). The proportion of HER2-enriched tumors was higher in the HER2-low/HR− group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR− and HER2-low/HR+ subtypes, compared to HER2-negative/HR− and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status. Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category

Molecular analysis for refractory rare cancers: Sequencing battle continues – learnings for the MOSCATO-01 study

International audienceBackground: For patients with metastatic rare cancers, treatments are limited. How systematic tumor sequencing can improve therapeutic possibilities in this population? Patients and methods: Patients with rare cancer were identified in the MOSCATO-01 trial. Patients’ outcome was measured by progression-free survival (PFS) and overall survival (OS). Results: The most frequently identified histologic subypes were ovarian adenocarcinoma (N = 13), carcinoma of unknown primary (N = 11), and leiomyosarcoma (N = 10). Ninety-nine (39%) of them had at least one targetable cancer molecular alteration Forty-nine patients (50%) received the therapy proposed by the molecular tumor board, and 13 patients (26%, 95%CI 15–41%) achieved a PFS2/PFS1 > 1.3. The median PFS2 on matched treatment subgroup was 2.3 months (95% CI 1.8–3.6) and the median OS was 11.4 months (95% CI 9–15.5). Conclusions: The molecular screening of patients with refractory, metastatic rare cancers might increase the therapeutic options. Facilitating access strategy to molecular-driven clinical trials or agnostic-approved treatment is crucial

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be “salvaged” through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies

Predictive Biomarkers for Response to Immunotherapy in Triple Negative Breast Cancer: Promises and Challenges

Triple negative breast cancer (TNBC) is a highly heterogeneous disease with a poor prognosis and a paucity of therapeutic options. In recent years, immunotherapy has emerged as a new treatment option for patients with TNBC. However, this therapeutic evolution is paralleled by a growing need for biomarkers which allow for a better selection of patients who are most likely to benefit from this immune checkpoint inhibitor (ICI)-based regimen. These biomarkers will not only facilitate a better optimization of treatment strategies, but they will also avoid unnecessary side effects in non-responders, and limit the increasing financial toxicity linked to the use of these agents. Huge efforts have been deployed to identify predictive biomarkers for the ICI, but until now, the fruits of this labor remained largely unsatisfactory. Among clinically validated biomarkers, only programmed death-ligand 1 protein (PD-L1) expression has been prospectively assessed in TNBC trials. In addition to this, microsatellite instability and a high tumor mutational burden are approved as tumor agnostic biomarkers, but only a small percentage of TNBC fits this category. Furthermore, TNBC should no longer be approached as a single biological entity, but rather as a complex disease with different molecular, clinicopathological, and tumor microenvironment subgroups. This review provides an overview of the validated and evolving predictive biomarkers for a response to ICI in TNBC