The prognostic role of circulating tumor cells (CTCs) has been clearly demonstrated in many types of cancer. However, their roles in diagnostic and treatment strategies remain to be defined. In this ...review, we present an overview of the current clinical validity of CTCs in nonmetastatic and metastatic cancer, and the main studies or concepts investigating the clinical utility of CTCs. In particular, we focus on breast, lung, colorectal, and prostate cancer. Two major topics concerning the clinical utility of CTC are discussed: treatment based on CTC count or CTC variations, and treatment based on the molecular characteristics of CTCs. Although some of these studies are inconclusive, many are still ongoing, and their results could help to define the role of CTCs in the management of cancers. A summary of published or ongoing phase II‐III trials is also presented.
This review article discusses the clinical utility of circulating tumor cells (CTCs) in various settings of screening and treatment of non‐metastatic and metastatic tumors. Two major aspects are considered, namely i) treatment based on CTC count or CTC variations, and ii) treatment based on the molecular characteristics of CTCs. A summary of published or ongoing phase II‐III trials with CTCs is also presented.
Purpose: Circulating tumor cells in blood from metastatic breast cancer patients have been reported as a surrogate marker for tumor
response and shorter survival. The aim of this study was to ...determine whether circulating tumor cells are present in the blood
of patients with large operable or locally advanced breast cancer before neoadjuvant chemotherapy and after neoadjuvant chemotherapy
before surgery.
Experimental Design: Blood samples of 7.5 mL were obtained on CellSave tubes from patients included in a phase II trial (REMAGUS 02). Circulating
tumor cells were immunomagnetically separated and fluorescently stained by the CellSearch system. Blood from 20 metastatic
breast cancer patients was used as a positive control.
Results: From October 2004 to July 2006, preneoadjuvant chemotherapy and/or postneoadjuvant chemotherapy blood samples were obtained
from 118 patients. At least 1 circulating tumor cell was detected in 22 of 97 patients with preneoadjuvant chemotherapy samples
(23%; 95% confidence interval, 15-31%; median, 2 cells; range, 1-17 cells). Circulating tumor cell positivity rates were 17%
in 86 postneoadjuvant chemotherapy samples and 27% in all 118 patients. Persistence of circulating tumor cells at the end
of neoadjuvant chemotherapy was not correlated with treatment response. After a short median follow-up of 18 months, the presence
of circulating tumor cells ( P = 0.017), hormone receptor negativity, and large tumor size were independent prognostic factors for shorter distant metastasis–free
survival.
Conclusion: Circulating tumor cells can be detected by the CellSearch system at a low cutoff of 1 cell in 27% of patients receiving neoadjuvant
chemotherapy. Circulating tumor cell detection was not correlated to the primary tumor response but is an independent prognostic
factor for early relapse.
Although the COVID‐19 pandemic peaked in March/April 2020 in France, the prevalence of infection is barely known. Using high‐throughput methods, we assessed herein the serological response against ...the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) of 1847 participants working in three sites of an institution in Paris conurbation.
In May–July 2020, 11% (95% confidence interval CI: 9.7–12.6) of serums were positive for IgG against the SARS‐CoV‐2 N and S proteins, and 9.5% (95% CI: 8.2–11.0) were neutralizer in pseudo‐typed virus assays. The prevalence of seroconversion was 11.6% (95% CI: 10.2–13.2) when considering positivity in at least one assay. In 5% of RT‐qPCR positive individuals, no systemic IgGs were detected. Among immune individuals, 21% had been asymptomatic. Anosmia (loss of smell) and ageusia (loss of taste) occurred in 52% of the IgG‐positive individuals and in 3% of the negative ones. In contrast, 30% of the anosmia–ageusia cases were seronegative, suggesting that the true prevalence of infection may have reached 16.6%. In sera obtained 4–8 weeks after the first sampling, anti‐N and anti‐S IgG titers and neutralization activity in pseudo‐virus assay declined by 31%, 17%, and 53%, resulting thus in half‐life of 35, 87, and 28 days, respectively.
The population studied is representative of active workers in Paris. The short lifespan of the serological systemic responses suggests an underestimation of the true prevalence of infection.
In May 2020, 11% of workers at Institut Curie living in Paris conurbation were seropositive and 9.5% had detectable but short‐lived neutralizing antibodies of SARS‐CoV‐2. Some 21% of these neutralizing sera actually belong to asymptomatic individuals. Only 2% of the PCR‐detected infections had not been followed by humoral immune response.
Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in ...clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed—(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.
Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our ...prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation‐specific bidirectional pyrophosphorolysis‐activated polymerization (bi‐PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch® technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1–20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4–11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression‐free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.
What's new?
In some cancers, tumor cells and tumor DNA find their way into the bloodstream and circulate around the body. These circulating markers present the tantalizing possibility of an easily performed test for disease prognosis. In this study, the authors sought to detect circulating tumor cells and DNA from metastatic uveal melanoma. They found that the two were highly correlated with each other, but not necessarily of strong prognostic value. Circulating tumor DNA, they report, was more frequently detected, and in patients with known mutations, might prove more useful for prognosis.
Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV‐associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD‐1 immune checkpoint ...inhibitor, demonstrated significant efficacy as single‐agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single‐agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof‐of‐concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.
What's new?
Immune checkpoint inhibitors emerged as a promising strategy against squamous cell carcinoma of the anal tract, a cancer associated with high‐risk human papilloma virus (HPV) infection. However, the radiological evaluation of treatment success is often hampered by tumor pseudo‐progression due to immune infiltration. Here the authors performed synchronous monitoring of blood HPV DNA levels during therapy using droplet‐digital PCR, uncovering the potential of circulating viral DNA as a useful biomarker for treatment success in anal cancer.
Cancer-Associated Fibroblasts (CAFs) represent the most prominent component of the tumor microenvironment (TME). Recent studies demonstrated that CAF are heterogeneous and composed of different ...subpopulations exerting distinct functions in cancer. CAF populations differentially modulate various aspects of tumor growth, including cancer cell proliferation, extra-cellular matrix remodeling, metastatic dissemination, immunosuppression and resistance to treatment. Among other markers, the Fibroblast Activation Protein (FAP) led to the identification of a specific CAF subpopulation involved in metastatic spread and immunosuppression. Expression of FAP at the surface of CAF is detected in many different cancer types of poor prognosis. Thus, FAP recently appears as an appealing target for therapeutic and molecular imaging applications. In that context, 68Ga-labeled radiopharmaceutical-FAP-inhibitors (FAPI) have been recently developed and validated for quantitatively mapping FAP expression over the whole-body using Positron Emission Tomography (PET/CT). In this review, we describe the main current knowledge on CAF subpopulations and their distinct functions in solid tumors, as well as the promising diagnostic and therapeutic implications of radionuclides targeting FAP.
Enhancers are cis-regulatory sequences that fine-tune expression of their target genes in a spatiotemporal manner. They are recognized by sequence-specific transcription factors, which in turn ...recruit transcriptional coactivators that facilitate transcription by promoting assembly and activation of the basal transcriptional machinery. Their functional importance is underscored by the fact that they are often the target of genetic and nongenetic events in human disease that disrupt their sequence, interactome, activation potential, and/or chromatin environment. Dysregulation of transcription and addiction to transcriptional effectors that interact with and modulate enhancer activity are common features of cancer cells and are amenable to therapeutic intervention. Here, we discuss the current knowledge on enhancer biology, the broad spectrum of mechanisms that lead to their malfunction in tumor cells, and recent progress in developing drugs that efficaciously target their dependencies.
Abstract
Background
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.
Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated ...with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.
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