Tracing Cancer Connections

Ann Stephens knew that colon cancer ran in her family, but it was the diagnosis of colon cancer for her beloved cocker spaniel, Cashew, that made Stephens realize the importance of early detection.

She was diagnosed with colorectal cancer after her first colonoscopy in 2005, which found 19 polyps — one of them malignant. Surgery and chemotherapy sent it into remission. But for the now 57-year-old resident of Issaquah, Wash., there was an unanswered question: Did she have a hereditary form of the disease, one caused by a mutation inherited from a parent at the moment of her conception? The prospect of getting a test to find out was frightening. “I was really scared,” she says, “even though at that point I knew I had cancer, and I had all these aunts and uncles with cancer, so there was obviously a familial connection. But if I knew I was genetically defective, what would that mean?”

As it turned out, testing showed that Stephens had a mutation in a gene called APC that normally represses tumor growth. A mutation in that gene may effectively take the foot off the brakes of cell division. Those rapidly dividing cells become polyps, which in turn can become cancerous.

Some people with these mutations have a syndrome called familial adenomatous polyposis (FAP), which is characterized by thousands of polyps in the colon and rectum at a young age. But Stephens had the milder form of that syndrome, attenuated FAP (AFAP), characterized by an older age of onset and fewer polyps.

That knowledge didn’t change her course of treatment, but it did have some implications for her follow-up care. And the test results provided crucial information to her family; her genetic counselor sent a letter to her two brothers and nine first cousins informing them that a mutation had been detected so that they could decide whether to get screened or be tested themselves.

“Every single one of them got a colonoscopy, and as a result, a few of them had genetic testing themselves,” she says. “I’m glad I did it.”

All cancers are caused by some kind of mutation — a change in a gene, which is a tiny piece of the very large instruction manual for building and operating our bodies. With cancer, that mutation somehow allows cells to grow out of control, past their usual lifespan. In the case of hereditary cancers, which account for only a small portion of all cancers, that harmful mutation is in a gene passed on from parent to child. (By contrast, an acquired mutation happens after conception occurs and isn’t passed on.)

The field of identifying these specific harmful mutations is relatively new — the first tumor suppressor gene, RB1, was identified in 1986. Mutations in that gene are responsible for hereditary retinoblastoma, a rare childhood eye tumor.

Because of the greater reach of the disease, the discovery in the mid-1990s of two genes associated with hereditary breast cancer, BRCA1 and BRCA2, had far wider implications.

Now, there are at least glimpses of the hereditary factors involved in other cancers, including colorectal, ovarian, melanoma, prostate, gastric and endocrine. But only in a handful of cancers have mutations been pinpointed and proved to be clinically useful for patients and their families. There are potential new mutations discovered all the time, but not all of them are ready for prime time.

“We can identify genes, but what that means over time is what needs to be elaborated upon,” says Robert Resta, MS, CGC, senior clinical specialist at the Hereditary Cancer Clinic at the Swedish Medical Center in Seattle. “The laboratory knowledge often outstrips the clinical knowledge.” And there are likely to be many mutations discovered in the future that raise the risk of cancer only marginally.

“If for each one of these individual common genetic variants, the risk increases just a little bit, what do you do?” asks David Goldgar, PhD, a professor at the University of Utah School of Medicine. “Would you want to spend a lot of money to find things that will likely only give you some information about slightly increased — or decreased — risk?”

It’s also important to know that even these inherited mutations shown to have a definite link to cancer do not guarantee that someone carrying them will get the disease. “What we’re talking about here is susceptibility, not destiny,” says Mary McMaster, MD, of the National Cancer Institute’s Division of Cancer Epidemiology and Genetics.

The odds of developing cancer depend on the mutation. Some, like the changes that produce full-blown FAP, nearly guarantee it. Others raise the risk of cancer significantly enough to consider measures including increased monitoring, prevention drugs such as tamoxifen (Nolvadex), and surgery. Some others may raise the risk by a small enough degree to prompt people into taking lifestyle measures that may prevent cancer.

Further complicating the hereditary cancer picture is that the risk isn’t uniform; some families with BRCA mutations see far greater incidence of breast cancer than others, for example. “Although these genes have definitely been shown to increase risk, that risk can be further modified by other genes we may not know about,” says McMaster. One candidate: a gene called HMMR. Mutations in this gene may interact with BRCA1 and BRCA2 to alter the odds of getting breast cancer. Learning more about those modifier genes, which are also thought to be at work in Lynch syndrome (a rare syndrome that predisposes people to colorectal and several other kinds of cancer) and probably other cancers, may eventually help stratify the risk among carriers — someone with a 50 percent chance of cancer may opt for a different strategy than someone with an 85 percent risk.

Other factors like age, obesity and sun exposure alter the risk of cancer, too. “It’s a very complex interplay,” says McMaster. “It’s easy to fall into the trap that the presence of one of these susceptibility genes means a patient is doomed to get the cancer.”

There are also plenty of cancers for which it’s known that there’s some kind of genetic component, but no definitive culprit. Identifying specific factors involved in prostate cancer, for example, has been extraordinarily challenging, says McMaster, even though family history is the strongest risk factor for the disease. A handful of potential genes have been identified, yet none is strongly enough associated with the disease to be tested for. (The exceptions are the BRCA1 and BRCA2 genes, which raise the risk of prostate cancer enough so that men with breast and ovarian cancers in their family should be tested to see whether they are also carrying the mutations.) Testicular cancer, too, has a strong familial component; brothers of those with the disease are eight to 10 times more likely to develop it, and sons of those with the disease are four times as likely. But as of yet, no mutation has been identified.

Given the complexity of the factors behind hereditary cancers, what good does it do to be tested, when a test is available? Who should consider testing for an inherited mutation, and how should they decide?

Two kinds of people might opt to peek into their genes: someone who has cancer and whose doctor suspects it might have a hereditary component, or someone who is cancer-free but worried about his or her risk because of a family history. For survivors, getting tested depends on whether the characteristics of the case suggest that there’s some familial link. In some cases that’s obvious; people with FAP, for example, have many more polyps at a much younger age than people with other forms of the disease.

In most cases, though, the process begins with a family history (see sidebar, next page). A genetic counselor will make a pedigree of the patient, noting the cancer cases in his or her family and at what age they occurred. (The closer the affected relatives are to the survivor, the more suspicious.) Some ethnic groups are also predisposed to certain hereditary cancers; Ashkenazi Jews are more likely to have harmful BRCA1 and BRCA2 mutations, and are also at higher risk of colon cancer, so they may be more likely to be referred for counseling and possible testing.

In Stephens’ case, it was her age that raised a red flag, says Anthony Back, MD, her oncologist at the Seattle Cancer Care Alliance and the University of Washington. “She was in her early 50s, which is young to have primary colon cancer — the usual age is 60 or 65,” he says. In addition to patients with younger-than-average onset or a family history of the disease, he may refer people with children for testing because of the implications for them if there is a mutation in the family.

Keep in mind that most cancers are not hereditary. That said, if you think you need genetic counseling, speak up. “From a patient standpoint, the key is to learn your family history and make sure your doctor hears you,” says Lisa Boardman, MD, assistant professor of medicine at the Mayo Clinic College of Medicine and a consultant in the Division of Gastroenterology and Hepatology.

A key question to ask your doctor, a genetic counselor and, ultimately, yourself is why you want to get tested. It may seem obvious: If you can pinpoint the precise origin of the cancer in your genetic code, why not know it? It’s not a slam-dunk, though. The knowledge may help patients and their families, or it might cause unnecessary fear, and the same knowledge can have very different effects on members of the same family, depending on their individual outlook.

Here are some questions a cancer survivor should ask a genetic counselor.

What will this test tell me?

You should know specifically what is being tested for and what it can and cannot tell you about the genetic components of your cancer. What are the odds that the results won’t be conclusive, and where do we go from there? Will the test tell me anything that I couldn’t find out from a detailed family history?

Will the results change my treatment?

The idea of tailoring drug regimens to cancer caused by a specific mutation is a logical one, and something that researchers are working on, but it’s not yet in practice. “That’s the way it will go, but it isn’t there yet,” says Tuya Pal, MD, a clinical geneticist at the Moffitt Cancer Center and Research Institute in Tampa, Fla. There have been some suggestions that hereditary colon cancer and hereditary breast cancer have treatment differences; however, it is not currently standard of care to treat those with hereditary cancer differently. Trials are under way in the United Kingdom to test whether women with BRCA1 or BRCA2 mutations respond better to carboplatin, a chemotherapy drug not usually used against breast cancer, than to traditional chemotherapy (docetaxel).

Discovering that cancer is caused by a specific mutation is more likely to affect surgical decisions. Women with BRCA1 and BRCA2 mutations are more likely to have a second cancer in the opposite breast, which means many opt to have a bilateral mastectomy. And some colo­rectal cancer patients with mutations that increase the risk of more polyps may ultimately decide to have the colon removed.

Will it change my follow-up care?

Because the BRCA1 and BRCA2 genes raise the chances of cancer in the opposite breast and of ovarian cancer, women who don’t have those organs removed may get additional follow-up — more frequent mammograms, or more sensitive imaging tests like MRIs. Ovarian cancer screening, unfortunately, is less advanced; neither transvaginal ultrasound nor the CA-125 blood test have been shown to find cancer early enough to make a difference in survival. “Right now I tell women there’s not yet evidence that screening helps, but given the high risk of ovarian cancer in mutation carriers, we and others recommend a transvaginal ultrasound and a CA-125 every six months,” says Karen Lu, MD, co-director for clinical cancer genetics and director of the high-risk ovarian cancer screening clinic at the University of Texas M.D. Anderson Cancer Center in Houston.

Because some genes put people at risk for more than one type of cancer, a positive mutation may prompt screening for other diseases. For example, knowing that she has a mutation in the APC gene, Stephens will have more frequent colonoscopies as well as monitoring for thyroid cancer. People with Lynch syndrome are more likely to get cancers of the endometrium, ovaries, stomach, small intestine, pancreas, kidney and urinary tract. Those cancers that can be caught early through screening may be more frequently tested for — but not all can be, so there’s a degree of worry associated with having that information.

What does it mean for my family members?

When Rena Henderson, a 58-year-old from Monterey, Calif., was tested for the BRCA mutations three years ago, it wasn’t for her own sake. Her own breast cancer was diagnosed and treated more than two decades earlier. “I had 22 positive nodes,” she says. “I had everything: a mastectomy, chemo once a week for a year, radiation.” She’s had no recurrences since then, but she does have a 23-year-old daughter, Karen. Rena’s own test came back positive for a deleterious mutation in the BRCA2 gene, which meant her daughter has a 50 percent chance of having the same mutation. Henderson says she could accept the information for herself, but she was devastated at what it could mean for her daughter.

Family members who find they are carriers may have a range of options — or, depending on the cancer, very few. In some cases, the only options may be radical. Inheriting a mutation in a gene called CDH1 makes stomach cancer an almost certainty, and the only real way to prevent the disease is to have the organ removed. Decisions about removing the breasts, ovaries, colon or other parts of the body in the absence of disease — and with no guarantee that it will ever come — are tough ones.

Another catch is that some insurance carriers may not cover genetic tests for unaffected relatives, which can run into the hundreds or thousands of dollars. Testing relatives is often cheaper than testing the original patient, however, since the lab needs to test only for the specific mutation that has already been shown to have caused the cancer in the family. “For the purposes of genetic testing, physicians should focus on the family member with cancer,” says Lu. “Once you’ve identified the mistake, then all your relatives just have to test for that one mutation.”

Although it sounds like a scary proposition to be a healthy person walking around with a gene that confers risk, don’t forget: Testing can also allay fears. If a relative doesn’t have the responsible mutation, that person’s risk, theoretically, returns to the average in the population. That’s one of the factors that went into Karen Henderson’s decision to have the test when she turns 25 — the earliest recommended age, since breast cancer in women younger than that probably isn’t caused by mutations in BRCA1 and BRCA2. “At first I was fairly reluctant,” she says. “Why would you want to know you have something wrong with you and live your life in fear? I didn’t want to be constantly anticipating cancer,” which has already loomed over her life. “My first memory of my mother is of her being in the hospital and me not understanding exactly what was going on,” she says. “I was always pretty much aware of it.”

The genetic counselor allayed her concerns, she says. “I saw that this was just a responsible, healthy way to take more control of my life, and just another step in early prevention,” she says. “If I have it, I have a 50 to 80 percent chance of breast cancer, but if I don’t, I have the same risk as any American woman.”

And her mom, who would like more than anything to spare her daughter the cancer she’s already faced, is happy that knowledge about this particular hereditary cancer is there to be learned.

“I feel like I did the right thing,” says Rena.

It's not a slam dunk, though. The knowledge may help patients and their families, or it might cause unnecessary fear.