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| ======= Breast Cancer ======= | ======= Breast Cancer ======= | ||
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| + | Powerpoint file: {{:a-look-inside-breast-cancer-1.pptx|}} | ||
| ===== Introduction ===== | ===== Introduction ===== | ||
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| === Incidence: === | === Incidence: === | ||
| - | The greatest incidence is found in European countries, followed by America and Canada. Rates of breast cancer are significantly lower in African countries. According to WHO, there were over 508 000 deaths around the globe in 2011. | + | The greatest incidence is found in European countries, followed by America and Canada. Rates of breast cancer are significantly lower in African countries. According to WHO, there were over 508 000 deaths around the globe in 2011 <sup>[4]</sup>. |
| === Distribution === | === Distribution === | ||
| - | Breast cancer affects women around the globe. Death rates are lower in developed countries as more treatment options are available in these regions. The number of cases is steadily increasing in developing countries where treatment and cancer tests are not as readily available. According the American Cancer society, it is projected that there will be 1.6 million new cases of breast cancer in the world. | + | Breast cancer affects women around the globe. Death rates are lower in developed countries as more treatment options are available in these regions. The number of cases is steadily increasing in developing countries where treatment and cancer tests are not as readily available <sup>[24]</sup>. According the Canadian Cancer society, it is projected that there will be 1.6 million new cases of breast cancer in the world <sup>[6]</sup>. |
| === Control of disease === | === Control of disease === | ||
| - | There are a variety of methods to treat breast cancer (see more in the treatment section). They can generally be divided into invasive and non-invasive. Moreover, continuous research is done by different organizations such as the Breast Cancer organization. | + | There are a variety of methods to treat breast cancer (see more in the treatment section) <sup>[4]</sup>. They can generally be divided into invasive and non-invasive <sup>[4]</sup>. Moreover, continuous research is done by different organizations such as the Breast Cancer organization <sup>[4]</sup>. |
| === Survival rates === | === Survival rates === | ||
| - | Although survival rates are increasing, low-income countries are still suffering from lack of available resources to diagnose and treat cancer. Survivability rates have reached over 80% in North America but still remain below 40% in developing and low income countries. | + | Although survival rates are increasing, low-income countries are still suffering from lack of available resources to diagnose and treat cancer. Survivability rates have reached over 80% in North America but still remain below 40% in developing and low income countries <sup>[5]</sup>. |
| - | Detection and treatment of breast cancer in earlier stages show an increase in success rates. In 2014, over 236, 968 women were affected in the US and 2141 men and led to 41, 211 deaths in women and 456 deaths in men. | + | Detection and treatment of breast cancer in earlier stages show an increase in success rates. In 2014, over 236, 968 women were affected in the US and 2141 men and led to 41, 211 deaths in women and 456 deaths in men <sup>[5]</sup>. |
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| === Stage 0: Carcinoma In Situ Stage=== | === Stage 0: Carcinoma In Situ Stage=== | ||
| - | There is abnormal but non-invasive cellular growth in the ducts, lobule, or nipple region. Generally clinical breast exams or mammograms are recommended followed by a tamoxifen hormone therapy | + | There is abnormal but non-invasive cellular growth in the ducts, lobule, or nipple region <sup>[44]</sup>. Generally clinical breast exams or mammograms are recommended followed by a tamoxifen hormone therapy <sup>[44]</sup> |
| === Stage 1 === | === Stage 1 === | ||
| - | The cancer is found and contained in the regions where abnormal cells began to grow. If the cancer is stage 1a, the tumour is less than 2cm in size and has not spread to lymph nodes. If the cancer is in stage 1b, the cancer has moved to the lymph nodes but is less than 0.2-2mm in size. | + | The cancer is found and contained in the regions where abnormal cells began to grow <sup>[44]</sup>. If the cancer is stage 1a, the tumour is less than 2cm in size and has not spread to lymph nodes <sup>[44]</sup>. If the cancer is in stage 1b, the cancer has moved to the lymph nodes but is less than 0.2-2mm in size <sup>[44]</sup>. |
| === Stage 2 === | === Stage 2 === | ||
| - | The cancer continues to grow but remains either in the breast or has extended a little beyond the lymph nodes. Stage 2a means the tumour is either less than 2cm but has crossed less than 4 auxiliary lymph nodes or the tumour is between 2-5cm in size but has not spread towards the lymph nodes. Stage 2b can be characterized by the size of the cancer being between 2-5cm in size spreading into the lymph nodes or the tumour being about 5cm but has remaining stationary. | + | The cancer continues to grow but remains either in the breast or has extended a little beyond the lymph nodes <sup>[44]</sup>. Stage 2a means the tumour is either less than 2cm but has crossed less than 4 auxiliary lymph nodes or the tumour is between 2-5cm in size but has not spread towards the lymph nodes <sup>[44]</sup>. Stage 2b can be characterized by the size of the cancer being between 2-5cm in size spreading into the lymph nodes or the tumour being about 5cm but has remaining stationary <sup>[44]</sup>. |
| === Stage 3 === | === Stage 3 === | ||
| - | The breast cancer has now spread beyond the region of the original tumour growth and is beginning to affect muscles and lymph nodes beyond the original site. In stage 3a the tumour is growing beyond 5cm in size. There are also small clusters of cancerous cells found in the lymph node region. Otherwise, the tumour is larger than 5cm and spreading to lymph nodes and nearby regions like the breastbone or under the arm. In stage 3b, the tumour can grow to any size as it spreads and invades of the skin near the breast and chest walls. | + | The breast cancer has now spread beyond the region of the original tumour growth and is beginning to affect muscles and lymph nodes beyond the original site <sup>[44]</sup>. In stage 3a the tumour is growing beyond 5cm in size. There are also small clusters of cancerous cells found in the lymph node region. Otherwise, the tumour is larger than 5cm and spreading to lymph nodes and nearby regions like the breastbone or under the arm <sup>[44]</sup>. In stage 3b, the tumour can grow to any size as it spreads and invades of the skin near the breast and chest walls <sup>[44]</sup>. |
| === Stage 4 === | === Stage 4 === | ||
| - | This is considered the most dangerous stage, as there is no treatment to cure the cancer. The cancer has spread to other regions around the body and has metastasized into regions of the brain, bones, liver, and lungs. Treatment can only prolong the individual’s lifespan. | + | This is considered the most dangerous stage, as there is no treatment to cure the cancer <sup>[44]</sup>. The cancer has spread to other regions around the body and has metastasized into regions of the brain, bones, liver, and lungs <sup>[44]</sup>. Treatment can only prolong the individual’s lifespan. |
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| **BCRA Gene** | **BCRA Gene** | ||
| - | The breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are tumour suppressor genes, and translational protein products expressed in all humans (A1). The specific locality of BRCA1 and BRCA2 gene is on chromosome 13 and 17, respectively (A2, A3). Moreover, the significance of such genes is predominantly due to the associated lifetime risk for breast cancer (BC) when mutations are present. This is evidently shown through a prospective cohort study by Kuchenbaecker et al. which revealed the cumulative BC risk to age 80 years to be 72% for BRCA1 and 69% for BRCA2. Additionally, further data has shown a rapid increase in BC incidence from adulthood until ages 30-40 for BRCA1, and until ages 40-50 for BRCA2. However, past the upper-limit for the peak-incidence of each respective gene, the frequency of BC presentation remains constant at 20-30 per 1000 persons until age 80 (A4). When the BRCA gene is translated into its BRCA protein product, it plays a role in the repairing double DNA breaks such as non-homologous end-joining and homologous recombination DNA repair (A5, A6). It also functions to facilitates cellular responses to DNA damage through blockage of cell proliferation and induction of apoptosis (A7). Thereby, a genetic mutation on BRCA1 and BRCA2 affecting in the functional capability of its protein products would ultimately lead to the susceptibility in mutated-BRCA carriers for BC. | + | The breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are tumour suppressor genes, and translational protein products expressed in all humans <sup>[39]</sup>. The specific locality of BRCA1 and BRCA2 gene is on chromosome 13 and 17, respectively <sup>[32]</sup><sup>[40]</sup>. Moreover, the significance of such genes is predominantly due to the associated lifetime risk for breast cancer (BC) when mutations are present. This is evidently shown through a prospective cohort study by Kuchenbaecker et al. which revealed the cumulative BC risk to age 80 years to be 72% for BRCA1 and 69% for BRCA2. Additionally, further data has shown a rapid increase in BC incidence from adulthood until ages 30-40 for BRCA1, and until ages 40-50 for BRCA2. However, past the upper-limit for the peak-incidence of each respective gene, the frequency of BC presentation remains constant at 20-30 per 1000 persons until age 80 <sup>[27]</sup>. When the BRCA gene is translated into its BRCA protein product, it plays a role in the repairing double DNA breaks such as non-homologous end-joining and homologous recombination DNA repair <sup>[2]</sup> <sup>[36]</sup>. It also functions to facilitates cellular responses to DNA damage through blockage of cell proliferation and induction of apoptosis <sup>[11]</sup>. Thereby, a genetic mutation on BRCA1 and BRCA2 affecting in the functional capability of its protein products would ultimately lead to the susceptibility in mutated-BRCA carriers for BC. |
| **Evidence that BRCA Involved in DNA Repair** | **Evidence that BRCA Involved in DNA Repair** | ||
| - | There are several studies which evidently validate the evidence of BRCA1 and BRCA2 in DNA repair. Firstly, a study conducted by Foray et al. reveals the inability of irradiated cells to repair DNA double-strand breaks due dysfunctional BRCA1 and BRCA 2 (A8). Secondly, an additional study has demonstrated the impairment of chromosomal-break repair by homologous recombination in BRCA1- and BRCA2-mutant cell-lines. It is further explained in the study that BRCA proteins conjugate with Rad51 recombinase to effectively repair DNA damage, and thus allowing for chromosomal stability (A9, A10). Lastly, Chen et al. reveals the coexistence of BRCA1 and BRCA2 in a biochemical complex which co-localize at the DNA replication sites post-application of hydroxyurea or UV radiation to cause double DNA breaks (A11, A12). | + | There are several studies which evidently validate the evidence of BRCA1 and BRCA2 in DNA repair. Firstly, a study conducted by Foray et al. reveals the inability of irradiated cells to repair DNA double-strand breaks due dysfunctional BRCA1 and BRCA 2 <sup>[17]</sup>. Secondly, an additional study has demonstrated the impairment of chromosomal-break repair by homologous recombination in BRCA1- and BRCA2-mutant cell-lines. It is further explained in the study that BRCA proteins conjugate with Rad51 recombinase to effectively repair DNA damage, and thus allowing for chromosomal stability <sup>[33]</sup>. Lastly, Chen et al. reveals the coexistence of BRCA1 and BRCA2 in a biochemical complex which co-localize at the DNA replication sites post-application of hydroxyurea or UV radiation to cause double DNA breaks <sup>[8]</sup><sup>[42]</sup>. |
| **Alterations in the Cell Cycle** | **Alterations in the Cell Cycle** | ||
| - | Apart from the susceptibility of BC due to the inability of mutant-BRCA to repair DNA breakages; there are additional genes, when unregulated, results in cancerous-cell phenotypes of the breast tissue (A 13). These genes are primarily responsible for regulation of the cell cycle which is an important mechanism for normal cell growth, survivability and replication. | + | Apart from the susceptibility of BC due to the inability of mutant-BRCA to repair DNA breakages; there are additional genes, when unregulated, results in cancerous-cell phenotypes of the breast tissue <sup>[1]</sup>. These genes are primarily responsible for regulation of the cell cycle which is an important mechanism for normal cell growth, survivability and replication. |
| - | Therefore, such disruption in cell-cycle regulatory factors can ultimately lead to sustained proliferative signaling, evasion of growth suppressors, replicative immortality, activation of invasion and metastasis, induction of angiogenesis, and resistance to cell death (A14). In breast cancer, the overexpression of cyclin D1 and E, down-regulation of cyclindependent kinase inhibitors, or the activation of tumour suppressor proteins, retinoblastoma and p55 are the known altered-regulatory cell-cycle proteins that result in the development of cell-malignancy (A15). | + | Therefore, such disruption in cell-cycle regulatory factors can ultimately lead to sustained proliferative signaling, evasion of growth suppressors, replicative immortality, activation of invasion and metastasis, induction of angiogenesis, and resistance to cell death <sup>[12]</sup>. In breast cancer, the overexpression of cyclin D1 and E, down-regulation of cyclindependent kinase inhibitors, or the activation of tumour suppressor proteins, retinoblastoma and p55 are the known altered-regulatory cell-cycle proteins that result in the development of cell-malignancy <sup>[28]</sup>. |
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| === Immunotherapy === | === Immunotherapy === | ||
| - | Current research has progressively contributed to the advancement of breast cancer treatment. The investigations have been especial towards engineered-viral therapy to provide additional modalities of treatment associated with enhanced efficacy. Presently, numerous oncolytic viruses for both monotherapy, and combination therapy are undergoing clinical trials to evaluate the safety and efficacy of treatments. One recent study conducted by Hemminki et al. reveals the impact of the oncolytic adenovirus Ad5/3-E2F- delta24-GMSF in inducing oncolysis and initiating a potent anticancer immune response towards solid non-metastatic tumours. The results showed a radiological disease control rate of 83%, and accumulate of immunological cells to tumours in 9/12 patients (A16). However, the monotherapeutic delivery of oncolytic viruses may not serve optimal success for metastatic and advanced stages of cancer. Thereby, oncolytic viruses can be combined with other anticancer remedies to maximized the efficacy of therapeutics in a synergetic manner. A study conducted by Cerullo et al. demonstrates the immunological effects of cyclophosphamide (CP) in combination with oncolytic adenovirus on cancer patients. The results show that CP-adenoviral treatments had higher rates of disease control than that of the virus alone, as well as overall patient-survivability (A17). | + | Current research has progressively contributed to the advancement of breast cancer treatment. The investigations have been especial towards engineered-viral therapy to provide additional modalities of treatment associated with enhanced efficacy. Presently, numerous oncolytic viruses for both monotherapy, and combination therapy are undergoing clinical trials to evaluate the safety and efficacy of treatments. One recent study conducted by Hemminki et al. reveals the impact of the oncolytic adenovirus Ad5/3-E2F- delta24-GMSF in inducing oncolysis and initiating a potent anticancer immune response towards solid non-metastatic tumours. The results showed a radiological disease control rate of 83%, and accumulate of immunological cells to tumours in 9/12 patients <sup>[22]</sup>. However, the monotherapeutic delivery of oncolytic viruses may not serve optimal success for metastatic and advanced stages of cancer. Thereby, oncolytic viruses can be combined with other anticancer remedies to maximized the efficacy of therapeutics in a synergetic manner. A study conducted by Cerullo et al. demonstrates the immunological effects of cyclophosphamide (CP) in combination with oncolytic adenovirus on cancer patients. The results show that CP-adenoviral treatments had higher rates of disease control than that of the virus alone, as well as overall patient-survivability <sup>[7]</sup>. |
| - | Apart from oncolytic therapies, natural killer (NK) cells have also been a significant focus in the field of immunology due to its role in cancer immunosurveillance and potential to eradicate cancer cells. A recent study conducted by Shenouda et al. demonstrates ex-vivo expansion of activated NK-cells in providing highly effective cytotoxicity against breast cancer cell lines (A18). The ability to accumulate personalized activated NK-cells would enable patients to restore or boost NK-cell levels to optimally combat cancerous cells. Ultimately, these findings may offer various modalities of management for more individualized approaches to breast cancer patients, as well as bridging the next step of innovation towards cancer treatment. | + | Apart from oncolytic therapies, natural killer (NK) cells have also been a significant focus in the field of immunology due to its role in cancer immunosurveillance and potential to eradicate cancer cells. A recent study conducted by Shenouda et al. demonstrates ex-vivo expansion of activated NK-cells in providing highly effective cytotoxicity against breast cancer cell lines <sup>[44]</sup>. The ability to accumulate personalized activated NK-cells would enable patients to restore or boost NK-cell levels to optimally combat cancerous cells. Ultimately, these findings may offer various modalities of management for more individualized approaches to breast cancer patients, as well as bridging the next step of innovation towards cancer treatment. |
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