A Comprehensive Review of Breast Cancer: Classification, Stages, Risk Factors, And Diagnostic Method

Abstract

Breast cancer is a leading health concern globally and the second highest cause of cancer-related deaths among women. Though predominantly found in women, it can also affect men, albeit infrequently. Its progression involves complex, multi-step processes that make prevention and treatment a significant challenge. The disease is characterized by its potential to spread aggressively to distant organs such as the liver, lungs, brain, and bones, complicating management and reducing survival rates in advanced stages. The classification of breast cancer spans stages 0 to 4, reflecting the size, type, and extent of tumor spread. Non-invasive tumors fall under stage 0, while stage 4 represents advanced, metastatic disease. Several risk factors contribute to its occurrence, including age, hormonal changes, genetics, lifestyle choices, and environmental exposures. Genetic mutations like BRCA1 and BRCA2, late menopause, lack of physical activity, alcohol consumption, and exposure to radiation significantly increase susceptibility to breast cancer. Early diagnosis has improved significantly due to advances in imaging technologies, such as mammography, MRI, and PET scans, alongside molecular diagnostic tools like biomarker identification and gene sequencing. Despite these developments, breast cancer’s diversity and complexity demand personalized treatment approaches and a deeper understanding of its underlying mechanisms. Enhancing preventive strategies and refining diagnostic methods are essential for reducing its global impact and improving patient outcomes.

Keywords

Introduction

       
           
       
Figure 1 – Types of breast cancer

       
           
       
Figure 2 – Stage 0 Breast Cancer

2.2 - Stage 1 –This stage describes as the invasive breast carcinoma and microscopic invasion is possible in this stage. It has two categories that are 1A and 1B stage. The category 1A describes the tumor which measures up to 2 cm and none of the lymph nodes are involved in it while stage 1B describes that small group of cancer cells larger than 0.2 mm founds in lymph node. ^[42]

       
           
       
Figure 3 - Stage 1 Breast Cancer

2.3 - Stage 2 - This phase is also known by two other names, 2A and 2B, respectively. The staging process's Phase 2A shows cancer that has been discovered in the circulatory and lymphatic systems but not in the chest cavity. Cancer can range in size from less than 2 centimeters to more than 5 centimeters. Phase 2B, however, shows that although the cancer may be more than 5 cm in size, it has not spread to the axillary lymphatic nodes.^[53]

       
           
       
Figure 4 – Stage 2 Breast Cancer

2.4 - Stage 3 -  That although there is no tumor in the breast, it may be found in 4–9 axillary lymph nodes or sentinel lymph nodes, whereas stage 3B indicates that the tumor may be any size but has resulted in breast skin swelling or ulceration and may have spread to up to 9 axillary lymph nodes or sentinel lymph nodes. Inflammatory breast cancer, or stage 3B, is characterized by red, heated, and swollen breast tissue. Nevertheless, step 3C details the dissemination of 3A, 3B, and 3C are the three subcategories into which it has been separated. Of them, stage 3A characterizes tumors involving 10 or more axillary lymph nodes. and the lymph nodes above and below the collarbone have also been affected.^[42]

       
           
       
Figure 5-  Stage 3 breast cancer

2.5 - Stage 4 – The disease has progressed to other organ systems, including the liver, brain, lungs, bones, and so forth. This is the advanced and metastatic stage of cancer.^[53]
       
           
       
Figure 6 - stage 4 breast cancer

3 - Sign and symptoms -

A lump under the armpit or in the breast is the typical sign of breast cancer. Conducting a monthly breast self-examination (BSE) is an excellent method of being acquainted with the size, texture, cyclical changes, and skin condition of the breasts.

 Breast cancer symptoms include breast swelling or lump (mass), breast swelling in the armpit (lymph nodes), clear or bloody nipple discharge, nipple pain, inverted (retracted) nipple, scaly or pitted skin on the nipple, persistent breast tenderness, and unusual breast pain or discomfort.

Underarm lymph nodes are found in advanced stages (metastatic) of the disease, often with additional symptoms such headaches, neurological discomfort or weakness, bone pain (bone metastases), shortness of breath (lung metastases), appetite loss (liver metastases), and inadvertent weight loss (liver metastases).^[38]

4 - Breast  cancer  risk factor -

4.1 . Demographic factors -

4.1.1- Gender -  Breast cancer growth is much of the time an illness that is novel to ladies and Male breast cancer  contains <1>[6]

4.1.2- Age - The greatest recognized risk factor for breast cancer, after gender,  age .^[1] as the incidence of breast cancer rises with age, about doubling every ten years until menopause, at which point it sharply declines. Breast cancer occurs more frequently at younger ages than lung cancer. In certain nations, the age incidence curve flattens off following menopause.^[4]  Women above the ages of 40 and 60 accounted for around 99.3% and 71.2% of all breast cancer-related deaths in America in 2016, respectively.^[2]

4.1.3 - Aob Blood group – Women who have blood type A and are Rhesus positive are more likely to get breast cancer, whereas women who have blood group AB and are Rhesus negative are less likely to do so, according to the findings of a review research. Despite a 2015 study that supported these findings, several studies did not discover a link between blood type and breast cancer.^[1]

4.2 - Reproductive factor

4.2.1- Age of menarche – Unobtrusive height in   breast  malignant growth risk is related with early  age  of menarche .^[8] also observation suggested that regular  ovulatory  feminine cycle increment a lady's  risk of breast cancer .  breast  malignant growth hazard could be multiple times more prominent among ladies whose periods become normal in something like one year of their most memorable feminine period than among ladies with a five years or longer defer in the beginning of standard cycle.^[7]  Age at menarche and breast malignant growth risk are likely by implication related, with sustenance being the conceivable normal element. Research gauge that the  risk of breast cancer can be diminished 10-20% for every year menarche is postponed. The consequences of a huge report uncovered that for every long term postpone in beginning of period,  breast malignant growth risk was decreased by around 10%.^[9]

4.2.2-  Late age of menopause – The  age  of menopause over 50 years is related with an expanded  risk of  breast malignant growth  . Ladies who experience menopause later have a drawn out ovarian action which expands the  risk of creating breast malignant growth .It has been seen that for  every   5 year  contrast   in age at menopause, the  risk  of BC   changes by around 17%. ^[9]  Ladies who arrive at menopause at a late age are bound to have a higher  risk  of breast cancer , albeit no reliable pattern is noticed . The higher breast malignant growth risk in ladies with a late menopause is in all likelihood made sense of by both the more extended length and more significant level of openness to estrogen and progesterone experienced by these ladies. They likewise may encounter a bigger number of anovulatory cycles bringing about an absence of cyclic progesterone. The impact of hormonal milieu on  breast malignant growth during anovulatory cycle is less clear.  Artificial  menopause by reciprocal oophorectomy likewise extraordinarily decreases breast cancer  risk and the impact is more prominent than that normal menopause . ^[7]

4.2.3-. Full term pregnancy – The risk of breast cancer is negatively correlated with the age at first full-term pregnancy (FP).^[11] Perhaps the relationship is due to a long-lasting hormonal alteration, a maturity of breast cells during pregnancy that makes them less vulnerable to carcinogenic transformation, or both. A increased risk of breast cancer has also been linked to late age at last FP, however not all studies have found this. Apart from the initial and final research, very few others have examined the impact of age at FP.^[1,10]

4.2.4 -  Abortion – Studies have uncovered that the breast  growths of women who have unconstrained or prompted abortion  quite early in life have a higher pace of cell multiplication and a higher recurrence of aneuploid growths contrasted and the growths of other young women with breast cancer. During the primary trimester of pregnancy, the breast  is portrayed by high mitotic action and expansion, and afterward in the mid to late pregnancy, cell separation prevail. In this manner, it is conceivable that those pregnancies that are not hindered for the rest of the main trimester could bring about the breast containing countless undifferentiated cells, comparative with the breast of women whose fetus removal was actuated right off the bat in pregnancy or the people who had no early termination by any means. ^[9] It has been proposed that abortion leave the breast  epithelium in a proliferative state with an expanded defenselessness to carcinogenesis.^[12]

4.2.5 - Ovulation menstrual cycle –

The ovulatory menstrual cycle may have a protecting role against breast cancer .^[1]

4.2.6 - Pregnancy  characteristics – ladies who were diagnosed to have pre -aclampsia and /or  hypertension in their first  pregnancy were at diminished hazard of breast cancer , contrasted with different ladies who didn't create pre -aclampsia and /  or hypertension during their first pregnancy.^[13]

 Pregnancy, particularly the primary pregnancy, assumes a significant part in the risk of creating breast cancer. The consequences of studies showed that the risk of breast cancer is nearly multiplied in ladies who bring forth their most memorable youngster before the 33 weeks of growth .the risk of creating breast cancer  increased in multiple  births^[1]

4.3 - Hormonal factors

4.3.1-  Contraceptive methods – Oral contraceptives (OCs) among the most broadly utilized strategies are of viable and reversible family planning  . Many inquiries exist concerning a potential relationship between the use  of OCs and the development  of cancer . Advantages and dangers of OCs use on cancer  were explored by Working Gatherings of the Worldwide Organization for Exploration on Malignant growth (IARC/WHO) in 2007, which reasoned that OC are cancer-causing to humans.^[14] . Family history of  breast cancer is a laid out risk factor for breast cancer. Likewise, there is proof that oral  contraceptive  use might be related with a moderate increase in breast cancer risk.^[15]

4.3.2-  Ovulation -  stimulating drug – The consequence of a case-control study showed that involving ovulation-invigorating prescriptions for over a half year builds the  risk  of creating  breast   cancer . Nonetheless, this finding was not affirmed in different examinations.

4.3.3 - Postmenopausal hormone therapy- Postmenopausal  hormone therapy (HT), specifically estrogen in addition to progestin, increment and breast cancer risk. Postmenopausal estrogen and progestin use for a long time or more improves the probability of creating breast cancer that is analyzed at a high level stage. It isn't known whether breast cancer severity is increased even more in ladies with dense  breast  who use  postmenopausal HT. ^[16]

4..4 - Hereditary factors

4.4.1- Genetic factors  - Hereditary breast cancer is mostly caused by germline mutations in genes that are susceptible to breast cancer (BCs), such as BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D.  Breast cancer is mostly caused by hereditary and genetic abnormalities in the BRCA1 and BRCA2 genes. ^[17]

4.4.2- Family history of breast cancer  -Family background of breast cancer  is generally perceived as a significant  risk  factor breast cancer ^[18] . family background of  breast cancer  in the sister, child, or male first-degree relative and maternal history of different diseases For rehash mammography, ladies with maternal history of  breast cancer  had a mean increment of 0.50 more mammograms in the beyond 6 years contrasted and ladies without maternal history of breast cancer . ^[19]

4.5 - Breast related factors

4.5.1- Lactation  -  Breastfeeding lessens chance of  Breast cancer .non-breastfeeding moms have been displayed to have a higher  risk  of reproductive  cancer . breast cancer  have been viewed as more normal in ladies who didn't breastfeed . ladies who breastfed for something like two years during their lifetimes had a fundamentally lower chance of creating breast cancer  than the individuals who breastfed for under two years. Contrasted and ladies who breastfed a sum of 0-11 months over their lifetimes, there was a 66.3?crease in breast cancer  risk in ladies who breastfed for 12-23 months, a 87.4?crease in ladies who breastfed 24-35 months and a 94?crease in ladies who breastfed 36-47 months. The mean span of breastfeeding per youngster for something like a year was likewise connected with diminished hazard of  breast  cancer.^[20] Breastfeeding is a positive, wellbeing advancing way of behaving, with breastfeeding term decreasing  breast cancer  risk. ^[21]

4.5.2 - Breast density  -  During the 2000s, breast  thickness was recognized as a  risk  factor for  breast cancer . A habitually cited size of this affiliation was a 4-to 6-overlap expanded risk in ladies with a percent mammographic thickness (PMD) at or higher than 75% compared  with ladies with a thickness underneath 5% or 10%.  . This made density one of the strongest known breast cancer risk factors. ^[22]

4.5.3- Benign breast disorders  - The  breast  of breast  malignant growth autonomously  increased with the presence of harmless breast  illness and with the increase  in breast thickness. Ladies with harmless  breast sickness and very thick breast  had a triple raised hazard of breast cancer  contrasted and those with dispersed fibro glandular thickness and without harmless  breast  illness . Ladies with harmless  breast  illness had a raised risk  for over 15 years autonomously of their breast thickness  category. Ladies with harmless breast illness and thick breast are at high  risk  for future breast cancer . ^[23]

4.6 -  life style  factors -

4.6.1- Obesity and  overweight – Epigenetic changes brought on by fat raise the risk of BC. Genomic modifications known as epigenetic changes impact  gene  expression   without changing the underlying DNA sequence. By modifying the action of hormone receptors, epigenetic modifications may impact hormone responses and contribute to the risk of   breast cancer  [BC] . ^[25] In addition to raising the chance of recurring breast cancer, obesity also raises the risk of serious comorbid conditions and lowers the quality of life for breast cancer survivors .^[24]

4.6.2 - Alcohol consumption – Expanded liquor utilization was related with higher gamble of breast malignant growth. Ladies who polished off ?1 glass of liquor each day  had a 33% higher gamble of breast cancer than nondrinkers in the unadjusted examination and 26% in the changed investigation ^[26]

4.6.3 - Diet – Diet might assume a part in both advancing and restraining human  breast  malignant growth development . ^[27]  Unfortunate dietary propensities described by the high admission of refined starches, sugar, and both immersed and trans-saturated fats, as well as the low admission of omega-3 unsaturated fats, regular cell reinforcements, and fiber, adjust irritation and, in this way, have all the earmarks of being connected to expanded hazard of  breast cancer  and mortality.^[28] responsive oxygen species (ROS); admission of phytoestrogen may lessen chance of  breast  malignant growth through genomic and non-genomic activity; vitamin D can diminish the  risk  of  breast cancer  by hindering the course of malignant growth intrusion .^[27]

4.6.4 .  Physical activity – Higher levels of physical activity may lessen a woman's chance of acquiring breast cancer when compared to women who engage in less physical activity.^[30]  PA at appropriate intensities may also operate as a preventive factor against the development of BC. Implementing public health initiatives that support and encourage an active lifestyle is crucial since it may lower the risk of BC. The association between physical activity and the risk of breast cancer will be better understood with the aid of future prospective research.^[30]

4.6.5- Vitamin D – By preventing the process of malignant invasion, vitamin D can lower the incidence of breast cancer [27]. The largest was an Italian research that collected data on dietary sources of vitamin D using a 78-item food frequency questionnaire. The study had 2,569 cases and 2,588 controls. The incidence of breast cancer was 34% lower for women who consumed the most vitamin D (>190 IU) than for those who consumed the least amount (<60>[31]

4.6.6 - Smoking – Smoking was related with an unobtrusive however essentially expanded chance of breast cancer, especially among ladies who began smoking at juvenile or peri-menarcheal ages. The general  risk of breast cancer related with smoking was more prominent for ladies with a family background of the sickness. ^[32] Menopausal status assumes a critical part in the connection among tobacco and breast cancer for all cancer subtypes. While smoking appears to expand the risk in premenopausal lady, bringing down chance of breast cancer among postmenopausal ladies with abundance weight may be related. ^[33]

4.7 - Other risk factor -

4.7.1- Air pollution – Air contamination has been connected with an increased risk   of  breast cancer  . Parts of air contamination are cancer-causing including  compound  that possibly increment oxidative stress  or DNA harm or have endocrine upsetting properties. Nitrogen dioxide (NO2) and nitrogen oxides (NOx), traffic-inferred air toxins, have been reliably connected with an increased risk of breast cancer .^[34]

4.7.2 - Night work - The night  shift work could increase the  risk  for breast   cancer . Having at any point worked extremely durable or turning night shift was related with an  increase risk  for  breast cancer compared with day work .^[35]

4.7.3 - Socioeconomic status –A connection between high financial status and  breast cancer .  breast cancer  is higher in ladies with higher financial status, which can be because of the immediate impacts of significant risk  factors like paralysis , and more established age at the  first childbirth  and during menopause. In expansion, stationary way of life and a high-fat eating routine in this friendly class can directly  and by  indirectly affect  the feminine cycle of ladies .^[1]

4.7.4 – Radiation -  Radiation therapy at moderate to high doses is known to raise the risk of breast cancer.  Women who underwent diagnostic chest X-rays for pneumonia or TB and radiation for a prior malignancy were shown to have higher risks for breast cancer.^[36]

4.7.5-  Diabetes  -  Women with type 2 diabetes have a marginally higher chance of getting breast cancer. Any organ with high amounts of estrogen receptors, such as the breast, endometrium, and ovaries, is more susceptible to cancer when insulin resistance results in a lower level of estrogen. many ways that the amounts of IGFBP-3, IGF-1, and cytokines raise the risk of breast cancer.^[37]

5 - Diagnosis –

Numerous techniques have been developed to diagnose breast cancer, primarily relying on imaging and molecular biotechnology analysis. ^{[ 55]}

• Imaging diagnosis
• Mammography
• Ultrasonography
• Magnetic resonance imaging
• Molecular Biotecnology examination
• Novel specific biomarker
• Nucleic acid  hybridiazation system
• Nucleic acid  hybridiazation
• Gene chip and next generation sequencing
• real  time fluorescence quantitative
• Protein hybridiazation  system
• Immunochemistry
• Western blot
• Flow cytometer
• Puncture biopsy system 

5.1.1- Mammography- The recommended method for screening and diagnosing BC is mammography (MG), which also assists physicians in gathering clinic data on BC patients . ^[55]  An x-ray of the breast called a mammography can show either benign or cancerous abnormalities. In order to create an x-ray picture, a little dosage of radiation is applied through the breast after compression between two plates. ^[57] The American Cancer Society [ACS] recommends annual mammograms for women starting at age 40. These screenings are especially helpful for women between the ages of 40 and 74. Age, ethnicity, personal history, radiologist experience, and technique quality all affect how sensitive a mammogram is. Premenopausal women and those with high breast density may have less sensitivity. Recently, contrast-enhanced (CE) digital mammography has been utilized as an additional breast screening method to mammography. CE uses tumor angiogenesis to identify breast cancer. It produces a little more radiation than mammography and employs intravenous iodinated contrast injections. CE mammography provides better detection accuracy than mammography and is more sensitive and performs better than both mammography and ultrasound .^[56] The following are some of their benefits: Quick screening, excellent precision, affordable, and appropriate for advertising.^[55] Among the numerous disadvantages of mammography include its use of ionizing radiation, its inability to be used on individuals with thick breasts, its comparatively high rates of false-positive and false-negative results, and its unpleasant nature. ^[56].

       
           
       
Figure 7 – Mammography

CONCLUSION-Breast cancer is still a major worldwide health issue, especially because of its complexity and variety, which make care and prevention more difficult. Personalized therapies, molecular diagnostics, and imaging technology advancements have all enhanced early detection and treatment results. But the disease's varied biochemical activity and potential for metastasis highlight how crucial it is to keep researching and developing new treatments. Improving public awareness, addressing risk factors, and supporting early detection initiatives can all help to drastically lower the worldwide incidence of breast cancer. Effectively battling this powerful illness requires cooperation in the fields of research, politics, and medicine.

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