The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5\u2009ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with 65 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P\u2009<\u20090.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p\u2009<\u20090.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P\u2009<\u20090.0001), HER2-positive (36.7 months vs. 20.4 months, P\u2009<\u20090.0001), and triple negative (23.8 months vs. 9.0 months, P\u2009<\u20090.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Study of biomarkers of response to systemic treatments and identification of new therapeutic targets in bladder and ureter cancers

Le cancer de vessie est responsable de 212 536 décès en 2020 dans le monde. Il est constitué de tumeurs n’infiltrant pas le muscle (TVNIM, à risque de récidives locales), et infiltrant le muscle (TVIM, à risque de disséminations métastatiques et de décès). 95% sont des cancers urothéliaux alors que 5% sont des cancers épidermoïdes. Au niveau moléculaire, ces tumeurs sont caractérisées principalement par des tumeurs luminales (incluant des Luminales-papillaires) ou basales (Ba/Sq). Le traitement en 2022 est principalement basé, pour les stades avancés, sur la chimiothérapie (incluant les anticorps drogues conjugués), l’immunothérapie par inhibiteur de point de contrôle immunitaire (IPI, anticorps anti-PD-1/L1) et les inhibiteurs de FGFR en cas d’altérations génomiques FGFR2/3. Ces traitements ont néanmoins une efficacité modérée.Les objectifs de cette thèse étaient dans les TVIM de rechercher des biomarqueurs de sensibilité ou de résistance aux traitements ainsi que de rechercher de nouvelles pistes thérapeutiques.Concernant la recherche de biomarqueurs de réponse ou de résistance dans les TVIM nous avons pu montrer que :- les structures lymphoïdes tertiaires, mesurées par l’expression du gène CXCL13, sont un biomarqueur prédictif majeur de réponse aux anticorps anti-PD-L1, et sont enrichies dans le type Ba/Sq, (étude réalisée via l’analyse de cohortes publiques comme IMVIGOR210) ;- les cellules plasmatiques semblent également un biomarqueur de réponse aux IPI dans les TVIM métastatiques (conclusion basée sur des résultats préliminaires des données de séquençage de noyaux uniques de la cohorte MATCH-R avant et pendant le traitement par IPI) ;- une combinaison thérapeutique par anti-FGFR (erdafitinib) + anti-EGFR (erlotinib) est efficace dans des PDXs (patient-derived xenografts) mutés pour FGFR3, cette efficacité étant probablement due à une surexpression d’ERBB2-3 et d’EGFR sous inhibiteur de FGFR ;- les tumeurs sarcomatoïdes présentaient une expression/activité plus faible d’EGFR et un switch vers FGFR1, responsable d’une moindre réponse à un inhibiteur d’EGFR par rapport aux autres TVIM Ba/Sq ;Nous avons pu identifier de nouvelles pistes thérapeutiques dans les lignées cellulaires de cancers urothéliaux :- RARy, partenaire de RXRα, cible identifiée dans la base publique de criblage par CRISPR-Cas9 de lignées cellulaires (DepMap). RARy est activé dans les TVIM en particulier dans les sous-types Ba/Sq et Luminales-papillaires, et son inhibition semble intéressante en particulier dans le sous type Ba/Sq.- Le birinapant (XIAP/cIAP1/2 inhibiteur, Smac-mimétique) qui est efficace dans certaines lignées de cancer de vessie selon les données de DepMap. L’efficacité du birinapant a été confirmée in vitro et in vivo au laboratoire dans les lignées UMUC14 et SCaBER, avec comme biomarqueur de sensibilité potentiel l’amplification de BIRC2 ou la surexpression de RIPK1.- FGFR1 qui est une nouvelle piste thérapeutique dans les cancers de vessie de type sarcomatoïde.Bladder cancer is responsible for 212,536 deaths worldwide in 2020. It includes tumors that do not infiltrate the muscle (NMIBC, at risk of local recurrence), and tumors that infiltrate the muscle (MIBC, at risk of metastatic dissemination and death). 95% are urothelial cancers while 5% are squamous cell cancers. At the molecular level, these tumors are characterized mainly by luminal (including luminal-papillary) or basal (Ba/Sq) tumors. Treatment in 2022 is mainly based for advanced stages on chemotherapy (including antibody-drug conjugates), immune checkpoint inhibitor (ICI, anti-PD-1/L1 antibodies) and FGFR inhibitors in case of FGFR2/3 genomic alterations. However, these treatments have a moderate efficacy.The objectives of this thesis were to search for biomarkers of sensitivity or resistance to these treatments and to look for new therapeutic approaches.Concerning the search for biomarkers of response or resistance in MIBC, we were able to show that :- tertiary lymphoid structures, measured by the expression of the CXCL13 gene, are a major predictive biomarker of response to anti-PD-L1 antibodies, and are enriched in the Ba/Sq type, (analysis of public cohorts such as IMVIGOR210);- plasma cells also appear to be a biomarker of response to ICI in metastatic MIBC (conclusion based on preliminary results of single nuclei sequencing data from the MATCH-R cohort before and during ICI treatment);- combination therapy with anti-FGFR (erdafitinib) + anti-EGFR (erlotinib) is effective in FGFR3-mutated PDXs (patient-derived xenografts), probably due to overexpression of ERBB2-3 and EGFR under FGFR inhibitor;- sarcomatoid tumors showed lower EGFR expression/activity and a switch to FGFR1, responsible for a lower response to an EGFR inhibitor compared to other Ba/Sq MIBC.We were able to identify new therapeutic approaches in urothelial cancer cell lines:- RARy, a partner of RXRα, a target identified in the public CRISPR-Cas9 screening cell line database (DepMap). RARy is activated in MIBC particularly in the Ba/Sq and Luminal-papillary subtypes, and its inhibition appears to be of interest particularly in the Ba/Sq subtype.- Birinapant (XIAP/cIAP1/2 inhibitor, Smac-mimetic) which is effective in some urinary cancer lines according to DepMap data. The efficacy of birinapant has been confirmed in vitro and in vivo in UMUC14 and SCaBER cell lines, with BIRC2 amplification or RIPK1 overexpression as potential biomarkers of sensitivity.- FGFR1 which is a new therapeutic lead in sarcomatoid bladder cancer

Neoadjuvant Endocrine Therapy in Breast Cancer Management: State of the Art

Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long time, neoadjuvant endocrine therapy (NET) was confined to frail patients in order to improve surgery outcome. Since the 2000s, NET now plays a central role as a research tool for predictive endocrine sensitivity biomarkers and targeted therapies. One of the major issues in early HR+/HER2- breast cancer is to identify patients in whom chemotherapy can be safely withheld. In vivo assessment of response to NET might be the best treatment strategy to address this issue

Invasive Lobular Carcinoma of the Breast: Toward Tailoring Therapy?

International audienc

Present and Future Research on Anal Squamous Cell Carcinoma

Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients

Long-term complete remission with ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients

Abstract Background Prostate cancer is one of the most common cancers in men and the fourth leading cause of cancer mortality worldwide. Although major progress has been achieved in the last years for patients with metastatic castrate-resistant prostate cancer (mCRPC), thanks to next-generation androgen receptor axis targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been widely approved and used for the treatment of prostate cancer. Two large studies with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095). Case presentation Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab. Immunohistochemical staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate biopsy samples from one of the two patients; they exhibited normal protein expression. Interestingly for this patient, a high CD3+ and CD8+ T cell infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T cells. Conclusion Ipilimumab produces clinical activity in patients with CRPC, including very long responders with no detectable residual disease

18F]FDG PET/CT Imaging for Predicting Outcomes in Breast Cance

International audienceBackground: [18F]FDG PET/CT is used for staging and could also provide information associated with clinical outcomes. The objective of this study was to determine the clinical utility of biomarkers measured using [18F]FDG PET/CT to predict the absence of pathological complete response (no-pCR) and recurrence. Methods: In this retrospective study, we included patients with non-special-type breast carcinoma who underwent [18F]FDG PET/CT before neoadjuvant chemotherapy between 2011 and 2019. Clinicopathological data were collected. Tumor SUVmax and total metabolic tumor volume (TMTV) were measured from PET images. The association between biomarkers and no-pCR was studied using logistic regression. The cut-off value was determined using the area under the ROC Curve. To predict 3-year recurrence-free survival (RFS), we used a multivariable Cox model, and the cut-off value was determined using time-dependent ROC and predictiveness curves. Results: Two hundred and eighty-six patients were included in the analysis. One hundred and twelve patients had a pCR (39.2%). The pCR rate was significantly higher in patients with a high nuclear grade (p 9.0 cm3) was significantly associated with no-pCR in the whole cohort (OR = 2.4, 95% CI: 1.3–4.2, p 13.5 cm3) was associated with shorter RFS (HR = 4.0, 95% CI: 1.9–8.4, p < 0.01). Conclusion: High TMTV in pre-therapeutic imaging is associated with no-pCR and recurrence. It can help in identifying high-risk patients and be considered as an intensified or alternative adjuvant therapy for closely monitoring patients

High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies

International audienceBackground: Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool.Methods: We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy.Results: The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response.Conclusions: This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses