What Are Biomarkers In Breast Cancer

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Basal Markers Deteriorate Er

Table 1

a Positivity for at least one of the highlighted markers.

Despite the various inclusions of basal markers in triple negative breast tumor classification, markers of this class are associated with the cancer hallmark of ‘invasion and metastasis’. Recent studies have shown that cytokeratins, P-cadherin and vimentin are closely linked with tumorigenesis and metastasis. Cytokeratins are proteins of keratin-containing intermediate filaments in the intracytoplasmic cytoskeleton of epithelial tissue. Vimentin is the major intermediate filament protein of mesenchymal cells . It regulates the interaction between cytoskeletal proteins and cell adhesion molecules , and thereby participates in cell adhesion, migration, invasion and cell signal transduction in tumor cells . TP63 has been reported to play a tumor suppressive role in cancer metastasis .

The poor prognosis of triple negative tumors is associated with the ‘activating invasion and metastasis’ hallmark. The ambiguities exhibited in tumor classification when basal markers are included suggest that breast tumors, regardless of which subtype they belong to, once harboring the ‘activating invasion and metastasis’ hallmark, exhibit either poorer prognosis or drug resistance .

Circulating Tumor Cells And Tumor

There is currently a major effort to identify biomarkers which can be obtained with minimally invasive methods and persist beyond surgery. The existence of circulating tumor cells in the blood of cancer patients was first reported in 1869, but only in the last decade has molecular methodology made it possible to detect them reproducibly . In parallel, advances in immunohistochemistry made it possible to identify disseminated tumor cells in the bone marrow.

For breast cancer, a high CTC count at diagnosis of metastasis is described as being a significant negative prognostic factor, and if the number of CTCs does not decrease, patients are likely to progress under chemotherapy . The future use of CTC measurements is very probably to predict therapy efficacy and resistance after initial exposure to therapy, and may be beneficial in monitoring response to treatment. Although many reports on the significance of CTCs have been published, in 2007, the American Society of Clinical Oncology tumor marker group concluded that treatment decisions should not be influenced by CTC counts . A particularly attractive concept that is beginning to meet the expectations is the identification of specific biomarkers on the CTCs, e.g. HER2 .

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Correlation Analysis Between Lr Model Classification And Survival Prognosis

Based on the classification result of LR classification model in the training set and validation set, the Kaplan-Meier curve method in R3.4.1 survival package version 2.41-1 was used to evaluate the correlation between the grouping conditions and survival prognostic information. Then, the expression levels of important feature DEGs in TCGA training dataset and GSE45725 validation dataset were displayed. In addition, receiver operating characteristic curve was drawn to compare the sensitivity and specificity. The area under the curve was calculated from the ROC curve. The genes based on the LR models were also verified in the different subtypes of breast cancer .

Understanding Brca1& brca2 Genetic Mutations

Unlike genomic mutations that are developed over time in our cells, the BRCA1 and BRCA2 mutations are inherited from a parent via either the sperm or the egg, which are labeled as germ cells. This term has nothing to do with germs but rather comes from gardening, in which seeds germinate to grow into a plant. These inherited genetic changes are therefore called germline mutations.

We all get 2 copies of every gene1 from our mother and 1 from our father. When the 2 copies of these genes are normal, they help to fix mutations that occur in other genes within the cell, much as a spell-checker does in a word-processing program, and therefore they prevent the development of cancer. However, when the genes are mutated in a way that prevents their normal activity, the person is at a much greater risk of getting breast, ovarian, or a few other types of cancer than people who have normal copies of the gene.

Therefore, BRCA1 and BRCA2 are called susceptibility genes. Many such genes have been identifiedsome are relatively specific to certain types of cancers and some result in different types of cancer, such as the p53 gene. According to the National Cancer Institute, about 70% of women who inherit a BRCA mutation will have breast cancer by age 80.

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Estrogen Receptor And Progesterone Receptor

Expression of estrogen receptor -alpha is a favourable prognostic factor and strongly predictive of a response to hormone therapy . Approximately 3040% of patients with ER-expressing advanced breast cancer will have an objective response to hormone treatment, and a further 20% of patients will achieve disease stabilisation. Moreover, the hormone therapy response in patients with early ER-expressing breast cancer, in terms of overall and disease-free survival, is well known . Hormone therapy is relatively non-toxic. Its long-lasting clinical activity justifies its use in any patient with an ER-expressing mammary tumour.

The technique used to test for ER can be applied inexpensively to fixed, paraffin-embedded tissue. It is therefore readily available in most Pathology Departments. Examining tissue under the microscope means that positive reactions can be assessed in tumour cells only, avoiding problems with low cell density or normal breast tissue included in the tumour growth. Detailed guidelines addressing methods for the immunohistochemical analysis of ERs and progesterone receptors are available .

What Are Tumor Markers

A tumor marker is anything present in or produced by cancer cells or other cells of the body in response to cancer or certain benign conditions that provides information about a cancer, such as how aggressive it is, what kind of treatment it may respond to, or whether it is responding to treatment.

Tumor markers have traditionally been proteins or other substances that are made at higher amounts by cancer cells than normal cells. These can be found in the blood, urine, stool, tumors, or other tissues or bodily fluids of some patients with cancer. Increasingly, however, genomic markers that are found in tumors themselves and in tumor fragments shed into bodily fluids are being used.

Many different tumor markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with multiple different cancer types

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Proliferation Markers Deteriorate Her2

More directly than hormonal receptors, proliferation markers have been used in breast tumor classification, especially among HER2- tumors. It has been widely acknowledged that increased cell proliferation is a key determinant of clinical outcome among breast cancer patients . Chemotherapy agents including CMF , taxanes and anthracycline-based treatment all affect cell division or DNA synthesis. Thus, concurrent assessment of proliferation and conventional IHC markers provides additional predictive value and more precise clinical implications than using IHC alone. Worth noting that proliferation markers are informative in further differentiating HR positive tumors and of limited value in ER-PR-HER2- or HER2 positive tumor classification .

Liquid Biopsy And Circulating Tumour Cells

Liquid biopsies, defined broadly as either circulating tumour cells of epithelial origin, tumour nucleic acids , or tumour exosomes in the blood of cancer patients, have received increasing attention as a new diagnostic tool. To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, an invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve tumour characterisation and disease monitoring over time, liquid biopsy may represent a new tool. Technologies for detecting and isolating CTCs include the FDA-validated CellSearch® system, but other technologies are gaining prominence .

CTCs have been proved to be a significant prognostic factor in both early and metastatic breast cancer . In fact, CTC positivity constitutes an individual risk factor for breast cancer relapse/death not inferior to the usual prognostic factors that are currently taken into account for adjuvant treatment decision . However, no definitive evidence supports its clinical utility at the moment. As opposed to CTCs enumeration, molecular characterisation of the CTCs might potentially be helpful as a predictive biomarker for therapy selection .

The use of NGS in liquid biopsy may further improve our ability to predict relapse, monitor patients, predict drug activity, or provide early detection of resistance.

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Multiple Gene Prognostic Assays

In the era of big data, analyzing the large number of sequences from various studies can help devise a systemic strategy combating BC. Several genetic aberrations in women have a predisposition to BC. Incorporating genes that have been implicated in BC as a potential biomarker can provide an advantage in early BC detection and treatment . With multigene signature analysis alongside other molecular tools, clinicians can now devise appropriate therapies and predict their outcome while minimizing detrimental effects. Currently, there are seven prognostic multigene signature analyzing tests for BC. However, not all are FDA approved. Some are recommended by agencies, such as the ASCO, American-National Comprehensive Cancer Network , and the European Society of Medical Oncology in their guidelines.

Tp53 Dysfunction Increases Tumor Drug Resistance

The tumor suppressor TP53 plays a critical role in many cellular signaling controlling cell proliferation, survival, apoptosis and, most importantly, genomic integrity . It acts as a gatekeeper of the genome when cells experience stress conditions such as DNA damage, hypoxia and oncogene activation. Thus, TP53 deficiency may lead to uncontrolled proliferation of damaged cells as the genomic stability is hampered which leads to a faster mutation speed. Approximately 25% to 30% tumors have a mutation on TP53 , which has been reported as an important prognostic marker in breast cancer independent of tumor size, node status and hormone receptor content . An interaction between TP53 and PR is revealed, where TP53-PR- tumors are found associated with the worst prognosis among all breast cancers . It has been shown that p53 mutation adversely affects breast cancer response to tamoxifen . Increasing evidences have suggested that TP53 dysfunction is responsible for the development of anti-oestrogen resistance among ER+ tumors , and ER-TP53- tumors may suffer from chemotherapy treatment failure . These evidences altogether suggest that ‘genome instability and mutation’ contributes to tumor drug resistance regardless of which subtype it belongs to.

Table 2

* Subtypes with detailed expression patterns and clinical implications discussed in the text, which take the majority of the breast tumor cases and are most commonly referred to.

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Specimen Preparation For Proteomic Analysis

All specimens were stored at 80°C after collection and frozen aliquots were shipped to Johns Hopkins on dry ice. No further processing was required for the NAF specimens received whereas DLF was first lyophilized and then dialyzed overnight against PBS to remove excess saline using Tube-O-Dialyzer with 1 kDa molecular weight cutoff . Protein concentration in each fluid was measured using the bicinchoninic acid protein assay kit .

Development Of Metastatic Tumors Correlates With Presence Of Human Cells In Mouse Bm

To investigate the clinical relevance of PDX models for studying BM DTCs in patients with breast cancer, we utilized a set of previously characterized PDX mouse lines . BM was collected from a total of 18 animals, spanning five different passages and representing initial implants from five different patients with a variety of molecular phenotypes . All but one patient developed distant, clinical metastatic disease.

Fig. 2

Expression of human-specific GAPDH and other biomarker genes of epithelial cell lineage and epithelial to mesenchymal transition , detected in the bone marrow of patient-derived xenograft mice. Expression of each transcript in the BM of tumor bearing mice is represented relative to that in non-tumor-bearing humanized NOD-SCID mice , using the dd CT method. Since human-specific transcripts were not detected in the BM of control mice, for calculation purposes, a CT value of 40 was assigned. *Animals that developed metastatic tumors. The association between metastatic outcome and gene expression was statistically significant for hGAPDH , STAM2 , DSCR3 and FOXC2 analyzed by the Fisher exact test

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Immune Response Genes Rescue Er

The interferon-rich subtype is recently identified from ER-PR-HER2- tumors, which is characterized by the over-expression of interferon-regulated genes . These tumors account for approximately 10% of breast tumor cases . Among the interferon-regulated genes differentiating tumors of this subtype from the other ER-PR-HER2- cancers, STAT1 and SP110 are of the most importance, where STAT1 is the transcription factor mediating interferon-regulated gene expression , and SP110 is reported to have the prognostic value . The relapse free survival of interferon-rich breast tumors is somewhere between the basal cancers and luminal A tumors, and is comparable with luminal B tumors , suggesting that the easier tumors fire the immune system the better outcome the patients show, and the more effective the appropriate therapeutic strategy might achieve.

Markers representing these three cancer hallmarks contribute to the current breast tumor classification. All conventional subtypes are summarized in Table 2.

Improved Gene Expression Profiling

Although the first generation gene expression profiling tools, Oncotype DX, and MammaPrint have greatly advanced the prognosis of breast cancer patients for metastasis risk and distant recurrence, a major drawback is that they are unable to accurately predict late distant recurrence of more than 5 years . Two newer gene expression profiling tools, EndoPredict and The Breast Cancer Index, have emerged successful in this aspect .

The breast cancer index is another RT-PCR-based assay, which combines two independent biomarkers namely a set of five cell cycle genes and the HOXB13 and IL17BR gene ratio to determine the recurrence probability of early stage ER+, lymph node negative breast cancer patients . Independently, both the five gene panel and the two gene ratio are associated with distant metastasis free survival rates . However, when combined, three groups could be formed, low-, intermediate-, and high-risk groups, which are significantly predictive of metastasis occurrence . Ten-year distant metastasis free survival for low-, intermediate-, and high-risk groups are 98, 87, and 60%, respectively . Additionally, in a study comparing the prognostic ability of BCI with Oncotype DX and another gene panel, BCI emerged as the only test capable of significantly predicting both early and late distant metastasis recurrence, whereas the other two were only able to predict early recurrence .

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Biomarkers For Molecular Subtyping Of Bc

Up to 10 different subgroups of molecular BC have been proposed, though 5 main groups have substantial clinical relevance: Luminal A: HR positive and HER2 negative Luminal B: HR+, and either HER2 positive or HER2 HER2-enriched BC: HR negative and HER2+ Triple-negative breast cancer /basal-like: HR and HER2 Normal-like BC, which like luminal A, is HR+, HER2, but its prognosis is slightly worse than luminal A.-

HR+ means that greater than 1% of tumor nuclei express ER and/or PR, as determined by IHC. Two hypotheses explain the estrogen and the ER roles in BC. The first suggests that ER binding stimulates mammary cell proliferation, increasing cell division and DNA synthesis, thereby increasing the risk for replication errors and accumulation of mutations in processes of DNA repair, cell proliferation, and apoptosis. The other hypothesis states that the metabolism of estrogen causes the formation of genotoxic by-products that directly damage DNA, causing mutations. HR+ cancer has the advantage of having a high response rate to hormonal therapy, including SERMs and AIs.

Nowadays, decision-making is based on numerous factors, including tumor morphology and grade classification, tumor size, presence of lymph node metastases, and expression of ER, PR, and HER2 .

Considering advanced breast cancer , PIK3CA mutations have a strong predictive value for treatment with -selective and -sparing PI3K inhibitors, and its use has recently entered clinical practice.-

Uses Of Biomarkers In Cancer Research

Developing drug targets

In addition to their use in cancer medicine, biomarkers are often used throughout the cancer drug discovery process. For instance, in the 1960s, researchers discovered the majority of patients with chronic myelogenous leukemia possessed a particular genetic abnormality on chromosomes 9 and 22 dubbed the Philadelphia chromosome. When these two chromosomes combine they create a cancer-causing gene known as BCR-ABL. In such patients, this gene acts as the principle initial point in all of the physiological manifestations of the leukemia. For many years, the BCR-ABL was simply used as a biomarker to stratify a certain subtype of leukemia. However, drug developers were eventually able to develop imatinib, a powerful drug that effectively inhibited this protein and significantly decreased production of cells containing the Philadelphia chromosome.

Surrogate endpoints

Some ideal characteristics of surrogate endpoint biomarkers include:

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Is Biomarker Testing Part Of Precision Medicine

Yes, biomarker testing is an important part of precision medicine, also called personalized medicine. Precision medicine is an approach to medical care in which disease prevention, diagnosis, and treatment are tailored to the genes, proteins, and other substances in your body.

For cancer treatment, precision medicine means using biomarker and other tests to select treatments that are most likely to help you, while at the same time sparing you from getting treatments that are not likely to help.

The idea of precision medicine isnt new, but recent advances in science and technology have helped speed up the pace of this area of research. Scientists now understand that cancer cells can have many different changes in genes, proteins, and other substances that make the cells grow and spread. They have also learned that even two people with the same type of cancer may not have the same changes in their cancer. Some of these changes affect how certain cancer treatments work.

Even though researchers are making progress every day, the precision medicine approach to cancer treatment is not yet part of routine care for most patients. But it’s important to note that even the standard approach to cancer treatment is effective and is personalized to each patient.