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Breast cancer continue to be one of the leading causes of cancer death in women, but mortality rates have decreased steadily over the past decades. Breast cancer grows as a result of DNA disruption and genetic mutations which may be affected by estrogen use. Occasionally, Genetic mutations or pro-cancer genes such as BRCA1 and BRCA2 will be inherited. Therefore, the family history of ovarian or breast cancer increases the risk of having breast cancer. The immune system is targeting cells with defective DNA or an irregular development in the normal individual. This occurs in those with breast cancer, leading to the development and spread of tumors (1).
Five to ten percent of all cases of breast cancer are due to genetic causes, but in women younger than 30 years, they may account for 25 percent of the cases. BRCA1 and BRCA2 are the two main genes responsible for an improved susceptibility to breast cancer (1,12).
Given a growing prevalence of breast cancer, gradual introduction of progressively successful adjuvant medical treatments is one of the major factors forthe growth.Due to the development of new prognostic and predictive biomarkers that enable the implementation of more individualized therapies to different molecular subgroups, the therapy of breast cancer has experienced many improvements in the last decades.
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Regarding the biological clinical behavior, These subgroups show specific differences .In addition to the established clinical prognostic factors of breast cancer, proven molecular biomarkers such as estrogen receptor and progesterone receptor have played a significant role in the selection for many years of patients benefiting from endocrine therapy.The movement towards an early breast cancer diagnosis due to improved imaging techniques and screening systems highlights the need for novel biomarker variables and combinations to measure patients ‘ residual risk and show the potential value of additional treatment approaches (1).
Both prediction and quantitative markers are highly relevant in medical decision-making processes to individualize therapy, but they do have distinct roles. The predictive and prognostic variables can be extracted from either the patient’s symptoms or the type of tumor.Prognostic factors are intended to forecast objective and objectively patient health results regardless of treatment, whereas predictive factors are intended to predict a patient’s reaction to a given therapeutic intervention and are correlated with tumor responsiveness or therapy resistance (13).
Prognostic factors essentially require definition in patient cohorts that did not undergo systemic adjuvant treatment. Predictive markers may be the focus of a specific therapy itself. For example, the oncogene HER2 is the target of the monoclonal antibody trastuzumab, and HER2 amplification predicts for a good response to anti-HER2 therapy. Lately, there has been an increase in implementation of marker combinations to define treatment-specific prognoses (13).
What’s meant by biomarkers?
According to the National Cancer Institute (NCI), a biomarker is “a biological molecule contained in blood, certain body fluids or tissues that are a sign of a natural or abnormal cycle, or of a disorder or disease,” such as cancer(14). Cell type has a distinctive molecular fingerprint, referred to as biomarkers, which are recognizable characteristics of a variety of genes, proteins or other molecular features, such as rates or activities (the ability of genes or proteins to perform their functions) (15).
Role of biomarkers in diagnosis breast cancer
In reaction to the cancer, a biomarker, also called a tumor marker, is created by the tumor or the body. And that can be contained in the tumor or on it. It can be found in the bloodstream (whole blood, saliva, or plasma) or in excretions or secretions (stool, vomit, sputum, or nipple discharge), and thus readily diagnosed non-invasively and serially or tissue-derived, requiring only biopsy or special imaging for determination (14). And, it can help doctors know more about each person’s cancer so they can give each patient the best treatment choices. Therefore, biomarkers are an objective measurement or evaluation of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention (15).
A comprehensive understanding of the importance of each biomarker will be very important not only for the accurate diagnosis of the condition, but also for the development of various treatment options that are currently available to patients(16).
Throughout cancer diagnosis and treatment, the subtle differences between normal and tumor cells are used. Such variations are referred to as tumor markers, and can be qualitative or quantitative throughout nature.This ensures that both the structures generated by tumor cells and the structures formed by host tissues in excessive amounts under the control of tumor cells will serve as tumor markers (17).
Knowledge about cancer biomarkers has grown tremendously in recent years, providing great opportunities to improve cancer patient care by improving the quality of treatment diagnosis and efficacy.
Recent technological advancements have caused several possible biomarkers to be investigated and a renewed interest in developing new biomarkers (16).
Besides their limitations, tumor markers are precious tools for screening a healthy and a high risk population for the incidence of cancer, making a diagnosis of a specific type of cancer, along with determining the prognosis and monitoring the course of the disease in the patient, at the time of remission or during the course of treatment Also, tumor markers have an critical role in monitoring the treatment response, along with early detection of disease recurrence (prior to development of clinically notable signs) (17).
Because of their incompetence, the determinations of tumor markers can only be extraordinarily applied as screening tools and not as the primary diagnostic tool; nevertheless, they play an important role in the diagnostic process and in clinical preparation in tandem with other diagnostic procedures. Besides, by combining various tumor markers we can achieve a greater specificity and sensitivity in the follow-up of one type of malignancy (17).
Due to the critical role biomarkers play at all stages of the disease, it is crucial that they undergo rigorous examination, including analytical validation and clinical validation and evaluation of clinical usefulness before they are integrated into routine clinical care (14,18).
In breast cancer, biomarker analysis is routine practice. It originally began with testing for hormone receptor expression to guide the treatment (19).
Ideal characteristics of tumor marker
A perfect tumor marker should be profoundly sensitive to keep away from false positive outcomes, and exceptionally explicit to a given tumor type, and solid with high prognostic worth, organ particularity and it should relate with tumor stages. Only a few tumor markers have stood the test of time and joined in the diagnostic or management processes for clinicians (16,17).
Advances in the management of breast cancer will be significantly helped by early detection, thereby promoting the diagnosis and treatment of breast cancer in its pre-invasive stage before metastasis. Early detection of breast cancer allows for improved treatment options, including surgical resection, which may include lumpectomy or mastectomy with certain axillary lymph nodes removed (20).
After early detection, radiation therapy, chemotherapy (before or after surgery), and hormone therapy (tamoxifen and aromatase inhibitors) also have utility for the rapeutic intervention.
Targeted biologic therapy with trastuzumab (Herceptin) or lapatinib (Tykerb) also has utility to treat HER2/neu-positive breast tumors. Unfortunately several breast cancer patients are detected too late in the disease process for surgical resection in the absence of good serum / plasma biomarkers to be an effective option.Thus, these patients are typically offered various therapeutic treatment modalities dependent upon tumor subtype (ER+ or ER−, HER2) (20).
Types of biomarkers
There is a vast range of biomarkers that can include proteins (such as an enzyme or receptor), nucleic acids (such as a microRNA or other non-coding RNA), antibodies, and peptides, among other types. A biomarker may also be a series of changes, such as gene expression, proteomic signatures and metabolomic signatures(14).
Among the most important molecular markers associated with breast cancer are the estrogen receptor (ER), the progesterone receptor (PR), the human epidermal growth factor receptor (HER2), and the proliferation index Mib1/Ki67, which are firmly established in all primary, recurrent and metastatic breast cancer patients (14).
In breast cancer the biomarkers mentioned below are more widely used. Once you are diagnosed with breast cancer, the doctor will prescribe that these biomarkers check the cancerous tissue. Testing is important because understanding whether or not there is a tumor marker can have a strong impact on your care choices (21).
Established biomarkers
Estrogen receptor
ER(a) expression is probably the most important biomarker in breast cancer, since it provides the index for endocrine response. ER-positive tumors (about 80% of breast cancer) use the steroid hormone estradiol as their key trigger for growth; thus, ER is the direct target of endocrine therapies (21).
The Oxford overview proves that patients with ER-negative disease have no benefit from 5-year adjuvant treatment with tamoxifen, but a few benefits may be derived in the uncommon group of ER- negative and progesterone receptor (PR)-expressing breast tumors. In contrast, such treatment reduces the annual breast cancer death rate by 31% in ER-positive disease. While the absence or presence of the ER is used to take treatment decisions, little attention has been paid on the value of the quantitative expression levels as a predictive indicator. Evidence from the 1970s suggests a direct correlation between ER expression levels and response to endocrine therapy (21).
The international group of Early Breast Cancer Trialists indicated that higher ER rates were associated with a lower risk of recurrence after receiving adjuvant tamoxifen. PR expression is heavily dependent upon ER’s involvement. Tumors that convey PR but not ER are rare and in some large series account for about 1% of all breast cancer cases. For this reason, tumors with PR expression lacking ER expression should undergo a retesting of their ER status to eliminate false ER negativity. In the rare cases of solely PR-expressing patients, some limited benefit from tamoxifen is described, but endocrine therapy is still widely recommended (21).
Progesterone receptor
PR expression is strongly dependent upon ER’s involvement. Tumors which express PR but not ER are rare and represent! In some large series 1 percent of all cases of breast cancer. For this cause, in order to eliminate false ER stigma, tumors with PR expression missing ER expression will undergo a re-test of their ER status. In the rare cases of solely PR-expressing patients, some limited benefit from tamoxifen is described, but endocrine therapy is still widely recommended (20).
There is evidence of the response to anti-estrogen treatment in metastatic breast cancer is better among patients with tumors expressing both ER and PR in opposed to those who only show ER positivity but lack the PR expression. Data from adjuvant trials comparing tamoxifen treatment with controls indicate a strong prognostic value for PR expression but suggest a little predictive significance. Patients with high levels of PR within their breast tumors have a better results than low expressors with tamoxifen, but the relative benefit from tamoxifen remains similar (20).
HER2
The oncogene HER2 was first identified to be an indicator of patient’s prognosis. In cases of HER2 being overexpressed (HER2 positive), breast cancer patients are more likely to suffer from relapse and tend to have a shorter total survival. Amplification of the HER2 gene and RNA/protein overexpression correlate strongly. Through the development of the monoclonal antibody trastuzumab, which is targeted at HER2, the amplification status of HER2 became also a highly predictive biomarker (21).
