Involved in: Breast cancer, ovarian cancer, male breast cancer, pancreatic cancer, prostate cancer, and certain other cancers.
Testing requires: A blood or saliva sample.
Prognosis: High likelihood for women to developing certain cancers, particularly breast and ovarian cancers, at unusually young ages. In women with a BRCA1 and BRCA2 mutation who already have breast cancer, breast cancer is more likely to recur. Women with a BRCA1 mutation are more likely to develop triple-negative cancer, which has poorer prognosis than other strains of breast cancer.
Treatment: Healthy women with an inherited BRCA1 or BRCA2 mutation can undergo enhanced surveillance, chemoprevention, or preventive removal of breasts and ovaries. Some studies suggest that cisplatin and PARP inhibitors are effective against cancer cells with BRCA1 or BRCA2 mutations.
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What do Angelina Jolie, Sheryl Crow, and Christina Applegate have in common? Aside from being awesome women in entertainment, all three have BRCA mutations that have impacted their lives. Sheryl Crow and Christina Applegate discovered their BRCA mutations after being diagnosed with breast cancer, while Jolie found out her status while she was still healthy, and chose preventive breast removal. In learning her BRCA status, Jolie joined the ranks of the new class of “previvors,” survivors of a family predisposition to cancer.
BRCA is not entirely a story of predisposition, however. While some patients are born with BRCA mutations that could increase their susceptibility to cancer, others develop BRCA mutations as a part of their cancer. Half, if not more, of these mutations occur this way. Whether acquired or inherited, BRCA mutations can be a point of vulnerability for a cancer to certain new drugs. This story will describe the importance of BRCA for both predisposition and for cancer treatment strategies.
BRCA and Cancer Predisposition
For centuries, doctors had suspected that breast cancer might run in families. In 1866 Parisian surgeon Paul Broca made a chart of his wife’s family, since of her 26 adult relatives, 15 of them had developed or died of cancer. Broca’s chart was one of the first to trace a breast cancer family. Broca was convinced that cancer could be inherited, but couldn’t unravel how. The thorny problem wouldn’t be solved for more than a century, until theories of heredity and genetics, the discovery of cellular DNA, and the means to sequence such DNA could be uncovered.
In 1990, California-based scientist Mary-Claire King fired the starting pistol in the race to uncover the breast cancer gene. Dr. King had already been responsible for DNA-related scientific discoveries—her doctoral thesis proved that human and chimp DNA were almost entirely identical, and her work identifying victims of political violence across the world had helped develop methods of forensic genetics. She turned her remarkable intellect to the task of unraveling the mystery of cancer families in the mid 1970s, and after more than 15 years of work, in late 1990, she produced evidence that a genetic mutation related to breast cancer risk was hiding out in a certain part of chromosome 17. Scientists around the world took up the search to pinpoint its exact location, and in 1994 the Utah-based lab of Myriad Genetics, helmed by scientist Mark Skolnick, identified BRCA1. One year later, Skolnick’s lab in Utah and Sir Mike Stratton’s lab in the UK had identified a second breast cancer gene, known as BRCA2, located on chromosome 13.
BRCA1 and BRCA2 are segments of DNA that every human has in each cell of the body, and every person has two copies of each gene. When BRCA1 and BRCA2 work properly, they are part of the body’s natural defenses against tumor formation. When both copies of BRCA1 or BRCA2 become damaged, cancer can result. In some breast cancer tumors, BRCA1 and BRCA2 have acquired mutations that turn one or both genes off, facilitating the growth of the tumor. Some patients have a flawed copy of BRCA1 or BRCA2, not just in their tumor, but in each cell of their bodies. Such men and women have inherited a flawed copy of BRCA1 or BRCA2 from their parents. Harmful and inherited BRCA1 and BRCA2 mutations raise a woman’s risk of developing breast and ovarian cancer, and raise a man’s risk of developing male breast cancer and prostate cancer. BRCA mutations may also raise the risk for cancers in certain additional organs such as the skin, pancreas, uterus, and others.
Harmful inherited BRCA mutations are comparatively rare—something like 1 in 400 to 1 in 600 people carry such mutations. For people with Ashkenazi Jewish heritage, these numbers are higher—about 1 in 40 such individuals carry a harmful mutation. Norwegian, Dutch, and Icelandic people also have a higher rate of BRCA mutations. Although BRCA carriers are rare in the general population, they account for about 5 to 10 percent of all breast cancer diagnoses and 15 percent of all ovarian cancer diagnoses. What kind of cancer risk do BRCA inheritors face? Right now, BRCA1 patients are thought to have a 55 to 65 percent lifetime risk of breast cancer on average and a 39 percent risk of ovarian cancer. BRCA2 patients are thought to have a 45 percent lifetime risk of breast cancer and an 11 to 17 percent risk of ovarian cancer. In addition, BRCA1 and BRCA2 patients experience a two- to threefold increase in lifetime pancreatic cancer risk (to about 3 percent and 5 percent lifetime chance for BRCA1 and BRCA2 patients respectively). These numbers are not absolute—as knowledge about the BRCA mutations and the patients who carry them grows, these numbers are changing, and have been largely revised downward in the last few years. But the truth is plain to see: having a BRCA1 or BRCA2 mutation dramatically raises a woman’s risk of developing breast or ovarian cancer.
Not all BRCA mutations are created equal. Because BRCA1 and BRCA2 are gigantic genes, there are many ways for them to go wrong. Each misspelling of a BRCA1 or BRCA2 gene comes with its own unique level of risk. Certain BRCA1 mutations might raise a woman’s risk of developing breast cancer as high 87 percent. Other misspellings are completely benign. The numbers on the chart above are averages for the risk levels women with harmful BRCA1 and BRCA2 mutations face. Depending on how rare your BRCA mutation is, your doctor may be able to give you a more accurate risk number.
Every human has a pair of BRCA1 and a pair of BRCA2 genes in each cell of the body—one copy of each from the mother and one from the father. People with a harmful BRCA mutation start out with one broken copy that may be inherited from either mother or father. If you have one parent with a BRCA mutation, your chance of having the same mutation is 50 percent. BRCA mutations are not the only inherited mutations that affect breast cancer risk. According to the National Cancer Institute, only 20 to 25 percent of hereditary breast cancers involve BRCA mutations. Other mutations that can affect breast cancer risk include TP53, CHEK2, ATM, and PALB2.
The Biology of BRCA
How does a BRCA mutation—whether inherited or acquired—cause cancer? At its core, cancer is a disease of unchecked cell growth. DNA regulates the cell cycle, ensuring that cells reproduce an appropriate number of times and self-destruct when things go wrong. When several crucial segments of DNA get screwed up by viruses, or environmental exposure, or errors that happen during cell replication, then this process is disrupted, and cells may not stop dividing, leading to cancer. A harmful BRCA mutation on its own is not enough to cause cancer; rather, it’s the first domino down in a long chain of events that can lead to cancer. People with inherited BRCA1 and BRCA2 mutations get cancer more frequently because they start up with DNA that is already messed up in one place. Just as a house built on two foundation stones, including one that is already starting to crumble, would be more likely to have problems than a house built on two solid stones, so, too, are people with one wonky BRCA gene more likely to develop cancer.
BRCA1 and BRCA2 are known as “tumor suppressors.” They produce proteins that put the brakes on cell replication. They are also involved in repairing breaks in cellular DNA. When they don’t work right, cellular DNA doesn’t get correctly repaired and may then acquire other mutations that can lead to cancer.
Cancer Treatments that Exploit BRCA Mutations
Mutations in BRCA1 and BRCA2, while causative of cancer when inherited, can also lead to vulnerabilities of the cancer to certain treatments. The mutation can either be inherited or, just as common, occur only in the cancer. Because these mutations cause deficiencies in the way the DNA repairs itself, enhancing the damage to the DNA can be lethal to cancer cells. Chemotherapies called DNA-damaging agents, including mytomycin-c and more common platinum-based therapies such as cisplatin, carboplatin, and oxaliplatin, act by causing extensive damage to DNA. Normal cells can repair this damage, whereas those that have deficiencies in DNA damage response, such as BRCA1 and BRCA2 mutations, cannot. So the healthy cells survive the DNA-damaging agents, but the cancer cells die. DNA-damaging chemotherapies can be very effective, but they come with many side effects and they don’t work for everyone.
Another more recent approach to exploiting such characteristics of cancer cells is something called synthetic lethality. This means taking advantage of a mutation in cells that impairs a process, rendering cells with those mutations sensitive to a particular drug. But because the drug effect depends on the mutation, normal cells without that mutation experience no effect or minimal effects. An example of that is the use of PARP inhibitors.
Cancer cells with acquired BRCA1 and BRCA2 mutations have an increased dependency on an enzyme called PARP to repair DNA. This is a kind of backup mechanism to normal BRCA function. Drugs that inhibit PARP in these cancer cells can be lethal, because the cells have no good way to repair DNA. Noncancerous cells nearby have both BRCA1 and BRCA2 and PARP mechanisms to do so. So DNA-damaging agents become more lethal to cancer cells if the patient is receiving a PARP inhibitor. Clinical trials are underway, combining PARP inhibitors and DNA-damaging agents, to exploit BRCA mutations in many cancer types including pancreatic cancer and lung cancer.
BRCA Predisposition: Testing and Implications
In general, breast cancer related to inherited BRCA mutations tends to be a little different from breast cancer in the broader population. It is more likely to strike younger women—women who have not yet gone through menopause. Diagnoses in the thirties or even the twenties are not unheard of in BRCA families. In BRCA1 patients, breast cancer is more likely to be “triple negative.” Cancer that is positive for estrogen receptors or progesterone receptors or the HER/neu protein pathway has an Achilles’ heel that doctors can target using particular drugs. Cancer that is triple-negative lacks all of these weaknesses, making it harder to treat. In addition, women with a BRCA mutation and breast cancer have a much higher rate of recurrence in the healthy breast compared to women with non-BRCA-related breast cancer.
Testing positive for a BRCA mutation can influence treatment for patients who have cancer. A BRCA-positive breast cancer patient might respond better to certain therapies or be eligible for studies aimed at unraveling the unique weaknesses of BRCA-related cancer. They might also choose preventive removal of the healthy breast or ovaries as part of their treatment. Women who test positive for a BRCA mutation but who do not have cancer have three treatment options:
- Intensive medical surveillance for breasts and ovaries aimed at catching cancer early.
- Chemoprevention—taking estrogen blockers to lower cancer risk in the short term, but with a side effect of temporary reversible menopause.
- Preventive surgery—removal of healthy breasts or ovaries to eliminate possible sources of cancer.
Each of the treatments has benefits and drawbacks. Surveillance is non-invasive, but can be challenging from a psychological and scheduling perspective, as it requires many doctors’ visits and uncertainty around waiting for test results. It also cannot prevent cancer, but merely catch it early. Chemoprevention can give patients the immediate relief of reducing cancer risk, but it has intense side effects and is only a temporary solution, as such drugs can only be taken for a limited amount of time, lest the risk of other forms of cancer climb. Surgery permanently lowers risk. Studies show that breast removal dramatically reduces a BRCA woman’s chance of developing breast cancer, and ovarian removal drops the risk of ovarian cancer and halves the risk of breast cancer. But surgery comes at the cost of bodily integrity, and can cause side effects such as loss of fertility and immediate surgical menopause in the case of ovarian removal, and numb skin and future operations in the case of breast removal and reconstruction. The decision of which is right for you will likely not be an easy one, and should be made in consultation with doctors, friends, and family you trust.
Genetic Tests for BRCA Mutations
Some of the most common personal or family history characteristics that may make genetic testing for BRCA mutations advisable include:
- A known BRCA1 or BRCA2 mutation in the family
- Breast cancer diagnosed at a young age (some studies use age 40 as a cutoff, while others use age 50)
- Triple-negative breast cancer
- Two breast cancer diagnoses
- Breast cancer affecting both breasts (bilateral breast cancer)
- Breast cancer at any age plus one or more close blood relatives with breast cancer who was diagnosed under the age of 50; one or more close blood relative with ovarian cancer; or two or more close blood relatives with breast cancer or pancreatic cancer at any age
- One or more family members on the same side of the family with a combination of breast cancer and one or more of the following: pancreatic cancer, prostate cancer, sarcoma, adrenocortical carcinoma, brain tumors, endometrial cancer, leukemia/lymphoma, thyroid cancer, dermatologic manifestations or macrocephaly, polyps of the GI tract, gastric cancer
- Ovarian cancer
- Male breast cancer
- Ashkenazi Jewish ancestry
- A family member with two or more breast cancer diagnoses or bilateral breast cancer
- Two or more family members with breast cancer on the same side of the family
- One or more family members with ovarian cancer on the same side of the family
- First- or second-degree relative with breast cancer who was diagnosed younger than age 45
These may not capture all personal or family history characteristics. If you think you are a candidate for genetic testing for BRCA mutations, talk to your doctor.