Abstract:The emergence of clinical resistance in repeatedly treated cancers extends from the primary tumor's capability to exploit genome instability to adapt, escape, and progress. Triple negative breast cancer serves as a good example of such a response demonstrating poor clinical outcome due to a high rate of cellular heterogeneity resulting in metastatic relapse. The capability to effectively track the emergence of therapeutic resistance in real-time and adapt the clinical response is the holy grail for precision m… Show more
“…In this respect, liquid biopsy allowing the identification of circulating tumor cells (CTCs) in the peripheral blood and the sequencing of the tumor DNA extracted from CTCs would provide the genetic profile of the malignancy [ 133 ]. As several studies have unveiled comparable mutation frequencies between the genomic profile of breast cancer biopsies and ctDNA [ 134 , 135 , 136 ], the assessment of the FGFR aberrations in ctDNA might be a promising strategy to monitor the sensitivity or resistance to therapies, hence facilitating patient-tailored precision medicine [ 45 , 137 , 138 ].…”
Section: Conclusion and Future Perspectivesmentioning
One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.
“…In this respect, liquid biopsy allowing the identification of circulating tumor cells (CTCs) in the peripheral blood and the sequencing of the tumor DNA extracted from CTCs would provide the genetic profile of the malignancy [ 133 ]. As several studies have unveiled comparable mutation frequencies between the genomic profile of breast cancer biopsies and ctDNA [ 134 , 135 , 136 ], the assessment of the FGFR aberrations in ctDNA might be a promising strategy to monitor the sensitivity or resistance to therapies, hence facilitating patient-tailored precision medicine [ 45 , 137 , 138 ].…”
Section: Conclusion and Future Perspectivesmentioning
One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.
“…The Cellsearch® test has been approved by FDA for the extraction and selection of CTCs from breast cancer patients (but also for prostate cancer) for the determination of their prognosis (Fig. 2 ) 55 , 56 . Fig.…”
Section: Liquid Biopsies For Breast Cancermentioning
The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow “real-time” understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.
“…Cancer therapeutic approaches that use DNA damage-inducing agents (taxanes, anthracyclines, platinum compounds) induce apoptosis, overloading the DNA damage response machinery. However, a high rate of DNA damage could also enhance the selection for resistant phenotypes with a high mutational burden [ 108 , 109 , 110 ].…”
Section: Genetic and Chromosome Instabilitymentioning
confidence: 99%
“…Interestingly, the dissociation of CTC clusters by cardiac glycosides not only resulted in molecular changes that decreased their stem-like traits but also suppressed their direct metastatic ability in preclinical in vivo models [ 151 ]. Additional clinical trials have used CTCs’ molecular features such PDL-1 expression in non-small-cell lung cancer and HER2 level in metastatic breast cancer as biomarkers for the identification of high-risk patients [ 110 , 150 , 152 ].…”
Section: Ctcs Information In Clinical Practicementioning
confidence: 99%
“…In triple negative breast cancer patients, Witzel et al (2018) described that the reactivation of HER2 represents a marker for metastatic progression. HER2-positive CTCs that were not hormone receptor-expressing were detected at higher frequency in patients with metastatic disease when compared to early-stage patients [110,111]. Powell et al (2016) reported that p53-deficiecy promotes tumor growth, increases in tumor cell shedding into the blood, and enhanced metastasis [112].…”
Section: Chromosome Instability and Metastasis Developmentmentioning
Circulating tumor cells (CTCs) can promote distant metastases and can be obtained through minimally invasive liquid biopsy for clinical assessment in cancer patients. Having both genomic heterogeneity and instability as common features, the genetic characterization of CTCs can serve as a powerful tool for a better understanding of the molecular changes occurring at tumor initiation and during tumor progression/metastasis. In this review, we will highlight recent advances in the detection and quantification of tumor cell heterogeneity and genomic instability in CTCs. We will focus on the contribution of chromosome instability studies to genetic heterogeneity in CTCs at the single-CTC level by discussing data from different cancer subtypes and their impact on diagnosis and precision medicine.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
