MMP9, matrix metalloproteinase 9. In early stage recurrence, the significant pathways with upregulated genes in the recurrence samples included the osteoblast and ossification pathway, the serotonin receptor 2 pathway, various prostate cancer genes and the epidermal growth factor EGF -EGFR pathway Fig.
Heat map representation of A pathway- and B metastasis-associated upregulated genes in early stage recurrent triple-negative breast cancer.
Each row represents a gene and each column represents a patient. Red indicates upregulation, green indicates downregulation and black indicates no change. The yellow box indicates genes that are upregulated in tumors with subsequent recurrence compared to those without. Significant pathways associated with upregulated genes in early astage recurrent triple-negative breast cancer.
Significant pathways associated with downregulated genes in early stagea recurrent triple-negative breast cancer. Notably, genes associated with tumor stemness and angiogenesis were not overexpressed in these tumor samples.
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In contrast to the observations for early recurrence, the significant pathways involving upregulated genes present in stage IIIc recurrence samples included the WNT signaling pathway, glycogen metabolism pathway, integrated pancreatic cancer pathway, mitogen-activated protein kinase MAPK cascade pathway, brain-derived neurotrophic factor BDNF signaling pathway and prostaglandin synthesis pathway Table III , while the significant pathways involving downregulated genes in the stage IIIc recurrence samples included the AMPK signaling pathway, interleukin IL -2 signaling pathway and BDNF signaling pathway Table IV.
Significant pathways associated with upregulated genes in stage IIIc recurrent triple-negative breast cancer. Significant pathways associated with downregulated genes in stage IIIc recurrent triple-negative breast cancer. Since cancer stemness involves self-renewal ability and aggressive behavior, it was not unexpected that a subset of overexpressed stemness genes, including CD44, WNT 4 and WNT 16, were identified in tumor samples obtained from patients with late stage IIIc TNBC and subsequent recurrence Fig.
In addition, a gene set associated with angiogenesis Fig.
Heat map representation of A stemness-associated and B angiogenesis-associated upregulated genes in stage IIIc recurrent triple-negative breast cancer. Red indicates upregulatio, green indicates downregulation and black indicates no change. In order to elucidate the possible networks involving the pathways identified in the present study, the above-mentioned upregulated and downregulated genes in the early stage and stage IIIc tumor samples were investigated using ingenuity pathway analysis.
By contrast, Fig. Arrow direction indicates a functional association between an upstream regulator and a downstream element. TNBC, triple-negative breast cancer. It has been suggested that TNBC is not a complete proxy for basal-like breast cancer. Although an appreciation of the significance of basal-like breast cancers predates gene-expression investigations by a number of years, this term was not in widespread use until later 14 , Several of the most well-known genes associated with basal-like breast cancer, including keratin 5 and keratin 17, do not differ significantly different between caucasian and Asian populations This observation is contradictory to the fact that the epidemiology and prognosis of breast cancer between different ethnicities is generally reported to be different There is no internationally accepted definition of these tumors.
However, clinical, microarray and immunohistochemical observations have demonstrated that this is not the case Furthermore, in the present study, the gene expression levels of basal-like breast cancer specific genes, including keratin 5 and keratin 17, were not uniquely upregulated, which was in agreement with those previously reported in Asian TNBC patients 16 , indicating that these types of cancer do not possess basal-like breast cancer characteristics.
Compared with previous study designs that used tumor and non-tumor samples for TNBC analysis, the present study was the first, to the best of out knowledge, to focus on the analysis of paired recurrent, vs. Therefore, the design of the present study was likely to identify potentially important biomarkers and therapeutic targets for the treatment and prevention of TNBC recurrence. It was hypothesized that the TNBC population is heterogeneous and that various subgroups will exhibit different, and possibly specific, expression signatures. The identification of such signatures offers potential perspective into the individualized treatment protocols that are available.
TNBC is a highly diverse type of cancer, and subtyping of TNBC tumors is necessary in order to identify appropriate molecular-based therapies. Evolving technologies are permitting increasing quantities of molecular data to be obtained from tumor tissues, which enable the development of more personalized treatment strategies In this context, whether all basal-like cancers are enriched with cancer stem cells or whether they have a disproportionately high content of cells undergoing epithelial-to-mesenchymal transition EMT remains to be elucidated In the present study, which focused on the molecular mechanisms in paired specimens obtained from patients with and without recurrence, the results suggested that the significant pathways involving upregulated genes that are present in stage IIIc recurrent samples included the WNT, glycogen metabolism, integrated pancreatic cancer, MAPK cascade, BDNF and prostaglandin signaling pathways.
These observations may be useful for biomarker selection, drug discovery and clinical trial design, all of which may assist in the identification of appropriate targeted therapies for patients with TNBC In the present study, similar deregulation of the inflammatory response pathway and the IL-2 signaling pathway were observed in the samples from patients with stage IIIc TNBC recurrence. According to the St Gallen consensus for chemotherapy guidelines 22 , all triple-negative patients are recommended to receive adjuvant systemic chemotherapy in combination of anthracycline-based regimens with taxanes, however, this approach often results in serious side effects in patients.
These may be used, alongside traditional chemotherapy treatments, to treat triple-negative patients with an unfavorable prognosis. The gene profiling in the current study may provide a prognostic predictor and, thus may become a clinically useful tool for the identification of triple-negative patients who are at low risk of recurrence. The subsequent provision of moderate doses of combined regimens, or the anthracycline-based regimens alone, in these patients can be offered to reduce patient side effects. Among the stage IIIc recurrence group, the prostaglandin synthesis and regulation signaling pathway exhibited significant alterations in expression.
COX-2, an inducible form of cyclooxygenase, is the rate limiting step in the production of prostaglandins, which has been suggested to be involved in long-term inflammation and the promotion of cancer growth. Therefore, the results of the present study suggest that this pathway is likely to be important in the late stages of tumor growth and metastasis.
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CA Cancer J Clin. Gradishar WJ: Tamoxifen-what next? View Article : Google Scholar. Yamamoto Y and Iwase H: Clinicopathological features and treatment strategy for triple-negative breast cancer. Int J Clin Oncol.
Breast Cancer Research Protocols
Mol Oncol. N Engl J Med. Am J Pathol. Mod Pathol.
PLoS One. Cancer Inform. Sotiriou C and Pusztai L: Gene-expression signatures in breast cancer. Breast Cancer Res. Cancer Invest. Weigelt B, Baehner FL and Reis-Filho JS: The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: A retrospective of the last decade. Finally, the functionalization of these nanosystems using technological approaches adds both specificity and biocompatibility. Some studies have already shown the great potential of magnetic resonance for molecular imaging of breast cancer using targeted nanoparticles Li et al.
Although these studies have been only conducted in animal models, it can be expected that, in the near future, the rapidly growing field of nanomedicine will facilitate the translation of these methodologies to the clinics. Although molecular imaging is able to visualize breast tumor morphology and functional and metabolic processes within the tumor at several levels, the sensitivity of the different molecular imaging techniques is varied depending on the type of marker used in signaling the biological processes. At present, the main milestones for future molecular imaging development in breast cancer are:.
To enhance knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis. To develop validated markers for chemosensitivity and radiosensitivity. To validate multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease.
To develop interventions and support to improve the survivorship experience. In , the charity Breast Cancer Campaign facilitated a series of workshops where specialists and other stakeholders revealed the main gaps in the prevention and treatment of breast cancer Eccles et al. Top problems in molecular imaging of breast cancer and recent research on the field to be highlighted are:.
There is a need to increase the use of functional screening techniques to learn about tumor heterogeneity, identify features associated with response or resistance to treatment and accelerate the rate at which promising ones enter clinical evaluation. They were created to maximize results while minimizing negative effects. Resistance to chemotherapy has brought to light the issue of tumor heterogeneity. The use of selective ER modulators, such as tamoxifen, in ER-expressing tumors was one of the first examples for successful targeted therapy based on the tumor's molecular classification Swaby et al.
What induces endocrine resistance in these tumors has been one of the longest standing and most intense areas of breast cancer research. The somatic evolution of tumor progression was discovered in , but the results raised additional questions that could not be answered at that time Greaves and Maley, One of the most exciting outcomes of comprehensive cancer-genome-sequencing studies is that we finally have the tools to follow clonal and subclonal evolution of tumors and see the complexity of cancers as a whole Polyak, Evaluation of emerging imaging biomarkers of primary and metastatic breast cancer.
A biomarker is a crucial tool for measuring the progress of disease and the effects of treatment for better clinical outcomes in breast cancer patients. The current questions of therapeutic choices can focus now on the understanding that breast cancer is truly a collection of genetically-specific heterogeneous diseases, each demonstrating different clinical behavior and therapeutic response De Mattos-Arruda et al.
Since , cf-DNA has been shown to represent a good non-invasive biomarker, as it can be isolated from human plasma, serum and other body fluids Utting et al.
It was also reported that the concentration of DNA in the bloodstream of patients with breast cancer was higher than healthy controls Fleischhacker and Schmidt, Thus, the detection of cf-DNA provides new opportunities for management of cancer patients, adding a useful new tool for diagnosis, staging and prognosis Esposito et al. Imaging of cf-DNA after chemotherapy treatment has been described by using fluorochrome-functionalized nanoparticles Cho et al.
Unfortunately, clinical usage is limited due to the need for the presence of cyclotron in 18F production. Generator produced isotopes, such as 99mTc and 68Ga, are readily available and affordable. The availability of a generator and kit chemistry to prepare 99mTc and 68Ga-based molecular probes may have a significant impact on nuclear medicine Liu et al. It has been shown that 99mTc-glucarate may behave as a suitable alternative to 18F-FDG as a promising breast tumor imaging agent and needs to be further investigated Gambini et al. Thus, using generator-produced isotopes to label glucose analogs is the major focus of ongoing research.
Identification and assessment of using imaging biomarkers currently associated with other cancer indicators in additional hallmarks such as hypoxia, invasion and changes in metabolism. During the past decades, researchers have tried to elucidate the mechanisms that underlie cancer-related death.
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However, this remains a challenge, as genomic instability causes a constantly changing genetic profile of tumors, and local variations in the microenvironment cause heterogeneity in tumor cell behavior Polyak, How to validate novel imaging biomarkers in adequately powered multi-center clinical trials. While applied molecular biology to cancer has made great advancements, the development of clinically validated biomarkers for primary breast cancer has remained an unconquerable task. Chemo-N0 — was the first prospective randomized multicenter trial in Node-negative breast cancer designed to prospectively evaluate the clinical utility of a biomarker.
The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy Klintman et al. Although still in their infancy, circulating mi-RNAs and cf-DNA are beginning to be recognized as vital to future strategies on therapies for breast cancer Ng et al. Methods of reporting intratumoral heterogeneity and locate the most beneficial areas for biopsies and radiotherapy. Within the plethora of imaging modalities, diffusion weighted magnetic resonance imaging DW-MRI has shown promise for the detection and characterization of breast cancer.
Apparent diffusion coefficient ADC values allow quantification of the diffusion signal, and can facilitate in differentiating benign and malignant breast tumors as well as identifying early response in tumors undergoing preoperative treatment Partridge and McDonald, and the references cited therein.
On the other hand, the heterogeneous nature of cancer still presents an important challenge in cancer imaging and therapeutics Seoane and De Mattos-Arruda, This heterogeneity also confers to the different breast cancer subtypes a specific invasional kinetic pattern, as has been recently shown by Yamaguchi et al. Although breast MRI accuracy for assessing residual disease is good and surpasses other diagnostic techniques, overestimation and underestimation of residual disease have also been observed.
This is largely because of the various treatment types and breast cancer subtypes Lobbes et al.
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With some limitations and taking into consideration that many of the experiments have been performed in mice, intravital microscopy IVM is another technique that has proven its power to elucidate the cellular and molecular events that underlie the hallmarks of cancer. Fluorescence-guided surgical procedures have also benefited from IVM, which translates into more promising uses in the clinical setting Ellenbroek and Van Rheenen, Extension of methods that identify and define subtypes of cancerous tumors —DCIS, TNBC and luminal types—with non-invasive procedures which may identify mixed lesions missed by homogenized or limited sample analyses and assess heterogeneity between metastases.
The development of new contrast agents for MRI opens a new way for non-invasive breast cancer characterization. Special attention is made to iron oxide nanoparticles, currently one of the best options in clinic due to its lack of toxicity Kievit and Zhang, ; Rosen et al. Meier et al.