What are the causes of breast cancer ?

Incidence and Survival


Breast cancer is the most common form of cancer among women. In 2018, with an estimated 2 million new cases diagnosed worldwide. Although breast cancer remains the leading cause of cancer death among women aged 35–55 years, survival has greatly improved in the last 2 decades with development of more effective and less toxic treatments.




Structure of the breast and its clinical significance


The breast is composed of glandular and fatty tissue in varying proportions. The glandular tissue consists of 15–20 segments. When active, milk is secreted by glands into small ductules which join, like rivulets to form lactiferous ducts, which ultimately open through the nipple as 15-20 fine pores. When milk is not being made, small amount of fluid continues to get secreted. The amount is so little that it is not usually noticeable. The soft breast tissue is supported by fibrous Cooper’s ligaments, which give it its characteristic shape. Invasion of Cooper’s ligaments by cancer shortens them, leading to the classic early sign of dimpling of skin. This sign can be more noticeable by contracting the pectoralis muscle or by raising arms above the head or by bending forwards. The lymphatics of the breast tissue converge in the subareolar plexus of Sappy, and then drain into the axilla (armpit).




Pathophysiology


The origin of breast cancers: Most breast cancers are epithelial tumors, arising from either the milk producing glands (lobular carcinomas) or, more commonly, from the draining ducts (ductal carcinomas); only a small number are non-epithelial involving the stroma - the tissue between glands and ducts. Ductal carcinomas account for over 90% of breast cancers and lobular carcinomas account for approximately 8%. Lobular cancers can be difficult to diagnose, as their diffuse nature and relative radiolucency mean that they often do not show up on mammograms. The prognosis of ducal and lobular cancers are not too different, but they may need different treatments. Phyllodes tumors are relatively rare stromal tumors that only very rarely exhibit the malignant features of a true sarcoma. Clinically and on imaging they resemble fibroadenomas, although they are often larger. Receptor status. Oestrogen and progesterone are important regulators of normal breast growth and development and play important roles in the pathogenesis of breast cancer. The hormone receptors in some breast cancers promote DNA replication and cell division when oestrogen or progesterone bind to them (e.g. an estrogen-receptor positive [ER+] tumor), The presence of the receptor for human epidermal growth factor 2 (HER2) correlates with a poorer prognosis at any given stage of cancer. The good news is that by blocking these receptors with drugs can stop cancer growth and may even lead to complete regression.




What factors change the chances of developing breast cancer?


Increasing physical activity, healtheir diet and avoiding alcohol are the practically modifiable risk factors. Age - getting older is by far the greatest risk factor for cancer in general. Every day, our DNA gets damaged and our cells repair almost all damages. If a critial part of DNA remains unrepaired, the cell can become cancerous. Naturally, the chance of missing out on a critical repair happening increases as one ages. However, one cannot stop ageing! Diet: increasing fruits, vegetables, grains, and reducing fats to less than 20% of calories in a day reduces the chance of dying after breast cancer diagnosis. Excercise and physical activity: Lack of excercise is associated with increased risk. Physical activity reduces the risk of both pre- and postmenopausal breast cancer, as well as the risk of recurrence after a diagnosis of breast cancer, apart from so many other advantages Obesity. Obesity confers an increased risk of breast cancer in postmenopausal women, and weight reduction is associated with a reduced risk. Alcohol: Alchohol increases the risk of development and relapse breast cancer. For every additional drink (or 5 g of alcohol) consumed per day, it is estimated that 11 additional breast cancers will occur per 1000 women. There is no lower limit of dose of alcohol below which the risk is not increased. Smoking Smokers have an increased risk of metastatic relapse (especially in the lungs) after treatment of breast cancer. Breast feeding: Prolonged breast feeding seems to lower the risk of breast cancer (4% reduction associated with every year of breast feeding) Children: Early full term pregnancy and more children seem to reduce the risk Geographic associations. The incidence of breast cancer is higher in more developed countries, perhpas due to greater population screening. Both genetic and environmental factors such as diet and sociocultural effects are also responsible for the variation between countries. Reproductive history. The risk is increased in women who have their first period an early age (< 12 years) or whose menopause is beyond 55 years. Conversely, early first pregnancy and long-term breast feeding (several months rather than a few weeks) reduce breast cancer risk. Having an abortion does not seem to increase the risk. The more aggressive breast cancers seen in pregnant women appear to be explained by the younger age of these patients rather than the pregnancy per se. Oral contraceptives The relative risk of breast cancer is slightly increased (relative risk of 1.24) with oral contraceptives particularly when taken before the first full-term pregnancy. The absolute increase is actually very small and oral contraceptives diminish the risk of ovarian and endometrial cancers.
Menopausal hormone replacement therapy (HRT) Several large observational studies have found that (HRT) increases the risk of developing breast cancer by a small absolute amount. Women taking HRT also have greater breast density on mammography, making it more difficult to detect small cancers. However, at present, HRT is the only effective treatment to control significant menopausal symptoms. So in many women the great immediate benefits and the potential risks which is small in absolute terms need to be considered in a balanced manner and an informed choice can be made.
Night work. Women who work night shifts appear to have an increased risk of developing breast cancer, probably due to changes in the levels of melatonin and disturbance of the circadian rhythm. Higher mammographic breast density is an independent indicator of higher risk of breast cancer, with a relative risk of up to 4 between the most and least dense breasts. Family history. Overall, 10–15% of breast cancers are attributable to family history, and half of these can be attributed to specific genes. The risk is particularly high if the affected relative is on the maternal side of the family, two first-degree relatives are affected, or the relative was young at the time of diagnosis (< 50 years) or had bilateral breast cancer. Having Ashkanezi Jewish or Polish ancestry increases the chance of having familial breast cancer. Genetic mutations. Mutations in these some genes ((BRCA1, BRCA2, PALB2, P53, etc). are implicated in approximately 4% of all breast cancers and in up to 25% of patients diagnosed before the age of 40 years; they are also linked to ovarian cancers. The breast cancer risk associated with mutations in BRCA2 is less than that with mutations in BRCA1, but the presence of the gene mutation carries additional smaller risks of male breast and prostate cancers and perhaps others. Other genes that are implicated in breast cancer risk are CHEK2, TP53 ATM (ataxia telangiectasia mutated), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer) and STK11 (Peutz-Jeghers syndrome). Today, it is possible to have a blood test to check if one is carrying any mutation in any of these genes, but before taking such a test a proper consultation with specialists is essential to understand the implications of even going ahead with the test.




The risk vs benefit of treatments


Treatment risks versus benefits. Proportional risk is perhaps the most important concept to arise from the many trials of systemic (adjuvant) therapy for early breast cancer. Sytemic treatments affect the whole body. Most treatments reduce the risk of breast cancer recurrence by a relatively constant proportion. Thus, in premenopausal women, chemotherapy reduces the risk of recurrence by 33% and oophorectomy by about 25%, while in postmenopausal women tamoxifen reduces the risk by about 40%. Thus, the benefit for a given woman in absolute terms depends on both the effect of treatment on the relative risk and the underlying individual risk factors. Fundamental to interpreting estimates of benefit is the understanding that the proportion being calculated relates to the number of adverse events, not the number of individuals at risk. For example, a premenopausal woman with a 1.5-cm tumor without nodal involvement may have a 10-year risk of recurrence of 10%. If adjuvant chemotherapy produces a relative risk reduction of about 30% then, in absolute terms, the patient gains 30% of the 10% risk of recurrence, which is about 3%. On the other hand, if the same woman has four nodes involved, her 10-year risk of recurrence is about 50%. The treatment offers a 30% relative risk reduction, leading to an absolute benefit of 30% of 50%: a 15% decrease in the probability of recurrence within 10 years. Competing adverse risks, including the toxicity of treatment, are generally not considered, so the data from which these recommendations are derived may overestimate benefit. In addition, the toxicity of treatment affects the entire population treated. Thus, if the risk of an adverse event is 25%, then 1 in 4 of those who receive the treatment will experience the effect. If only 3 in 100 benefit from a reduction in the recurrence risk, it might be said that 25 people experience side effects in order for 3 to accrue a benefit. Understanding these concepts is fundamental to understanding risks versus benefits.





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