Circulating Tumor Cells (CTC) and pathological Complete Response (pCR) are strong independent prognostic factors in Inflammatory Breast Cancer (IBC) in a pooled analysis of two multicentre phase II trials (BEVERLY 1 & 2) of neoadjuvant chemotherapy combined with bevacizumab
Vassili Soumelis - Programme d’analyse globale et intégrative du micro-enviro...SiRIC_Curie
Programme d’analyse globale et intégrative du
micro-environnement tumoral - Vassili SOUMELIS, MD, PhD
Laboratoire d’Immunologie Clinique et Inserm U932
The OncoScan(TM) platform for analysis of copy number and somatic mutations i...Lawrence Greenfield
The OncoScan microarray offers high-quality copy number, genotype, and somatic mutation data with whole-genome coverage and high resolution in cancer genes for use with challenging FFPE samples.
The Molecular Analysis on Circulating Tumor Cells to Determine Prognostic and...QIAGEN
Circulating tumor cells (CTCs) is an emerging source used molecular cancer diagnostics. Through expression profiling of CTCs, it allows a deeper understanding about which metabolic pathways enable tumor cells to survive in the circulation, how they become resistant to a drug regimen, how they transform and adapt and, finally, which cellular markers should targeted for future therapies.
This webinar will introduce the AdnaTest CTC detection platform which has been proven in several clinical trials to provide prognostic and predictive information in breast, ovarian and prostate cancer. The platform by itself is still open for research and allows access to any potential target of interest. Join us to learn more about this novel platform, its technology and applications in liquid biopsy.
Vassili Soumelis - Programme d’analyse globale et intégrative du micro-enviro...SiRIC_Curie
Programme d’analyse globale et intégrative du
micro-environnement tumoral - Vassili SOUMELIS, MD, PhD
Laboratoire d’Immunologie Clinique et Inserm U932
The OncoScan(TM) platform for analysis of copy number and somatic mutations i...Lawrence Greenfield
The OncoScan microarray offers high-quality copy number, genotype, and somatic mutation data with whole-genome coverage and high resolution in cancer genes for use with challenging FFPE samples.
The Molecular Analysis on Circulating Tumor Cells to Determine Prognostic and...QIAGEN
Circulating tumor cells (CTCs) is an emerging source used molecular cancer diagnostics. Through expression profiling of CTCs, it allows a deeper understanding about which metabolic pathways enable tumor cells to survive in the circulation, how they become resistant to a drug regimen, how they transform and adapt and, finally, which cellular markers should targeted for future therapies.
This webinar will introduce the AdnaTest CTC detection platform which has been proven in several clinical trials to provide prognostic and predictive information in breast, ovarian and prostate cancer. The platform by itself is still open for research and allows access to any potential target of interest. Join us to learn more about this novel platform, its technology and applications in liquid biopsy.
The Presence and Persistence of Resistant and Stem Cell-Like Tumor Cells as a...QIAGEN
Epithelial ovarian cancer is the fifth leading cause of cancer-related deaths of women in the United States and Europe and ranks as the second most common type of gynecological malignancy. Most cases are diagnosed in advanced stages and although the response rates to platinum-based chemotherapy are high, the majority of patients nevertheless have poor survival rates. Although the reasons for these poor outcomes are likely to be multifactorial, one particular area of interest has recently focused on hematogenous tumor cell dissemination that has been shown to originate from disseminated tumor cells (DTCs) in the bone marrow (BM) and circulating tumor cells (CTCs) in the blood. Here, we demonstrate that the negative prognostic impact of CTCs and DTCs arise from specific cellular phenotypes and are associated with platinum-resistance and stem cell-associated proteins.
Liquid Biopsy Overview, Challenges and New Solutions: Liquid Biopsy Series Pa...QIAGEN
A liquid biopsy is often described as a sensitive and specific blood test to detect circulating tumor cells (CTCs). CTCs, shed by both the primary and metastasized tumors, carry specific information about their origins and markers that will enable us to discover new diagnosis, prognosis and therapeutic targets. This slidedeck gives an overview of the recent progress in exploring the predictive potential of circulating biomarkers, including circulating tumor cells, circulating tumor DNA, microRNAs, long non-coding RNAs (lncRNAs) and exosomes. Addressing both biological and technical aspects, we detail the isolation and characterization of circulating biomarkers. Challenges and solutions are also featured.
CTC Detection and Molecular Characterization – Challenges and SolutionsQIAGEN
Circulating Tumor Cells (CTCs) have been extensively explored as circulating biomarkers in various cancers. Due to their rarity, heterogeneity and stem cell-like properties, detecting and profiling CTCs from blood samples is very challenging. In this webinar, Dr. Siegfried Hauch will introduce the well-known AdnaTests, which uses the Combination of Combinations Principle (COCP) to enable enriching and detecting CTCs in whole blood with high specificity and sensitivity, and how to overcome challenges in CTC enrichment and detection. The AdnaTests combine an immunomagnetic capturing method that increases purity, and is followed by molecular profiling of the captured CTCs. In addition, leukocyte contamination is another issue in CTCs detection and may lead to false positive results due to illegitimate expression of target genes or false interpretation. The AdnaWash is developed to reduce leukocyte contamination to such a level that whole gene panels can be analyzed while maintaining the required specificity and sensitivity.
Sequencing 60,000 Samples: An Innovative Large Cohort Study for Breast Cancer...QIAGEN
This slidedeck focuses on the design of a large cohort study for assessing breast cancer risk and how an innovative digital sequencing approach is able to solve the previously unmet challenges of this type of NGS study design. Our speaker, Dr. Fergus J. Couch of the Mayo Clinic, presents on the design of this NCI-funded project, which comprises the sequencing of 60,000 samples to assess the risk of breast cancer through association with targeted genes. The design and size of the study requires an accurate, robust and high-throughput sequencing method. The investigators are using a digital DNA sequencing approach from QIAGEN that incorporates molecular barcodes to tag and remove PCR duplicates and increase NGS assay sensitivity. The approach also uses proprietary chemistry that enables uniform sequencing to efficiently utilize sequencing power and deliver optimized results.
Manuel Salto-Tellez on Personalised medicine and the future of tissue pathologyCirdan
Personalised / Precision Medicine has revolutionized cancer treatment and, in parallel, is also deeply transforming the way we practice tissue pathology. The aim of this talk is to briefly review the status of molecular diagnostic tests applicable to tissues and cells, as well as the main technical and conceptual areas that, in my opinion, will be dictating the evolution of tissue pathology and its integration with the molecular era. These areas are, among others – a) digital pathology in the pipeline of therapeutic pathology; b) tissue-based NGS and its integration in routine diagnostics; c) the promise of liquid biopsy diagnostics and its necessary “partnership” with tissue molecular testing; d) Pathology IT, databases and bioinformatics; and e) the training of future tissue pathologists. In the process of this review, it may be apparent that a solid, integrated, morpho-molecular approach to pathology may serve our patients better.
Clinical Genomics for Personalized Cancer Medicine: Recent Advances, Challeng...Yoon Sup Choi
I reviewed recent advances, challenges, and opportunities to implement clinical cancer genomics. Case studies of advanced systems, such as Foundation Medicine, MI-ONCOSEQ are introduced for benchmark. A few fundamental limitations to establish personalized oncology are also discussed.
Kshivets O. Esophageal and Cardioesophageal Cancer SurgeryOleg Kshivets
5-YEAR SURVIVAL OF ESOPHAGEAL AND CARDIOESOPHAGEAL CANCER PATIENTS AFTER RADICAL SURGERY SIGNIFICANTLY DEPENDED ON PHASE TRANSITION “EARLY-INVASIVE CANCER”, LYMPH NODE METASTASES AND CELL RATIO FACTORS
Circulating cell free DNA is a potential tumor marker in a non-invasive blood test for the treatment and evaluation of cancer and recurrence monitoring. As circulating tumor DNA is often present at low frequencies within circulating cell free DNA, targeted sequencing on the Ion Torrent™ platform is an optimal tool or mutation detection with very little sample input required. Here, we demonstrate a complete workflow from isolation through molecular characterization of circulating tumor DNA. We have optimized a protocol using magnetic beads to isolate circulating cell free DNA. This protocol is easily automated to process up to 192 samples a day. It is also easily scalable for any input volume and can elute in volumes down to 15 μL resulting in no loss of low frequency alleles. We demonstrate comparable performance between this bead based isolation and column based isolation. We have completed molecular characterization of circulating cell free DNA using the multiplexing capabilities of AmpliSeq™ and the Ion PGM™. With the Ion AmpliSeq™ Cancer Hotspot Panel v2, we performed targeted sequencing of 50 genes of interest, covering 2800 COSMIC mutations. We demonstrate good reproducibility of amplicon representation as well as allelic frequencies. Through saturation studies and subsampling, we have determined the limit of detection of hotspots circulating cell free DNA on the Ion PGM™ to be below 1%. We further demonstrate proof of principle of this workflow on circulating cell free DNA and matched FFPE samples. Our results verify the accuracy and ease of our workflow. This protocol, from isolation through targeted sequencing, will not only result in a simple sample preparation for circulating cell free DNA but also facilitate rapid mutation detection to advance cancer research.
Types of immunotherapy
Oncology
cancer vaccines
adoptive T cell transfer
oncolytic viruses
monoclonal antibodies
cytokine
treatment of cancer with immunotherapy
The Presence and Persistence of Resistant and Stem Cell-Like Tumor Cells as a...QIAGEN
Epithelial ovarian cancer is the fifth leading cause of cancer-related deaths of women in the United States and Europe and ranks as the second most common type of gynecological malignancy. Most cases are diagnosed in advanced stages and although the response rates to platinum-based chemotherapy are high, the majority of patients nevertheless have poor survival rates. Although the reasons for these poor outcomes are likely to be multifactorial, one particular area of interest has recently focused on hematogenous tumor cell dissemination that has been shown to originate from disseminated tumor cells (DTCs) in the bone marrow (BM) and circulating tumor cells (CTCs) in the blood. Here, we demonstrate that the negative prognostic impact of CTCs and DTCs arise from specific cellular phenotypes and are associated with platinum-resistance and stem cell-associated proteins.
Liquid Biopsy Overview, Challenges and New Solutions: Liquid Biopsy Series Pa...QIAGEN
A liquid biopsy is often described as a sensitive and specific blood test to detect circulating tumor cells (CTCs). CTCs, shed by both the primary and metastasized tumors, carry specific information about their origins and markers that will enable us to discover new diagnosis, prognosis and therapeutic targets. This slidedeck gives an overview of the recent progress in exploring the predictive potential of circulating biomarkers, including circulating tumor cells, circulating tumor DNA, microRNAs, long non-coding RNAs (lncRNAs) and exosomes. Addressing both biological and technical aspects, we detail the isolation and characterization of circulating biomarkers. Challenges and solutions are also featured.
CTC Detection and Molecular Characterization – Challenges and SolutionsQIAGEN
Circulating Tumor Cells (CTCs) have been extensively explored as circulating biomarkers in various cancers. Due to their rarity, heterogeneity and stem cell-like properties, detecting and profiling CTCs from blood samples is very challenging. In this webinar, Dr. Siegfried Hauch will introduce the well-known AdnaTests, which uses the Combination of Combinations Principle (COCP) to enable enriching and detecting CTCs in whole blood with high specificity and sensitivity, and how to overcome challenges in CTC enrichment and detection. The AdnaTests combine an immunomagnetic capturing method that increases purity, and is followed by molecular profiling of the captured CTCs. In addition, leukocyte contamination is another issue in CTCs detection and may lead to false positive results due to illegitimate expression of target genes or false interpretation. The AdnaWash is developed to reduce leukocyte contamination to such a level that whole gene panels can be analyzed while maintaining the required specificity and sensitivity.
Sequencing 60,000 Samples: An Innovative Large Cohort Study for Breast Cancer...QIAGEN
This slidedeck focuses on the design of a large cohort study for assessing breast cancer risk and how an innovative digital sequencing approach is able to solve the previously unmet challenges of this type of NGS study design. Our speaker, Dr. Fergus J. Couch of the Mayo Clinic, presents on the design of this NCI-funded project, which comprises the sequencing of 60,000 samples to assess the risk of breast cancer through association with targeted genes. The design and size of the study requires an accurate, robust and high-throughput sequencing method. The investigators are using a digital DNA sequencing approach from QIAGEN that incorporates molecular barcodes to tag and remove PCR duplicates and increase NGS assay sensitivity. The approach also uses proprietary chemistry that enables uniform sequencing to efficiently utilize sequencing power and deliver optimized results.
Manuel Salto-Tellez on Personalised medicine and the future of tissue pathologyCirdan
Personalised / Precision Medicine has revolutionized cancer treatment and, in parallel, is also deeply transforming the way we practice tissue pathology. The aim of this talk is to briefly review the status of molecular diagnostic tests applicable to tissues and cells, as well as the main technical and conceptual areas that, in my opinion, will be dictating the evolution of tissue pathology and its integration with the molecular era. These areas are, among others – a) digital pathology in the pipeline of therapeutic pathology; b) tissue-based NGS and its integration in routine diagnostics; c) the promise of liquid biopsy diagnostics and its necessary “partnership” with tissue molecular testing; d) Pathology IT, databases and bioinformatics; and e) the training of future tissue pathologists. In the process of this review, it may be apparent that a solid, integrated, morpho-molecular approach to pathology may serve our patients better.
Clinical Genomics for Personalized Cancer Medicine: Recent Advances, Challeng...Yoon Sup Choi
I reviewed recent advances, challenges, and opportunities to implement clinical cancer genomics. Case studies of advanced systems, such as Foundation Medicine, MI-ONCOSEQ are introduced for benchmark. A few fundamental limitations to establish personalized oncology are also discussed.
Kshivets O. Esophageal and Cardioesophageal Cancer SurgeryOleg Kshivets
5-YEAR SURVIVAL OF ESOPHAGEAL AND CARDIOESOPHAGEAL CANCER PATIENTS AFTER RADICAL SURGERY SIGNIFICANTLY DEPENDED ON PHASE TRANSITION “EARLY-INVASIVE CANCER”, LYMPH NODE METASTASES AND CELL RATIO FACTORS
Circulating cell free DNA is a potential tumor marker in a non-invasive blood test for the treatment and evaluation of cancer and recurrence monitoring. As circulating tumor DNA is often present at low frequencies within circulating cell free DNA, targeted sequencing on the Ion Torrent™ platform is an optimal tool or mutation detection with very little sample input required. Here, we demonstrate a complete workflow from isolation through molecular characterization of circulating tumor DNA. We have optimized a protocol using magnetic beads to isolate circulating cell free DNA. This protocol is easily automated to process up to 192 samples a day. It is also easily scalable for any input volume and can elute in volumes down to 15 μL resulting in no loss of low frequency alleles. We demonstrate comparable performance between this bead based isolation and column based isolation. We have completed molecular characterization of circulating cell free DNA using the multiplexing capabilities of AmpliSeq™ and the Ion PGM™. With the Ion AmpliSeq™ Cancer Hotspot Panel v2, we performed targeted sequencing of 50 genes of interest, covering 2800 COSMIC mutations. We demonstrate good reproducibility of amplicon representation as well as allelic frequencies. Through saturation studies and subsampling, we have determined the limit of detection of hotspots circulating cell free DNA on the Ion PGM™ to be below 1%. We further demonstrate proof of principle of this workflow on circulating cell free DNA and matched FFPE samples. Our results verify the accuracy and ease of our workflow. This protocol, from isolation through targeted sequencing, will not only result in a simple sample preparation for circulating cell free DNA but also facilitate rapid mutation detection to advance cancer research.
Types of immunotherapy
Oncology
cancer vaccines
adoptive T cell transfer
oncolytic viruses
monoclonal antibodies
cytokine
treatment of cancer with immunotherapy
Clinical Experiences of CK/HT in Hepatocellular Carcinomaaccurayexchange
Chul-Seung Kay1,3 , Seok-Hyun Son1, Myung-Soo Kim1, Jung-Hyun Kwon2
Department of Radiation Oncology1 & 2Internal Medicine2
3Catholic Comprehensive Hospital for Advanced Cancer3
Incheon St. Mary Hospital
The Catholic University of Korea
Current controversies in cervical cancer management (2014)Jyotirup Goswami
Overview of the current controversies in the management of cervical cancer, including screening, prevention, staging, chemoradiation,teletherapy techniques, brachytherapy techniques
Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
DERIVATION OF MODIFIED BERNOULLI EQUATION WITH VISCOUS EFFECTS AND TERMINAL V...Wasswaderrick3
In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Salas, V. (2024) "John of St. Thomas (Poinsot) on the Science of Sacred Theol...Studia Poinsotiana
I Introduction
II Subalternation and Theology
III Theology and Dogmatic Declarations
IV The Mixed Principles of Theology
V Virtual Revelation: The Unity of Theology
VI Theology as a Natural Science
VII Theology’s Certitude
VIII Conclusion
Notes
Bibliography
All the contents are fully attributable to the author, Doctor Victor Salas. Should you wish to get this text republished, get in touch with the author or the editorial committee of the Studia Poinsotiana. Insofar as possible, we will be happy to broker your contact.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
1. Circulating Tumor Cells (CTC)
and pathological Complete Response (pCR)
are strong independent prognostic factors
in Inflammatory Breast Cancer (IBC)
in a pooled analysis of two multicentre phase II trials
(BEVERLY 1 & 2)
of neoadjuvant chemotherapy combined with bevacizumab
Jean-Yves Pierga, François-Clément Bidard, Aurélie Autret, Thierry Petit, Fabrice André, Florence
Dalenc, Christelle Levy, Jean-Marc Ferrero, Gilles Romieu, Jacques Bonneterre, Florence
Lerebours, Thomas Bachelot, Pierre Kerbrat, Emmanuelle Charafe-Jaufret, Jérôme Lemonnier,
Patrice Viens
Institut Curie, Paris and Université Paris Descartes; Institut Paoli Calmettes, Marseille,Paul Strauss Cancer Center and
University of Strasbourg; Gustave Roussy, Villejuif, Institut Claudius Regaud, Toulouse, Centre François Baclesse, Caen,
Centre Antoine Lacassagne, Nice, Institut du Cancer de Montpellier, Montpellier; Centre Oscar Lambret, Lille,
Centre Léon Bérard, Lyon, Centre Eugene Marquis, Rennes; R&D UNICANCER, Paris, Institut Paoli Calmettes, Marseille,
France
2. Introduction
• Inflammatory breast cancer (IBC) is a highly aggressive form of locally
advanced breast cancer
– Representing up to 5% of breast cancers1
– Characterized by high vascularity and increased microvessel
density
• The 5-year survival is # 40% 1,2
• Bevacizumab, targeting VEGF, significantly improves progression-free
survival and response rate in patients with advanced breast cancer but
not overall survival3
• In neoadjuvant setting of non-IBC, bevacizumab increases tumor
response rate4,5
1. Dawood S. Expert Rev Anticancer Ther 2010. 2. Cristofanilli M, et al. Cancer 2007 3. Miles D. Ann Oncol 2013 4. Bear HD NEJM 2012 5. von Minckwitz G NEJM 2012
4. • CTC count is an independent prognostic factor in early breast cancer1–3
- In the REMAGUS 02 study in patients receiving neoadjuvant chemotherapy,
20–25% of patients had ≥1 CTC/7.5 mL3
- A similar rate (22%) was reported in the GeparQuattro trial4
- Higher incidence of 35% to 54% of CTC has been reported in non metastatic
IBC 5,6.
- We have recently reported that CTC detection is an independent prognostic factor
in 52 primary HER2+ IBC7
• The potential of Circulating Endothelial Cells (CEC) to predict the efficacy of
anti-angiogenic therapy remains debated
1. Rack BK, et al. JNCI 2014 . 2. Bidard FC, et al. Ann Oncol 2010;21:729–33. 3. Pierga JY, et al. Clin Cancer Res 2008;14:7004–10. 4. Riethdorf S, et al. Clin
Cancer Res 2010;16:2634–45. 5. Pierga, Lancet Oncol 2012. 6. Mego M Breast Cancer Res. 2015;17(1):2.7. Pierga J.Y Clin Cancer Res 2015;
Introduction
5. • The BEVERLY 1 & 2 studies were evaluating bevacizumab in combination
with chemotherapy in neoadjuvant setting in patients with HER2-negative and
HER2-positive IBC (T4d), respectively.
BEVERLY 2 HER2-positive IBC
BEVERLY 1 HER2-negative IBC
• An ancillary study was evaluating circulating tumor cells (CTCs) and circulating
endothelial cells (CECs) as candidate biomarkers
• We present a pooled analysis of these two prospective trials.
Introduction
8. Methods
• CTC and CEC were detected in 7.5 ml and 4 ml of blood respectively
• CellSearch® system
– CTC detection : EpCAM+ immunoselection
followed by cytokeratin, CD45 and HER2 staining
– CEC detection : CD146+ immunoselection
followed by CD105 and CD34 staining
9. HER2 Cytokeratin
Example of CTC detection
• HER2 CTC staining and correlation with primary tumor status in BEVERLY
studies has been performed
10. Objectives
• To describe CTC and CEC counts at baseline and during treatment
• To correlate CTC and CEC counts with pathological response.
• To evaluate the prognostic value of CTC and CEC counts and changes
on disease-free survival (DFS), recurrence-free survival (RFS), and
overall survival (OS)
Endpoints:
- CTC and CEC counts at the five specified timepoints
- Pathological response rate (Sataloff TA, NA/NB)
- DFS, RFS, and OS at 3 years (current analysis) and 5 years
11. Patients characteristics (n=152 patients, all T4d M0)
Value
Median age, years (range)
ECOG performance status, N (%)
0
1
Lymph node involvement, N (%)
N0
N1
N2
N3
Histology: no special type (ductal)
Tumor grade, N (%)
I
II
III
Receptors, N(%)
ER positive
HER2 positive
Triple negative subtype
49 [21-75]
135 (93%)
10 (7%)
40 (26%)
78 (51%)
17 (11%)
9 (6%)
140 (93%)
4 (3%)
53 (35%)
87 (57%)
61 (40%)
52 (34%)
55 (36%)
12. Results: Baseline CTC and CEC counts
• From October 2008 to September 2010, 152 patients were included
• 137 were evaluable for both CTC and CEC at baseline
• At baseline, 55 patients had ≥ 1 detectable CTC (39%)
– Median CTC count for positive cases was 4, range [1-559]
• CECs were detected in all patients except one
• Median CEC count was 15, range [0-696]
• No correlation was observed between baseline CTC and CEC counts
13. Changes in CTC count during neoadjuvant therapy
CTCs /7.5 mL
-20
0
20
40
60
80
100
120
140
160
NumberofCTC
CTC before C1 CTC before C5 CTC before surg CTC after surg
After 4 cycles of chemotherapy, a
dramatic drop of CTC to a rate of
9% was observed (p<0.0001) .
14. Changes in CEC count during therapy
CEC/4 ml
1
10
100
1000
10000
NumberofCEC(log)
CEC before C1 CEC before C5 CEC before surg CEC after surgery CEC at 1 year
p<0.001
Significant
increase during
docetaxel +
bevacizumab
Surgery
15. Correlation for HER2 status between CTC and primary tumor
Each case with HER2 discrepancy had a low CTC count ( < 5 CTC/7.5ml) and/or less than 25% of discordant CTC
1. Ligthart & Bidard, et al. Ann Oncol 2013
HER2
negative
primary
HER2
positive
primary
16. Results: correlation with pCR
• pCR rate was 40% (95% CI 31-48% ) after central review (Sataloff TA, NA/NB)
• At multivariate analysis higher pCR rates was associated with
– Hormone Receptors negative status HR=3.36 [1.33, 8.49] p=0.01
– HER2 positive status HR=6.90 [2.83, 16.7] p<0.0001
– cN0 status at baseline HR=2.77 [1.09, 7.02] p=0.03
• No correlation between pCR and CTC or CEC levels and changes
17. Results: Univariate analysis for survival
• Median follow-up was 43 months.
Disease-Free Survival Overall Survival
p (log rank) HR [95%CI] p (log rank) HR [95%CI]
Age : > 50 years 0.11 0.7 [0.4-1.1] 0.62 0.9 [0.4-1.6]
cN status : cN1, N2, N3 0.02 2.2 [1.1-4.2] 0.03 2.7 [1.1-6.9]
Tumor grade: III 0.90 1.0 [0.6-1.7] 0.37 1.3 [0.7-2.6]
Hormone R. Status: no expression 0.003 2.2 [1.2-3.7] <0.001 3.3 [1.5-6.6]
HER2 status: positive 0.35 1.3 [0.7-2.3] 0.51 1.3 [0.6-2.8]
Triple Negative 0.11 1.5 [0.9-2.4] 0.02 2.1 [1.1-3.8]
pCR (central review): No <0.001 3.3 [1.6-6.5] 0.009 3.7 [1.3-10]
CTC at inclusion: ≥1CTC <0.001 2.8 [1.6-4.7] <0.001 4.3 [2.1-8.7]
CEC at inclusion: <20CEC 0.13 1.5 [0.9-2.7] 0.1 1.8 [0.9-3.6]
18. Disease Free Survival (ITT)
CTC=0 at C1 n=54
CTC ≥ 1 at C1 n=55
CTC=0 at C1 n=85
HR=2.80, 95%CI[1.65-4.76]
3-year DFS: 70% vs. 39%
20. Multivariate analysis for Disease-Free Survival (ITT)
p (Cox model) HR [95%CI]
cN status : cN1, N2, N3 0.09 2.1 [0.9-4.9]
Triple Negative 0.01 2.5 [1.2-5.3]
pCR (central review): No 0.003 3.2 [1.5-6.8]
CTC at inclusion: ≥1CTC 0.004 2.6 [1.4-4.8]
21. Multivariate analysis for Overall Survival (ITT)
p (Cox model) HR [95%CI]
cN status : cN1, N2, N3 0.12 2.7 [0.8-10]
Triple Negative 0.04 2.9 [1.1-7.9]
pCR (central review): No 0.03 3.3 [1.1-9.7]
CTC at inclusion: ≥1CTC 0.008 3.1 [1.3-7.2]
22. Early dissemination and tumor response
• pCR reflects tumor sensitivity to treatment and is correlated with
improved overall survival 1
• However not all patients with pCR are cured
• CTCs reflect early tumoral dissemination
• Could CTC detection identify pCR patients still at risk of relapse?
1Cortazar P et al, Lancet 2014
23. Disease-Free Survival (ITT)
According to CTC at baseline & pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,
133 had centrally reviewed pCR
137 evaluable for CTC
24. Disease-Free Survival (ITT)
According to CTC at baseline & pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,
133 had centrally reviewed pCR
137 evaluable for CTC
3-year DFS (87%)
3-year DFS (30%)
25. Overall survival (ITT)
According to CTC at baseline and pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,
133 had centrally reviewed pCR
26. Overall survival (ITT)
According to CTC at baseline and pCR
N=125*
pCR yes /CTC=0 at C1 n=35
pCR yes /CTC≥ 1 at C1 n=15
pCR no /CTC=0 at C1 n=46
pCR no/CTC ≥ 1 at C1 n=29
*143 patients had surgery,
133 had centrally reviewed pCR
3-year OS (93%)
3-year OS (53%)
27. Conclusions
• This is the largest prospective study evaluating CTC with a standardized
method in non-metastatic IBC.
• We observed a high CTC detection rate of 39% at baseline, with a strong
and independent prognostic value for DFS and OS.
• Combination of pCR after neoadjuvant treatment, with CTC at baseline,
isolates a subgroup of IBC (25%) with excellent survival.
• CTC count should be part of IBC stratification in prospective trials.
28. Perspectives
• Proposal of post-neoadjuvant immune-therapy in patients
with absence of pCR and/or presence of CTC at baseline
IMENEO expected data, as of June 2015
• An International MEta-analysis on individual
data in non-metastatic breast cancer (IBC and
non-IBC) treated by NEOadjuvant therapy has
been initiated (IMENEO study)
29. Acknowledgments
Patient
Beverly1 Sponsored by UNICANCER
Beverly2 Sponsored by Roche
With the financial support of
The Ligue Nationale Contre le Cancer
Roche
Chugai Pharma
Technical support
Circulating Tumor Biomarker lab,
SIRIC, Institut Curie
21 French participating centers
Gustave Roussy, Villejuif, France
Centre Paul Strauss, Strasbourg, France
Institut Claudius Regaud, Toulouse, France
Institut Curie, Paris, France
Centre François Baclesse, Caen, France
Centre Val d'Aurelle, Montpellier, France
Centre Oscar Lambret, Lille, France
Centre Antoine Lacassagne, Nice, France
Centre Eugene Marquis, Rennes, France
Centre Jean Perrin, Clermont Ferrand, France
Centre Léon Bérard, Lyon, France
Centre Paul Papin Center, Angers, France
Institut Curie, Saint Cloud, France
Institut Jean Godinot, Reims, France
Centre Alexis Vautrin, Nancy, France
Centre Catherine de Sienne, Nantes, France
Clinique Armoricaine, Saint Brieuc, France
Institut de Cancérologie de l’Ouest, Nantes, France
Hôpital Civil, Strasbourg, France
Institut Bergonié, Bordeaux, France
Institut Paoli Calmettes, Marseille, France
Editor's Notes
in the neoadjuvant setting in IBC pts enrolled in two phase II multicentre trials, evaluating bevacizumab (15mg/kg q3w) in combination with sequential neoadjuvant chemotherapy of 4 cycles of FEC followed by 4 cycles of Docetaxel in HER2 - tumor (BEVERLY 1) or Docetaxel, trastuzumab in HER2 + (BEVERLY 2).
in the neoadjuvant setting in IBC pts enrolled in two phase II multicentre trials, evaluating bevacizumab (15mg/kg q3w) in combination with sequential neoadjuvant chemotherapy of 4 cycles of FEC followed by 4 cycles of Docetaxel in HER2 - tumor (BEVERLY 1) or Docetaxel, trastuzumab in HER2 + (BEVERLY 2).