Breast cancer is regarded as one of the leading causes of death in most of the developing countries (Stephens et al., 2012). It affects mostly the female however; males are also affected (DeSantis, Ma, Bryan & Jemal, 2014). The main reason which are highlighted as the main causative agent of breast cancer include sudden genetic mutation and presence of genetic pre-disposition for the development of breast cancer. All these are non-modifiable factors underlying the development of breast cancer (Goldhirsch et al., 2014). The type of breast cancer is mainly determined by the affected breast tissues (Alexandrov et al., 2013). Based on the site of occurrence, breast cancer can be sub-divided into ductal carcinoma, invasive ductal carcinoma and invasive lobular carcinoma (Jafari-Koshki, Schmid & Mahaki, 2014; Khamis et al., 2012; Buchsbaum & Oh, 2016). The following assignment aims to provide a detailed overview of the breast cancer. The paper will initiate with highlighting different malignancies which are associated with breast cancer. Then the paper will discuss the molecular pathology underlying the breast-cancer with a special mention to the invasive ductal carcinoma. Upon discussing the pathophysiology, the paper will highlight the common molecular diagnostic methods which are used for the detection of breast cancer. At the end, the paper will analyse how prognosis of breast cancer is associated with several different factors, along with the possible method of treatment of this complex disease and future projection of the advanced grade treatment.
Different malignancies for the breast cancer
Different malignancies which are associated with breast cancer include: Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC) and Ductal Carcinoma (in-situ) (DCIS). IDC is further sub-divided into Tubular Carcinoma of the Breast, Medullary Carcinoma of the Breast, Mucinous Carcinoma of the Breast, Papillary Carcinoma of the Breast, Cribriform Carcinoma of the Breast (American Cancer Society, 2018). Other types of breast cancer include inflammatory breast cancer, lobular carcinoma (in-situ), Paget’s disease of the nipple, phyllodes tumors of the breast and metastatic breast cancer (American Cancer Society, 2018).
(Source: American Cancer Society, 2018)
There are two leading models in order to discuss the molecular pathology underlying the breast cancer. The sporadic clonal evolution model hypothesised that the breast epithelial cell can undergo random mutations leading to the development of cancer. Alternatively cancer stem cell model propose that only stem cell and the progenitor cells have the capability to initiate and maintain the tumour progression (Bombonati & Sgroi, 2011). The main strength of the paper is it provides a distinct aspect of two different hypothesis of underlying the pathophysiology of breast cancer however, fails to what is the probability that one cancer cell line will follow sporadic clonal evolution model of stem cell model. A genetic screening further will help to elucidate this topic further.
Basic molecular pathology of breast cancer underlines the concept of generation of the cancerous differentiation among the cells of the mammary gland, initiated under the action of the DNA or genetic mutation due to overexposure of estrogen or due to the inheritance of faulty genes like BRCA1, BRCA2 and P52 (Allison, 2012). The study undertaken by Allison (2012) employed advanced molecular testing technologies in order to elucidate the underlying molecular pathology of breast cancer and this is the main strength of their article and this validating the data further. However, the article failed to highlight the controls, which are used in the molecular testing techniques.
Ductal Carcinoma (DCIS) is defined as the proliferation of the epithelial cells which is separated from the breast stroma by an intact layer myoepithelial cells and its basement membrane. This process is known as intraductal neoplastic proliferation. DCIS is defined as a non-obligate precursor of IDC. Nearly 40% of the lesions of DCIS progress towards invasive ductal disease if they are not treated in time. However, at present there are no technologies to predict which DCIS is more susceptible in developing IDC. The reason behind this is, no significant drivers of this invasive pathophysiology have been identified (Cowell et al., 2013). However, the study conducted by Kim et al. (2015) highlighted that synchronous DCIS and invasive form of breast cancer are significantly similar under qualitative analysis. This similarity can be explained under the domain of intra-tumour genetic heterogeneity which is mainly visible under subsets of DCIS. Kim et al. (2015) are of the opinion that the process of disease progression is the “evolutionary bottleneck” which results in the selection of specific sub-sets of tumour cells with specific epigenetic aberrations. These epigenetic aberrations are mainly conducted through chromosomal aberrations or through change in the copy number of the gene leading to invasive disease progression. This change in the copy number of the gene or the chromosomal aberration as detected by the comparative genomics hybridization clear states the hypothesis highlighted by the sporadic clonal evolution model (Cowell et al., 2013). The study conducted by Kim et al. is helpful in providing genomic difference and difference in the exponential multiplication underlying pure ductal carcinoma and synchronous carcinoma in-situ in invasive breast cancer but the authors failed to highlight how the tissues were collected and the nature of the samples used for the collection of the cancerous tissues.
However, the research conducted by Kreso and Dick (2014) highlighted that main pathophysiology of the development of the breast cancer is mainly guided by the principle of the stem cell model. Kreso and Dick (2014) are of the opinion that the mutations, which are responsible for the promotion of the breast cancer originates from the stem cell at the germ, line however, these mutations remain dormant and becomes vulnerable towards expression with age or under the action of certain clonal mutations. The main strength of the study conducted by Kreso and Dick (2014) is they integrated cancer stem cell approach with cancer genetic data in order to drive the genetic heterogeneity. Kreso and Dick (2014) provided a detailed description about the tissue or the cell line use for the study and this is can be defined as additional strength of their study.
Molecular diagnostic test used to screen breast cancer is screening of estrogen (ER) and progesterone receptors (PR). The presence of hormonal receptor is assessed in the clinic via the process of ligand binding assay or via immune histo-chemical staining (IHC) of tissue sections (terHoeve et al., 2017). The immune histochemical staining is defined under the concept of immunohistochemistry (IHC). In immune-histochemistry, fine sections of the malignant tissues are produced and then hormone markers are used to bind to the prepared set of tissues. The binding of the markers with the set of hormones (estrogen and progesterone) helps to determinate the stage and grade of cancer along with the identification of the cell type.
Another major molecular diagnostic method is the use of molecular marker of human epidermal growth factor receptor 2 (HER2). In breast cancer, there occurs an over-expression of HER2. The presence of HER2 is done via IHS or via FISH technique (Fluorescence In-situ Hybridization) (terHoeve et al., 2017). The study conducted by Wolff et al. (2013) also highlighted that human epidermal growth factor receptor 2 testing is a promising technique for the detection of breast cancer via the use of FISH. FISH is a type of cytogenetic technique which is employs fluorescent probes as binding parts of chromosomes in order to show high degree of sequence complementarity. FISH is based on DNA probes annealing to specific target sequence of the sample DNA. Attached to the probes of the DNA are fluorescent reported molecules. Under the fluorescence microscopy provides confirmation of the absence and presence of any specific genetic aberration (Ratan et al., 2017). The study conducted by Cox et al. (2013) argued that micorbubbles and contrast enhanced ultrasound (CEUS) is used for the detection of the breast cancer that has propagated in the lymph nodes. This technique is mainly suitable for the pre-operative patients. However, Cox et al. (2017) did not provide any specific techniques to the detection of the severity of cancer recurrence among the post-operative patients.
Figure: Principle of FISH
(Source: Bishop, 2010)
(Source: terHoeve et al., 2017)
The prognosis of breast cancer depends on the type of breast cancer, the grade or the stage of breast cancer, the size of tumour, the status of the lymph node of the breast cancer, the overall status of the ER and HER2 (Assi et al., 2013). Stage is the first prognosis factor underlying breast cancer. According to Assi et al. (2013), there is comparatively lesser risk that early stage breast cancer will return back thus it has more favourable prognosis. The diagnosis of the breast cancer at later stages of life has higher risk of recurrence and thus have less favourable prognosis. Mainly the side of lymph nodes and the size of tumour are considered while analysing the prognosis of the breast cancer. If the breast cancer has propagated in the lymph nodes then there is higher risk of recurrence and this signifies less chances of prognosis. The second important prognosis factor is the size of the tumour. The tumours of the breast which are larger than 5 cm are more likely to come back and thus less favourable prognosis. The grade of the tumour is also considered while determining the prognosis of breast cancer. Low-grade tumours are less likely to spread throughout the tissues and thus have better prognosis than high-grade tumour. The hormone receptor-positive tumours mainly have good prognosis as they are less aggressive. The presence of the HER2 gene also alters the prognosis of breast cancer. HER2-positive breast cancer signifies that the cancer cells make too many copies or has higher risk of over-expression and thus decreasing the overall prognosis. The age of the individual also affects the prognosis of the breast cancer. Women who are younger than 35 years of age are more likely to get diagnosed with aggressive breast cancer with high grade tumours. This breast cancers are mainly advanced grade cancer at the time of diagnosis and are more likely to re-occur and thus has less rate of prognosis in comparison to the post menopausal women who more than 35 years of age (Assi et al., 2013). However, contrasting results were highlighted in the study conducted by Hughes et al. (2013), the authors here are of the opinion that severity of the detection of breast-cancer is also higher among the women who are 70 years old. Successful lumpectomy and periodic application of tamoxifen at times failed to reduce the vulnerability of recurrence.
The treatment of breast cancer is mainly based on hormonal therapy and chemotherapy. Hormonal therapy for breast cancer is mainly used after surgery as a form of adjuvant therapy. Hormonal therapy helps to reduce the overall risk recurrence of the disease. At times, the hormonal therapy is initiated before surgery in the form of neo-adjuvant therapy and is usually continued for 5 years (Burstein, Lacchetti & Griggs, 2016). According to Burstein, Lacchetti and Griggs (2016), 2 out of 3 breast cancers are hormone receptor-positive. Hormone receptor-positive cells have receptor proteins that bind to the hormones estrogen or hormone progesterone. Binding with the hormones helps the cancerous cell to grow fast. So in hormone therapy, the hormonal receptors of the cancerous cells are blocked and thereby preventing the cancerous cell from growing. In the majority of the hormonal therapy for the breast cancer, estrogen binding receptors are used. The main drugs which are used for the hormonal therapy of the breast cancer include Tamoxifen. Tamoxifen mainly blocks the estrogen receptor present on the breast cancer cells. This in turn prevents estrogen from connecting to the cancer cell and thereby preventing them to divide and grow. Toremifene or Fareston also works in similar way like Tamoxifen but is used less often and is only used for the treatment for metastatic breast cancer. There drugs are mainly taken orally and are also associated with side-effects like hot flashes, vaginal dryness or discharge and mood swing (Burstein, Lacchetti & Griggs, 2016). The main strength of the study conducted by Burstein, Lacchetti and Griggs (2016) is structure of the study. The authors opted for systematic review of the randomized control trials. However, they only selected two articles for the review this might be regarded as one of the drawback of the study.
Recently the researchers are planning to target the PI3K/AKT/mTOR and Raf/MEK/ERK pathways for the treatment of breast cancer (Saini et al., 2013). The targets of these pathways are most done by the chemotherapeutic drugs which will act as an antagonist to one of the components of the pathway. This hampers the downstream signalling of the pathway and thereby causing cessation of the pathway and its effect on the malignant proliferation of the breast cancer tissue (Saini et al., 2013).
The future molecular diagnosis of breast cancer is mainly based on the designing of the biomarkers for the effective detection of the stage and the type of breast cancer. The prognostic biomarkers will selectively aim to identify the somatic germ line mutations, level of DNA methylation and the levels of micro RNA and circulating tumour cells in breast cancer (Kalia, 2015). Use of the biomarkers for the detection of the somatic germ line mutations will help in the generation of the personalised medicines. According to Kalia (2015) personalised medicine is an emerging practice of medicine that employs the genetic profile of an individual for disease treatment. However, study conducted by Kalia has sudden limitations like it mainly used to identified somatic cell mutations and not the germ-line mutations. The study conducted by Piva, Spandidos and Gambari (2013) highlighted that microRNA functions and microRNA therapeutics are now used to design novel drug targets for breast cancer treatment. The main strength of their study is, the authors utilised the expression profile of oncogenic miRNAs and tumor suppressor miRNAs and this helped them to obtain case specific data.
Conclusion
Thus from the above discussion, it can be concluded that breast cancer is a complex disease with several different variation in the disease occurrence and requires thorough treatment along with regular monitoring for better health outcomes. Some of the common and widely known breast-cancers include invasive ductal carcinoma, invasive lobular carcinoma and ductal carcinoma in-situ. The underlying pathology of breast cancer is mainly guided by the two different hypotheses. One hypothesis is guided by sporadic clonal evolution model and another hypothesis is guided by the cancer stem cell model. The popular molecular diagnostic approaches which are used for the detection of breast cancer include immuno-histochemical techniques, fluorescence in-situ hybridization and ligand binding assays for the detection of human epidermal growth factor. Early detection of the breast cancer promotes quality prognosis along with providing the basis of the thorough therapy plan. The treatment of breast cancer mainly includes surgery and hormonal therapy. Future molecular diagnostic methods are mainly targeting the use of biomarkers for devising personalised medicines.
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