MED-NERD
Breast cancer
Outline:
- Overview
- Incidence
- Types
- Risk factors
- Symptoms
- Diagnosis
- Treatment
- Prevention
- Prognosis
- References
Overview:
Human breast is formed from three parts: lobules (the glands producing milk), ducts(the tubes carrying milk to the nipple), and connective tissue (consisting of fibrous and fatty tissue). Breast cancer is characterized by overgrowth of breast depending on the type of cells that became cancerous. The ducts and lobules are the main sites from which breast cancer develops.
Incidence:
-Breast cancer is the second most common cancer in women and the leading cause of death in women worldwide with approximately 23% of postmenopausal cancer deaths.
-In the United states, more than 250,000 women diagnosed with breast cancer yearly, and about 80% of cases are estrogen receptor-positive (ER+).
-One out of eight women in the US is at risk of breast cancer.
-About 1.67 million new cases of breast cancer were diagnosed in 2012, 25% of cancers were among women, 794,000 in developed countries, and 883,000 cases were in less developed countries.
-In 2015, breast cancer caused about 570,000 deaths worldwide.
-In 2016, about 99.3% and 71.2% of breast cancer deaths in the US were recorded among women aged 40-60 years.
-In 2017, nearly 30% of new cancer cases were breast cancer.
-The number of breast cancer in women is 100 times higher than in men.
-Black women have higher mortality rates than white women.
-In 2020, about 2.26 million new cases of invasive breast cancer were reported worldwide.
-85% of breast cancer arise from epithelial lining of ducts and 15% in glandular tissue of the breast.
Types:
1-Non-Invasive breast cancer:
It is limited to the lobules or ducts and includes ductal carcinoma in situ and Lobular carcinoma in situ (LCIS). This type can progress into invasive breast cancer. Ductal carcinoma in situ is the most common non-invasive breast cancer that is limited to the ducts and includes ductal comedocarcinoma.
2-Invasive breast cancer:
Cancer cells present in ducts or lobules and can pass to different parts of the breast or different parts of the body through lymphatic or systemic circulation producing metastasis. Most common organs involved in metastasis are brain, bone, lung, and liver. It is the most common carcinoma in females. About 6% of Australian and European females suffer from invasive breast cancer before the age of 75. Invasive carcinoma includes: Infiltrating lobular carcinoma (ILC), Infiltrating ductal carcinoma, Medullary carcinoma, Mucinous carcinoma (also recognized as colloid carcinoma), and Tubular carcinoma.
Inflammatory breast cancer:
It is an uncommon and fast growing type of cancer in which cancer cells block lymph vessels and the breasts become swollen with dimples. Treatment involves surgery, imaging, radiation and chemotherapy.
Paget’s disease of the breast:
It usually causes changes in the shape of breast nipple and it is uncommon type of breast cancer with about 1-3% of all breast cancers. Patients present with red itchy rash in the nipple area that may spread to normal skin. It resembles eczema and psoriasis, but usually affects one breast starting in the nipple not the areola. Pathogenesis of Paget's disease is not clear, however warning signs include bloody oozing discharge from the nipple, lump detected in the breast, and flattening or inversion of nipple. Diagnosis can be reached by punch biopsy. Prognosis of the disease is good in local conditions without spread.
Phyllodes tumour:
It is rare type of tumour which arises from connective tissue of the breast and may be either benign or malignant. Approximately less than 10 females die of Phyllodes tumour yearly in the US. It can be treated surgically.
Triple-negative breast cancer:
It is a destructive type of cancer commonly in premenopausal women characterized by deficiency of estrogen receptor expression, progesterone receptor, and human epidermal growth factor receptor 2. It occurs nearly in 10-15% of white females.
Risk factors:
Factors increasing the risk of breast cancer include: female sex, positive family history, older age, hormone therapy, exposure to radiation, early menarche, late menopause, dense breast tissue, lack of breastfeeding, nulliparity, Genetic variants (mutations in breast cancer genes susceptibility 1 and 2 (BRCA1/2) genes), and unhealthy lifestyle. Patients with more than 3% risk of breast cancer are at increased risk of developing breast cancer over the next five years. In an American female, the lifetime risk of breast cancer is about 12.38%.
Age:
Old age is associated with higher risk of developing breast cancer. In 2016, about 99.3% and 71.2% of breast cancer deaths in the US were recorded among women aged 40-60 years. It is important to do a mammography screening in women aged 40 or older.
Family history:
Approximately a quarter of all breast cancers have family history. In UK, a cohort study of over 113,000 women concluded :
•In case of first-degree relative with breast cancer, women have a 1.75-fold higher risk of developing breast cancer.
•In case of two or more first-degree relatives with breast cancer, the risk increases up to 2.5-fold or more.
Reproductive factors (early menarche, late menopause):
The risk of breast cancer is increased nearly by 3% with each 1-year delay in menopause, decreased by 5% with each 1-year delay in menarche, and decreased by 10% with each additional
Hormonal factor (estrogen):
Estrogen, whether endogenous or exogenous, increases the risk of breast cancer. Endogenous estrogen is produced by the ovaries in premenopausal women, while exogenous estrogen is mainly from hormonal replacement therapy (HRT) and oral contraceptives. Stopping the use of oral contraceptives for more than 10 years is not associated with increased risk of breast cancer. The Million Women Study in UK showed an increased risk of 1.66 among users of HRT compared to non-users. Moreover, the recurrence rate of breast cancer is higher in case of using HRT. The risk decreases after stopping HRT for two years.
Lifestyle:
Unhealthy lifestyle including excessive alcohol consumption, fatty diet, and smoking increase the risk of breast cancer. Alcohol raises the level of estrogen-related hormones and stimulate estrogen receptor pathway. A meta-analysis of 53 epidemiological showed increased risk of breast cancer by 32% for each 35-44 grams of alcohol intake per day, and for each additional 10 grams per day, the risk increases by 7.1%.
Fatty diet especially saturated fat is associated with poor prognosis of breast cancer and 1.3 relative risk of mortality.
Smoking and drink is associated with 1.54 relative risk of breast cancer, especially smoking at early age. In breast fluid from non-lactating women, mutagens from cigarette smoke have been found that indicates the relation between smoking and breast cancer.
Additional risk factors:
•Klinefelter syndrome is a rare genetic disorder in men obtaining an extra X chromosome with higher levels of estrogen and lower levels of androgens.
•Injury to or surgical removal of testicles may increase the risk of breast cancer.
•Liver cirrhosis is associated with higher levels of estrogen in men, therefore increasing breast cancer risk.
See: Gestational Trophoblastic Neoplasia (GTN): Choriocarcinoma
Symptoms:
Some breast cancers are asymptomatic. The following symptoms may indicated breast cancer:
•A new lump or swelling in breast or armpit.
•Thickening and pain in any part of the breast.
•A change in the shape and size of breast.
•Nipple discharge especially blood.
•Irritation and redness of breast skin.
•A change in the appearance of nipple (inversion of nipple or other abnormalities).
Diagnosis:
Diagnosis of breast cancer includes: examination, imaging, and needle biopsy.
-Physical examination through finding: Lump or change in breast contour, nipple inversion, Paget disease, ulceration, skin tethering, Oedema or peau d’orange, Dilated veins, hardness, irregularity, fixation to skin or muscle, focal nodularity.
Imaging and Screening:
Including: Breast self-examination, clinical breast examination, mammography, ultrasonography, magnetic resonance imaging.
Needle Biopsy:
Obtaining breast tissue (core biopsy) guided by imaging for newly diagnosed breast cancers without surgery.
Treatment:
Treatment of breast cancer include: pharmacologic agents, radiotherapy, and surgery. The type of treatment depends on the type of breast cancer. Advanced metastatic cancers are not curable, requiring only palliative therapy ( relieving the symptom). Surgery includes lumpectomy or total mastectomy. Following surgery, radiation therapy may be used to eradicate residual tissue to reduce recurrence. Ductal carcinoma in situ is mainly treated surgically with or without radiation.
Pharmacologic agents include:
• Hormone or endocrinal therapy (eg, tamoxifen, aromatase inhibitors)
• Chemotherapy (eg, cyclophosphamide, carboplatin, doxorubicin, methotrexate)
• HER2-targeted therapy (monoclonal antibodies [eg, pertuzumab, trastuzumab ]; antibody-drug conjugates [eg, ado-trastuzumab emtansine, trastuzumab deruxtecan); tyrosine kinase inhibitors [eg, neratinib, tucatinib])
• CDK4/6 inhibitors (eg, palbociclib, abemaciclib, ribociclib)
• PIK3CA inhibitors (alpelisib)
• mTOR inhibitors (everolimus)
Endocrine therapy:
It Includes: selective ER modulators (SERMs), aromatase inhibitors (AIs), selective ER down regulators (SERDs) as adjuvant treatment of ER+ breast cancer.
-SERMs (e.g., tamoxifen): Compete estrogen at the binding site of estrogen receptor with mixed agonist/antagonist actions. Mainly used in premenopausal females. Clinical trials have shown about 30% reduction of ER-positive breast cancer 5 years following treatment with tamoxifen, however no significant reduction have been noticed in ER-negative cancers. Tamoxifen has some side effects, especially in patients older than 50, years, including: stroke, deep-vein thrombosis, endometrial cancer, and pulmonary embolism.
-AIs (e.g., letrozole, exemestane, anastrazole): Prevent the conversion of androgen to estrogen and deplete systemic estrogen level. Used in postmenopausal females.
-SERDs (e.g., fulvestrant): The mechanism of action may be blocking ER transcriptional activity, ER protein degradation, and recently it was suggested that SERDs suppress ER activity mainly by impairing intra-nuclear ER mobility.
Undesirable side effects of breast cancer treatment have led to developing alternative methods including herbs as a natural alternative.
Prevention:
Early detection is the main key of breast cancer prevention. Prevention methods include screening, biological, and chemoprevention.
Screening:
Screening methods can be used for early diagnosis and prevention of breast cancer including Mammography (which is widely used), and Magnetic Resonance Imaging (MRI), which is more sensitive than mammography and have been studied over the last decade.
-Mammography obtains high-resolution images using low energy X-rays applied to the breast within 20 minutes without contrast-enhancing agent. Analysis of 11 randomized trials concluded that females aged 50-70 years after being screened using mammography, had a noticeable reduction in breast cancer mortality.
-MRI is more sensitive and can measure small tissues up to 0.5 mm³. It is useful especially in detection of invasive ductal carcinoma, axillary nodal metastasis, occult primary breast cancer, small tumours or tumours resistant after neoadjuvant chemotherapy. On the other hand, MRI is less specific than mammography with 37-100% detection rates. If mammography results are normal, MRI can be used especially in high risk patients.
Biological prevention (monoclonal antibodies for the breast):
Approximately, 20-30% of breast cancers have HER2 protein overexpression or known as HER2 gene amplification. The first HER2-targeted agent approved by the FDA is Trastuzumab (Herceptin), which is a recombinant humanized monoclonal antibody. It acts by direct interaction with the C-terminal portion of domain IV that presents in the extracellular part of HER2. Suggested mechanisms of action of trastuzumab include:
- Immunological by activating the immune system against cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC).
- Suppression of cancer cells growth and proliferation via recruiting ubiquitin for internalization and degradation of HER2.
- Inhibition of the MAPK and PI3K/Akt pathways.
Chemoprevention:
It is defined as using pharmacologic or natural agents to inhibit invasive breast cancer development through blocking DNA damage that is responsible for carcinogenesis or arresting the progression of the already damaged cells. More than 70% of breast cancers are ER-positive, therefore estrogen receptor is a main target for chemotherapy. Selective estrogen receptor modulators (SERMs) and the aromatase inhibitors (AIs) are two examples of anti-estrogen drugs.
*Other preventive methods regarding lifestyle include: regular exercise, avoiding alcohol, avoiding fatty diet, maintaining healthy weight. Regular exercise may reduce the risk of breast cancer nearly by a third.
Prognosis:
-Mortality rates from breast cancer declined by 39% in the US from 1990 to 2015.
-About 80% and up to 90% of 5-year survival rate in developed countries.
-Less than 40% of 5-year survival rate in developing countries like South Africa, 66% survival rate in India.
-About 43,780 deaths from breast cancer were expected in 2022.
The noticeable decrease in mortality especially in high income countries is due to early detection using screening methods and increased awareness about breast cancer.
See: Gestational Trophoblastic Neoplasia (GTN): Choriocarcinoma
References:
(1) Trayes KP, Cokenakes SEH. Breast Cancer Treatment. Am Fam Physician. 2021 Aug 1;104(2):171-178.
https://www.aafp.org/pubs/afp/issues/2021/0800/p171.html
(2) Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell. 2020 Apr 13;37(4):496-513.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169993/
(3) Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biol Res. 2017 Oct 2;50(1):33.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625777/
(4) Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, Shi W, Jiang J, Yao PP, Zhu HP. Risk Factors and Preventions of Breast Cancer. Int J Biol Sci. 2017 Nov 1;13(11):1387-1397.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715522/
(5) Breast cancer, Centre for disease control and prevention (CDC).
https://www.cdc.gov/cancer/breast/index.htm
(6) What is breast cancer? American cancer society.
https://www.cancer.org/cancer/breast-cancer/about/what-is-breast-cancer.html
(7) Breast cancer, National Health Service (NHS).
https://www.nhs.uk/conditions/breast-cancer/
(8) Pavani Chalasani, MD, MPH , breast cancer, medscape.
https://emedicine.medscape.com/article/1947145-overview#a1
(9) Breast cancer, World Health Organization (WHO).
https://www.who.int/news-room/fact-sheets/detail/breast-cancer
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