Breast Cancer: Risk Factors, Classification, Diagnosis and Treatment

Last Updated on March 18, 2020

Breast cancer is a type of cancer that starts in the breast. It occurs when breast cells start growing out of control and proliferate rapidly forming a lump.

Epidemiology

Breast cancer is the most common cancer in women affecting about 12% of women worldwide. Also, it is the leading cause of cancer death in women. Lung cancer is the second-most-common cause of cancer-related deaths in women.

The incidence of breast cancer varies from region to region around the world. It is highest in the developed countries while lowest in less-developed or developing countries.

The incidence has increased over the last couple of decades possibly related to modern lifestyles.

The incidence of breast cancer increases with age with the majority of the cases occurring in older women above the age of 40 years. Only about 5% of all breast cancers occur in women under 40 years of age. Although rare, it can also occur in breastfeeding women.

Read more about Breast Cancer While Breastfeeding

Increased awareness, early detection, and advances in treatment have led to increased survival rates and reduced death rates associated with breast cancer.

Risk Factors

Age

The incidence of breast cancer increases with age. More than 70 % of all breast cancers occur in women who are 50 years or above in age. It is rare in young women. Only about 5% of all breast cancers occur in women under 40 years of age.

Gender

Although breast cancer can occur in both men and women, it is 100 times more common in women. This is because the breast tissue in women is much more exposed to hormones such as estrogen that promote abnormal cell growth.

Race

The risk of developing breast cancer is slightly more in white women as compared to African-American women. However African-American women have higher breast cancer-associated death rates. Asian, Hispanic, and Native American women also have a lower incidence of breast cancer.

Family history

The risk of breast cancer is increased in women who have single or multiple first-degree relatives (mother, sister, and daughter) diagnosed with breast or ovarian cancer. This increased risk is due to the inherited mutation in one of two genes, BRCA1 and BRCA2. BRCA gene mutations account for about 5% to 10% of all breast cancers.

Read more about BRCA Gene Mutation and Testing

Personal history of breast cancer

Women diagnosed with breast cancer have a 3 to 4 fold greater risk of developing new cancer in the other breast or different parts of the same breast. This risk is in addition to the risk of the recurrence of original cancer after successful treatment.

Being overweight

Increased weight or obesity is a risk factor for breast cancer. This is because the fat present in the body increases the levels of the hormone estrogen.

Alcohol

Regular alcohol consumption increases the risk of breast cancer.

Early menarche and late menopause

Women who began menstruating before the age of 12 years or those who had menopause after 55 years of age have a higher risk of breast cancer. This happens because the breast cells in these women have been exposed to hormones like estrogen and progesterone for a longer period of time.

Timing and number of pregnancies

Women who had their first pregnancy after age 35 or who have never had a full-term pregnancy have a higher risk of breast cancer. Multiple pregnancies, on the other hand, reduce the risk of breast cancer. This happens because multiple pregnancies reduce the total number of menstrual cycles that a woman undergoes in her lifetime thereby reducing the exposure to estrogen. Moreover, pregnancy causes breast cells to mature fully.

Oral contraceptives

The use of oral contraceptives (OCs) slightly increases the risk of breast cancer. This risk returns to normal after the pills have been discontinued for 10 years. The progestin (synthetic progesterone)-only pill (mini-pill) is not associated with an increased breast cancer risk. It is recommended for women who have side effects from combination OCs or those who are at risk of thrombosis such as smokers.

Postmenopausal hormone therapy

Postmenopausal hormone therapy (HRT) increases the risk of breast cancer. The risk is directly related to the length of exposure. The use of HRT for 5 or more years increases the risk to about 1.35 times which returns to normal 5 years after discontinuation. Also, the risk is greater in women taking combination estrogen plus progestin therapy than in those taking estrogen-only preparations.

Drug diethylstilbestrol (DES)

Pregnant women in the United States who were given the drug diethylstilbestrol between 1940 and 1971 to prevent miscarriage, have a higher risk of breast cancer. Women whose mothers took DES while pregnant with them are also at increased risk.

Other

Smoking, exposure to cancer-causing chemicals, working in night shifts which causes changes in hormones are also risk factors for breast cancer.

Signs and Symptoms

A lump in the breast or the armpit which is usually hard and painless. The lump may be fixed to overlying skin which means that it does not move beneath the skin. It may even be attached to the underlying structures of the breast.
Change in the skin over the breast, such as dimpling or redness or scaling and crusting of the skin of the breast.
The skin may have a pitted appearance resembling an orange peel.
Change in the size, shape or appearance of a breast.
A newly inverted nipple, change in the shape or appearance of the nipple.
Discharge from the nipple which could be bloody.

Diagnosis of Breast Cancer

Mammogram

Mammography uses low dose x-rays to examine the breasts. The breasts are exposed to a small amount of ionizing radiation and pictures of the inside of the breasts from different angles are obtained. It is the most effective non-invasive test to detect breast cancer.

Breast ultrasound

Ultrasound uses high-frequency sound waves to obtain pictures of the inside of the breasts. It is non-invasive and free of harmful radiation. It can capture images of areas of the breast that are difficult to see with mammography. It can distinguish between fluid-filled (cystic) and solid breast lumps. During pregnancy and lactation, ultrasound is considered superior to mammography because the hormone-induced changes in breast tissue cause an increase in the density of breast tissue making interpretation of mammograms difficult.

Breast MRI (Magnetic Resonance Imaging)

MRI uses a powerful magnetic field, radiofrequency pulses and a computer to produce images of the inside of the breasts. A contrast material is injected through a vein into the body before obtaining the images. MRI can be used to diagnose breast lumps in select high-risk patients, in cases of dense breast tissue or when findings of mammogram and ultrasound are not conclusive.

Nipple discharge cytology

The discharge from the nipple can be smeared on a glass slide and examined under a microscope to look for the presence of malignant cells.

Fine needle aspiration cytology (FNAC)

In this procedure, a fine needle is inserted into the lump and some material is aspirated. This material is then spread on a glass slide, stained with appropriate stains and examined under a microscope. The procedure may be performed under the guidance of ultrasound.

It is a quick, relatively painless, non-invasive, outdoor procedure to diagnose breast cancer.

Biopsy

It is a small surgical procedure carried out under local anesthesia. A small piece of the breast lump is removed (and after a series of steps including processing, fixation, and staining) it is examined under a microscope. It is the best method to confirm whether cancer is present or not. However, the processing and other steps involved make it a lengthy procedure. The results are available in about 3-4 days.

A breast biopsy can be of various types

Core needle biopsy: A needle larger than that used for FNAC and having a special tip is used to remove a tiny sample of breast tissue.

Stereotactic biopsy: Mammography is used to precisely identify the suspicious area and then that area is biopsied.

Vacuum-assisted biopsy: A probe with a vacuum is inserted through a small incision in the skin and a sample of breast tissue is removed. It is performed under imaging guidance (ultrasound or mammogram or MRI).

Surgical biopsy: A small cut is made in the skin and part or whole of the lump is removed.

Incisional biopsy: Only a part of the lump is removed.

Excisional biopsy: The entire lump is removed. It is also called lumpectomy.

Staging breast cancer

Once breast cancer has been diagnosed, additional testing may be carried out to determine the stage or extent of the disease. This helps to determine the prognosis and the best treatment options available. However complete information about the stage of cancer becomes available only after breast cancer surgery.

The following additional tests may be performed

Blood tests, such as a complete blood count
Tumor markers such as receptors for estrogen (ER), progesterone (PR) and HER2 along with proliferation factors.
Mammogram of the other breast to look for signs of cancer
Bone scan
Computerized tomography (CT) scan
Positron emission tomography (PET) scan

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Classification of Breast Cancer

There are several methods to classify breast cancer.

Histopathology

The primary way to classify breast cancer is by its histological appearance which means how it looks under the microscope. The majority of the breast cancers arise from the epithelium lining the ducts or lobules of the breast, and these cancers are classified as ductal or lobular carcinoma or cancer respectively. Ductal carcinoma is much more common than lobular carcinoma.

When the cancer cells are confined to a particular tissue compartment such as ducts or lobules but do not invade the surrounding tissue, it is known as Carcinoma in situ. On the other hand, when the cancer cells do not remain confined to the original tissue compartment and start spreading to the surrounding tissue, it is called invasive carcinoma. Once cancer has spread to the tissue outside the breast ducts or lobules, it can start spreading to other nearby organs and tissue.

Non-invasive or in situ carcinomas

Ductal carcinoma in situ (DCIS)
Lobular carcinoma in situ (LCIS)

Invasive carcinomas

Invasive ductal carcinoma
Invasive lobular carcinoma
Tubular carcinoma
Cribriform carcinoma
Mucinous carcinoma
Carcinoma with medullary features
Invasive micropapillary carcinoma
Invasive papillary carcinoma
Metaplastic carcinoma
Spindle cell carcinoma
Carcinoma with neuroendocrine features
Secretory carcinoma
Inflammatory breast carcinoma

Other, less common types of breast cancer include:

- Phyllodes tumor: It arises from the connective tissue of the breast. The majority of phyllodes tumors are benign but some are cancerous.
- Paget disease of the nipple: It begins in the ducts of the nipple, but later affects the skin and areola of the nipple.
- Liposarcoma
- Angiosarcoma
- Rhabdomyosarcoma
- Osteosarcoma
- Leiomyosarcoma
- Malignant lymphoma

Grading of breast cancer

Well-differentiated (low grade)
Moderately differentiated (intermediate grade)
Poorly differentiated (high grade)

This classification is also based on the microscopic appearance of cancer cells. It compares the appearance of breast cancer cells to the appearance of normal breast tissue. Cancerous cells lose their differentiation. Well-differentiated cancers appear more like normal breast cells and have a good prognosis. Poorly differentiated cancers are the ones whose tissue looks least like normal breast tissue. They have the worst prognosis. Moderately differentiated tumors have an intermediate prognosis.

Staging of breast cancer

It is done according to the size of the tumor and whether it has spread to lymph nodes or other parts of the body. Breast cancer is staged from 0–4, with further subdivided categories for each stage. With the increasing stage, the prognosis keeps on worsening.

Stage 0: (carcinoma in situ or non-invasive breast cancer) The cancer cells are limited to within the ducts (Ductal carcinoma in situ) or lobules (Lobular carcinoma in situ) and have not invaded surrounding tissues.
Stage 1: The tumor measures up to 2 cm across. It has not affected any lymph nodes, or there are small groups of cancer cells in the lymph nodes.
Stage 2: The tumor is 2 cm across and has started to spread to nearby nodes, or the tumor is 2–5 cm across and has not spread to the lymph nodes.
Stage 3: The tumor is up to 5 cm across, and it has spread to several lymph nodes or the tumor is larger than 5 cm and has spread to a few lymph nodes.
Stage 4: Cancer has spread to distant organs (called distant metastasis), most often the bones, liver, brain, or lungs. It is also called metastatic breast cancer or advanced breast cancer.

Read more about Metastasis or Metastatic Disease

In 2018, breast cancer staging was updated to include other cancer characteristics. This included:

Tumor grade
Estrogen- and progesterone-receptor (ER/PR) status
HER2 status
Oncotype DX score: If the cancer is estrogen-receptor-positive, HER2-negative, and there is no cancer in the lymph nodes

Adding information about tumor grade, hormone-receptor status, HER2 status, and Oncotype DX test results has made determining the stage of breast cancer more complex, but also more accurate.

Read more about Staging of Breast Cancer

Receptor status

Breast cancer cells have specific receptors on their surface and in their cytoplasm and nucleus. Chemicals such as hormones bind to these receptors to produce their effect on the breast cell.

Three important receptors may or may not be present on breast cancer cells. These include

Estrogen receptor (ER)
Progesterone receptor (PR)
HER2

Cancer cells that have estrogen receptors (ER-positive) depend on estrogen for their growth, Hence they can be treated with drugs to block estrogen effects (e.g. tamoxifen). They generally have a better prognosis.

Normally, HER2 receptors help control how a healthy breast cell grows, divides, and repairs itself. But in about 10% to 20% of breast cancers, the HER2 gene doesn’t work correctly and makes too many copies of itself (known as HER2 gene amplification). All these extra HER2 genes tell breast cells to make too many HER2 receptors (HER2 protein overexpression). This makes breast cells grow and divide in an uncontrolled way.

If untreated, HER2 positive breast cancers are much more aggressive than HER2 negative breast cancers. However HER2 positive cancer cells respond to drugs such as the monoclonal antibody trastuzumab (in combination with conventional chemotherapy), and this has dramatically improved its prognosis.

Cancer cells that do not have any of these three receptors (ER, PR, or HER2) are called triple-negative breast cancers.

Prevention of Breast Cancer

Perform breast self-exam regularly

It is very important for women to perform breast self-exam regularly. This helps them to become familiar with their breasts and to recognize any new change in the breast.

Though self-breast exams and breast awareness can’t prevent breast cancer, it can help in early recognition of any change or lump in the breast making early diagnosis and treatment of breast cancer possible.

Breast cancer screening

Breast cancer screening exams and tests including clinical breast exams and mammograms should be carried out regularly for early detection of breast cancer.

Read more about Screening of Breast Cancer

Avoid alcohol

If not possible to avoid alcohol completely, it should be taken in moderation. Do not consume more than one drink per day.

Exercise regularly and maintain a healthy weight.

Regular exercise, reducing the calorie intake per day and keeping body weight in control is important to reduce the risk of breast cancer.

Consume a healthy diet

Limiting the amount of junk food, eating less red meat and refined carbohydrates and consuming plenty of whole grains along with fresh fruits and vegetables are important to adopt a healthy eating pattern. It has been found that women who eat a Mediterranean diet composed of extra-virgin olive oil and mixed nuts have a reduced risk of breast cancer.

Limit postmenopausal hormone therapy

Since combination hormone therapy increases the risk of breast cancer, the benefits and risks must be weighed-in before continuing it for the long term. Discuss with your doctor about the lowest dose of hormone therapy possible for the shortest amount of time.

Prevention of breast cancer in women having high risk

The following women are considered as having a high risk of breast cancer:

Strong family history of breast cancer
Inherited changes in BRCA1 and BRCA2 genes
Precancerous breast condition such as in-situ ductal or lobular carcinoma

Preventive medications: Estrogen-blocking drugs, such as selective estrogen receptor modulators and aromatase inhibitors can be given to reduce the risk of breast cancer. Since these medicines are associated with many side effects, so they should be given to women having a very high risk of breast cancer.

Preventive surgery: Women with a very high risk of breast cancer can opt for surgical removal of their healthy breasts (prophylactic mastectomy). They may also get their healthy ovaries removed (prophylactic oophorectomy) to reduce the risk of both breast cancer and ovarian cancer.

Treatment

Treatment of breast cancer depends on the type of breast cancer and the stage of the disease (meaning the extent to which it has spread within the body).

The various treatment modalities available to treat breast cancer can be grouped as follows.

Surgery

The tumor and some surrounding healthy tissue are removed during an operation. The axillary lymph nodes, which are under the arm are also usually removed. It includes

Lumpectomy or breast-conserving surgery (removing only the cancerous breast lump)
Mastectomy (removing the entire breast)
Double mastectomy (removing both the breasts): this is done in cases where cancer has spread to both the breasts or prophylactically in case of BRCA gene mutations
Lymph node removal

Since breast cancer frequently involves the axillary nodes, these lymph nodes should be removed to examine whether they have been involved by cancer or not.

Chemotherapy

Special medicines are given to the patient which helps to shrink or kill the cancer cells in the body. These drugs can be either given orally or injected through the veins.

It may be given before surgery to shrink a large tumor, so as to make surgery easier and reduce the risk of recurrence (called neoadjuvant chemotherapy).

It may also be given after surgery to reduce the risk of recurrence (adjuvant chemotherapy)

Usually, a combination of drugs is given in a specific number of cycles over a set period of time. Common drugs include Capecitabine (Xeloda), Carboplatin, Cisplatin, Cyclophosphamide, Docetaxel, Doxorubicin,etc.

Radiation therapy

High-energy rays are delivered to the affected part of the body to kill the cancer cells. The most common type of radiation treatment is external-beam radiation therapy which is given from a machine outside the body.

It is usually given after surgery to lower the risk of recurrence in the breast. If there is cancer in the axillary lymph nodes, radiation therapy may be given to the same side of the neck or underarm near the breast or chest wall.

Hormonal therapy

Tumors that have receptors on their surface for certain hormones can be treated using hormonal therapy. Certain hormones stimulate the growth of cancer. In these patients, medications can prevent the tumor from getting the hormone or stop the body from making the hormone. These drugs include tamoxifen and aromatase inhibitors such as anastrozole, etc. Pre-menopausal women can also have their healthy ovaries removed (ovarian ablation) so that the body stops making hormones that help cancer grow.

Targeted therapy

Women with HER2-positive breast cancer can be given trastuzumab (Herceptin), a drug that stops the HER-2 protein from making the cancer cells grow. Other targeted therapies for HER2-positive positive cancer include ado-trastuzumab emtansine (Kadcyla), pertuzumab (Perjeta), etc.

Certain women who have hormone receptor-positive and HER2-negative cancers can be given targeted therapies that block certain proteins called CDKs and hence slow the growth of cancer.

Biological therapy or Immunotherapy

This includes drugs that stimulate the body’s immune system to fight cancer cells. It can also be used to reduce the side effects of other cancer treatments. An example is the drug atezolizumab (Tecentriq) which blocks a protein called PD-L1. The expression of the PD-L1 protein on the tumor cell surface helps the tumor cells to escape immunosuppression.

Supportive and emotional care

A breast cancer diagnosis can be overwhelming for the patient. Providing emotional support and care is an essential part of the treatment which should not be ignored.

It is important for the patient to know about the details of her cancer- the type, stage, and hormone receptor status. Knowing about cancer and the treatment options available helps the patient feel more confident about treatment decisions.

The patient can find out about support groups whether local in their area or online. Talking with other breast cancer survivors help the patient to open up about her own fears and insecurities.

Family and close friends can provide a crucial support network for the patient during cancer treatment.

Meditation, yoga, relaxation, massage, music therapy, etc can help by providing the much needed emotional calmness.