Mammograms, Metastasis and Monogenic Mutations: A Beginner’s Guide to Navigating Breast Cancer

Breast cancer — and all of its complex tests, diagnoses and treatments — starts with a single rogue cell.

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Breast cancer is one of the most prevalent cancers in women.  In fact, nearly one in every eight women in the United States will be diagnosed with breast cancer at some point in their lifetime.  Cancer screening tests are more important than ever with increasing cancer rates in younger people and the increased  risk of developing cancer as people age.  Understanding individual risk through genetic testing allows healthcare providers to tailor cancer screening strategies to effectively detect the earliest stage of disease.

‍Basic Breast Anatomy

The basic function of a woman’s breast is to produce and deliver milk to infants.  As an organ, the breast is situated on top of the upper ribs and associated muscles.  The breast is made up of different tissues and structures with specific functions:

• Lobules are the breast glands responsible for making milk.
• Ducts are small channels in the breast that carry milk from the lobules to the nipple.
• The nipple is the breast structure where ducts merge to release milk to a feeding infant.  The dark skin directly around the nipple is called the areola.
• Fat and connective tissue in the breast makes up the stroma, which supports the milk-producing lobules and breast ducts.
• Blood and lymph vessels transport blood and lymph fluid, respectively, through the breast.  Lymph vessels specifically move lymph fluid, which contains waste products and immune cells, away from the breast.  The lymph fluid is transported to lymph nodes, which clean the fluid and monitor for infection.

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Types of Breast Cancer

Breast cancer is cancer in any of the cells of the breast.  There are different types of breast cancer depending on what cell type the cancer occurs in.

• Ductal Carcinoma In Situ (DCIS) is a cancer of the cells lining the breast ducts.  The in situ designation indicates that the cancer has not spread beyond the breast ducts.
• Invasive Ductal Carcinoma (IDC) is also a cancer of the cells lining the breast ducts.  Invasive cancers, in contrast to in situ cancers, have invaded the surrounding breast tissue.  Invasive ductal carcinomas account for 70 to 80 percent of all breast cancers.
• Invasive Lobular Carcinoma (ILC) is a cancer of the lobular gland cells of the breast.  Invasive lobular carcinomas have spread beyond the milk-producing lobular gland to surrounding tissue.
• Triple-Negative Breast Cancer cells lack progesterone and estrogen receptors, don’t overproduce a protein called HER2 and tend to be more aggressive cancers that can be more difficult to treat.  About 10 to 15 percent of all breast cancers are triple negative.
• HER2-Positive Breast Cancers produce higher than normal levels of the protein HER2, which make cancers grow and spread more aggressively.  Roughly 15 to 20 percent of breast cancers are HER2 positive. 
• Inflammatory Breast Cancer (IBC) is a rare form of breast cancer that occurs when lymphatic vessels are blocked by the cancer, contributing to pain, redness and swelling of the breast.

Breast cancers are graded by the Gleason Score (one to three) to characterize how different the cancer cells appear compared to normal cells and how likely a cancer is to grow and spread to different areas of the body.  Pathologists score three features of a cancer cell and add the scores to determine the grade of a cancer.

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1. Grade 1 cancers have added Gleason scores between three and five and are less likely to spread, or metastasize.
2. Grade 2 cancers have Gleason scores of six or seven, grow faster and look less like normal cells compared to Grade 1 cancers.
3. Grade 3 cancers have Gleason scores of eight or nine and look very different from normal cells.  These cancers are the most likely to spread and grow.

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Stages of Breast Cancer

Like all cancers, breast cancers are given a stage to determine how much cancer is in the body.  Generally, lower stages have spread less and higher stages have spread more.  Stage 0 indicates a carcinoma that hasn’t spread.  Stages ranging from I to IV can include a letter to indicate different levels of spreading within a stage.  Like numbers, the earlier the letter, the less a cancer has spread.  Staging uses seven key characteristics to determine how much cancer is in the body.

1. The size of the tumor and whether it has spread to other local tissues
2. Whether or not the cancer has spread to lymph nodes and how many lymph nodes are affected
3. Whether or not the cancer has spread to distant sites (metastasis)
4. Estrogen receptor status
5. Progesterone receptor status
6. HER2 status
7. Cancer grade

Stage 0 carcinomas, like Ductal Carcinoma In Situ, are typically treated through lumpectomy or simple mastectomy to remove the cancerous cells.  Hormone therapy may also be used for DCISs that are progesterone- and/or estrogen-receptor positive. 

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Stage I-III cancers are usually treated with surgery of tumor(s) and surrounding lymph nodes and radiation therapy.  The more a cancer has spread, the more likely other systemic therapies will be used to combat the cancer, including:

• Chemotherapies that kill quickly dividing cells
• Hormone therapies to combat progesterone- and/or estrogen-receptor positive cancers
• Targeted drugs that interfere with proteins that help cancer cells survive 
• Immunotherapies that boost the patient’s immune system to selectively kill cancer cells

Stage IV breast cancer is metastatic cancer that has spread to other areas of the body.  Breast cancer typically spreads to the bone, liver and lungs.  Metastatic breast cancer is considered incurable.  Treatments are focused on shrinking tumors and prolonging and improving quality of life.  The same systemic therapies used in Stage I-III cancers are commonly used in Stage IV breast cancer.

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Risk Factors of Breast Cancer

Breast cancer is caused by “misspellings” in breast cell DNA that cause cells to grow and divide uncontrollably.  Some carcinogens, like cigarette smoke, can cause more “misspellings,” or mutations, in DNA which can cause our genes to work improperly.  If enough genes involved in controlling cell growth and division acquire mutations and work improperly in a cell, it can become a cancer cell, rapidly growing and reproducing itself to form a tumor.

Some risk factors of breast cancer include:

• Age: Older people have had more time to acquire mutations in their DNA, increasing their likelihood of developing breast cancer.
• Sex: Women are more likely to develop breast cancer than men.  Male breast cancer occurs in only 1 of every 833 U.S. men, however some breast cancer variants can increase a man’s risk for other cancers.
• History of certain breast conditions: Patients with a history of lobular carcinoma in situ (LCIS) or atypical breast hyperplasia are at an increased risk of developing breast cancer.
• History of breast cancer: Patients that develop breast cancer in one breast are more likely to develop cancer in the other breast.
• Radiation exposure: Radiation can mutate DNA, increasing the likelihood of developing breast cancer.
• Genetic influences: People with a mother, sister or daughter that is diagnosed with breast cancer have a family history and increased risk of the disease.  Some people are also born with mutations in genes that increase the risk of developing hereditary breast cancer.
• Hormonal factors: Starting menstruation before the age of 12, starting menopause later in life and giving birth to your first child after the age of 30 can increase breast cancer risk.  Never being pregnant and taking hormone replacement therapy can also increase risk.
• Alcohol consumption
• Obesity

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Breast Cancer Genetics

Roughly five to ten percent of breast cancers are thought to be hereditary, or caused by a gene mutation that was inherited from a parent.  Hereditary breast cancers are often diagnosed earlier than other breast cancers and can also increase the risk of developing other types of cancer.  

The most common genes that are mutated in hereditary breast cancers are BRCA1 and BRCA2.  Both of these genes make proteins that are responsible for repairing damaged DNA.  Mutations in either gene increases the risk of additional mutations throughout the genome.  Many other genes can also cause hereditary breast cancer.  Mutations in a single gene, like BRCA1 or BRCA2, that cause breast cancer are considered monogenic breast cancer mutations.  

In contrast, other changes in gene “spelling,” called variants, can also be associated with increased breast cancer risk.  These gene variants are much more common in the population, and different combinations of gene variants can result in different risk levels for breast cancer.  Since many genes are assessed to calculate risk in this case, this risk factor is polygenic.  Some research suggests that as much as 18 percent of the familial risk for breast cancer can be attributed to polygenic risk factors for the disease.

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Prevention and Lifestyle Changes

While genetic predispositions, age and a family or personal history of breast cancer can’t be changed, there are many lifestyle factors that a person can change for the prevention of breast cancer.  Some of the lifestyle changes that can decrease the risk of breast cancer include:

• Limiting or eliminating alcohol consumption
• Quitting tobacco use
• Eating a healthy diet
• Exercising regularly

People with a family history can also undergo genetic testing for breast cancer to assess hereditary breast cancer risk, which can help healthcare providers screen for disease at the appropriate frequency to detect breast cancer at an earlier and more treatable stage.  

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Symptoms of Breast Cancer

The primary symptoms of breast cancer are changes in the breast.  Some of the most concerning changes include:

• A mass or lump that feels different compared to surrounding breast tissue
• A change in the appearance of the breast, primarily in its shape or size 
• Dimpling, pitting, peeling, flaking, redness or other change in breast skin or the areola
• New nipple inversion
• Discharge from the nipple
• Persistent breast pain

It is important for patients to follow up with their healthcare providers with any new, persistent or troubling symptoms.  Early detection of breast cancer, or any cancer, greatly improves disease outcome.

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‍Screening and Diagnosis

Breast cancer screening tests are designed to detect the disease at early stages before a patient ever develops symptoms.  Mammograms are specialized chest x-rays and one of the primary tests used by healthcare providers to screen patients for breast cancer.  Mammograms, together with monthly self-examinations of breast tissue, give most patients the best odds of detecting breast cancer at an early stage when treatments are more successful. 

Current guidelines suggest that women with a family history of breast cancer start yearly mammograms at age 40.  All women ages 45 to 54 should receive yearly mammograms.  Women 55 years of age and older may choose either yearly mammograms or one mammogram every two years.  Mammograms should continue as long as a patient is healthy and expected to live a decade or longer.  Some patients with increased risk of developing breast cancer may require more frequent screening mammograms or other tests to detect the earliest stages of disease.

When screening tests or patients detect a mass in breast tissue, diagnostic procedures for breast cancer are often performed to determine whether or not the lump is benign (noncancerous) or malignant (cancerous).  These tests include:

• Ultrasounds to better characterize a mass in breast tissue
• Biopsies, or samples of tissue that are further analyzed for signs of cancer
• Liquid biopsies, or samples of bodily fluids that may contain cells, DNA or other molecules that are characteristic of cancer cells 
• Magnetic resonance imaging scans (MRIs) for more detailed pictures of breast tissue

These tests allow healthcare providers to not only diagnose breast cancer but also determine the stage of the particular cancer.  Importantly, ultrasounds, biopsy tests or MRIs do not guarantee a cancer diagnosis.  Rather, the tests are used to determine if cancer is present, which cancer it is and how much cancer is in the body. 

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Treatment for Breast Cancer

Thankfully, breast cancer patients have many more treatment options than were available even 20 years ago.  Different treatments and therapies are appropriate for different stages of breast cancer, as previously discussed.

• Surgery, in the form of mastectomy or lumpectomy, removes a breast cancer tumor from the body.
• Targeted radiation therapy uses high energy particles to kill breast cancer cells  
• Chemotherapy works to slow or kill rapidly dividing cells throughout the body
• Hormone therapies starve breast cancers that depend on estrogen or progesterone to grow and proliferate more rapidly
• Targeted therapies neutralize proteins, like HER2, that may accelerate breast cancer growth
• Immunotherapies stimulate the immune system to attack and kill breast cancer cells

A breast cancer diagnosis, or any cancer diagnosis, is a devastating event for both the patient and their family.  Fortunately, events designed to increase breast cancer awareness and support for breast cancer, like breast cancer awareness month in October each year, are helping the public learn more about the disease, its prevention and early detection.  In turn, proactive screening for disease and new breast cancer therapies are improving disease outcomes for more and more patients each year.  In fact, women diagnosed with breast cancer since 2010 have a much lower risk of dying from the disease compared to women diagnosed in the 1990s.

Our increased understanding of the familial impact of breast cancer and the genetic underpinnings of the disease have also improved our risk assessment of patient relatives. Direct-to-consumer genetic testing kits, like Preciseli Preactiv, can provide family members with actionable information to customize breast cancer screening strategies for anyone sharing a high-risk mutation. Preciseli testing additionally provides one-on-one genetic counseling consultations to help people fully understand their cancer risk. With proper screening and early detection, breast cancer outcomes will continue to improve, providing patients and families the hope and resolve necessary to overcome this complex disease.