When Angela T. enrolled in the genetic-testing program at Memorial Sloan-Kettering two years ago to find out whether she was predisposed to breast and ovarian cancer, it was in many ways the end of a long, difficult journey. For nearly 30 years, she had wondered not so much if she’d get sick but when. Over and over during this odyssey, she’d been forced to confront the most fundamental questions about who she was and whether some inherited characteristic meant her body was destined to fail her. Now there was a possibility she could get some answers.
She wanted to wake up in the morning, as she imagined most other women did, without worrying about lumps, ominous masses, or suspiciously dense tissue. At 49, she wanted relief from a dizzying cycle of more than two decades of mammograms, sonograms, MRIs, breast exams, and biopsies. Every three months it was off to the gynecologist, the breast surgeon, or both. After a while, she began to refer sardonically to these quarterly interruptions in her life as “AMA week.” (“Will this be the week they find something?”) During one twelve-year period, Angela had four biopsies.
“And it’s not so long ago that when you signed to go in for a biopsy,” she says, “you didn’t know how you’d wake up. You either came out and were told it was a benign cyst or you had no breast.”
Ever since high school, Angela (she asked that her name be changed) had lived with the burden of knowing that her family was its own little cancer cluster. While she obsessed about her own body and health, she watched as other women in the family got sick. First one aunt, then another. Then it struck her mother. To understand just how pernicious the disease has been and how deeply it infiltrated Angela’s family, it’s perhaps necessary to know only that her mother and her mother’s three sisters all had breast cancer by the age of 45. One of the sisters also had ovarian cancer. Two weeks after Angela was married, her mother died at the age of 47. Only one of the aunts is still alive.
But on that morning when she walked down East 68th Street toward the hulking redbrick edifice of Sloan-Kettering to attend her first genetic-counseling session, she had no unrealistic expectations, no false hope that a blood test – no matter how sophisticated the technology – was going to solve all her problems. Or even answer all her questions.
“Why?” her friends asked insistently. “Why do you want to know?”
And the truth is that in the beginning, at the start of genetic counseling, Angela wasn’t sure she did want to know. All she really wanted was to get on with her life – and, of course, to prolong it. She wanted to continue to work with kids; to watch her two sons, now in their early twenties, grow and develop as men; and to someday become a grandparent.
“I really felt,” Angela says, “that if I was going to be tested, then I wanted to have a pretty clear idea of what I would do if I tested positive.”
If Angela agreed to give a blood sample, it would be screened for inherited mutations in two genes thought to play a crucial role in some breast and ovarian cancers – BRCA 1, which was discovered only in 1994, and BRCA 2, which was identified a year later. Even though there is little understanding of what these genes do, scientists believe that defects found in one or both of them are responsible for nearly 10 percent of the approximately 180,000 cases of breast cancer diagnosed in the U.S. every year. In general, a woman has a 10 percent chance of developing breast cancer by the age of 85. These odds can rise to more than 80 percent – depending on age and specific family history – among women who have BRCA mutations. Ovarian cancer is much less common; a woman has only a 1.4 percent chance of getting it by 85. The odds jump 40 percent, however, for women who carry the BRCA mutations.
Angela knew that given her family history, there was a strong likelihood a genetic mutation was being passed from one generation to the next. But testing positive would mean she’d have to make some very difficult decisions. To begin with, having a BRCA mutation doesn’t guarantee a woman will get cancer. It only increases the likelihood. And the options currently available to a BRCA carrier are at best rather limited, and at worst strikingly unappealing. Once a women is identified as high-risk, her clearest strategy is vigilance; she can maintain a rigid program of regular examinations so that if a cancer develops, it can be found and treated early.
The newest avenue being pursued is what’s referred to as chemo-prevention. That is using the drugs Tamoxifen and Raloxifene in high-risk women before the onset of disease. The problem here is the potential for substantial side effects. Tamoxifen, for example, is believed to greatly increase a woman’s risk of uterine cancer over time.
There are two far more extreme strategies as well. One is to have a preventative oophorectomy, which is the surgical removal of the ovaries. Because the current screening techniques for early-stage ovarian cancer are not especially effective, an oophorectomy is an option some women – particularly those who’ve already had kids – consider seriously. Even more radical is a preemptive mastectomy, which is a far more complicated and psychologically loaded choice. (In the past year, about 50 of these kinds of oophorectomies, and five mastectomies, have been done at Sloan-Kettering.)
Genetic testing is one of the first tangible benefits of the golden age of biotechnology. It’s easy to forget that it was only twenty years ago that researchers even began to examine the notion of cancer as a genetic disease. Opening the window wider and wider on the way genes work, and fail, will – like Darwin’s theory of natural selection and Einstein’s quantum physics – change the way we look at the world.
But this new era is fraught with frightening issues, questions that would have been unimaginable just ten years ago. And while progress is taking place at the speed of light, the science can still seem painfully inadequate, particularly for someone at risk. If genetic testing for breast and ovarian cancer can predict only probabilities, not certainties, and if the treatment options are severely limited anyway, what’s the point? Particularly when you think about the potential psychological impact of telling a woman she’s a walking biological time bomb.
Not to mention the enormously complicated family issues, the potential for insurance-company discrimination, and the further potential for discrimination against particular racial or ethnic groups that show a genetic propensity for certain maladies.
For many people, none of these issues is as disturbing as the fact that the entire idea of genetic testing strikes them as some haunting scientific remnant of the Third Reich. For some time, the search for the causes of cancer has focused on external factors: the environment, pesticides, carcinogens in food, tobacco. But now it’s possible to say the cause is actually within the individual; in fact, it’s in our DNA, the very essence of what makes us who we are. Eugenics, then, hardly seems out of the question.
“We are on the verge of being able to map the entire human genome,” says Dr. Harold Freeman, the director of surgery at Harlem Hospital, referring to the fact that the National Institutes of Health and several private companies believe that by 2003 they will have identified every one of the 100,000 or so genes in the human body. “This is a scientific achievement that’s the equivalent of splitting the atom. It’s powerful knowledge, and we can use it to create a bomb or we can use it to create energy and help people,” cautions Freeman, who’s also the chairman of the President’s Cancer Panel.
“There’s no question that we’re in a transition period where clearly we have to think these issues through,” says Dr. Kenneth Offit, chief of the clinical-genetics service at Sloan-Kettering. “But it’s a miraculous eventuality that when people get sick you can explain why it happened. Think of it this way. It’s December 7 and you’re in Pearl Harbor. You know the planes are coming, you know from which direction they’re coming, and you can turn on the radar. You may not shoot down every one, but think of the impact.”
The less appealing version of that metaphor is the one that may come a little closer to the current reality as it concerns BRCA 1 and 2. You’re in Pearl Harbor, you know the attack is coming, but you’re not sure on which day and you have no ammunition to fire at the incoming planes anyway. “Keep in mind,” says Offit, who discovered the most common BRCA 2 mutation, “that the twelve or so genes that we’ve uncovered that cause disease have pretty much all been found in the last five years. That should give you some idea of the pace of the research. Our best-case scenario when BRCA 1 was discovered was we’d have a relatively simple test that would provide the opportunity to save lives. And that’s exactly what’s happened.”
Angela waited a year after her initial genetic-counseling session to have her blood drawn. In the meantime, she persuaded her lone surviving aunt to go in and be tested. This was critical. In families with a pattern of inherited cancer, the most effective way to test those who don’t have cancer is to first find the genetic defect in a relative who does. This way, researchers know what they’re looking for. While there are several common defects – most Jewish women of Ashkenazi descent who are affected have one of three mutations; that’s why they’re so easy to screen – some families have mutations that are unique to them.
Consequently, unless doctors first identify the genetic marker in a family member who’s sick, a negative test result is not conclusive. It can simply mean the testers missed the defect. BRCA 1 and 2 are very large, complex genes. When researchers know what defect they’re looking for, it’s as if they’ve been told to find a misspelled word on page 367 in volume B of the encyclopedia. Otherwise, it’s as if they’ve been told there’s a misspelled word somewhere in the encyclopedia. Find it.
“My aunt has a daughter who also got tested and she turned out to be negative,” Angela says. “And I began to think, Wow, maybe there’s a chance I could beat this thing. It hadn’t really occurred to me until I started the genetic-counseling process that there was even a chance I could be negative.”
So, in the middle of the summer of 1997, Angela had her blood drawn. Several weeks later, the day after she and her husband returned from California, she got a call to come in for her results. “I knew at that moment I’d tested positive. I knew that a negative result could be given over the phone. Otherwise they wanted to see you, to present the various options.”
But Angela already knew what she was going to do. “The disease had been an albatross around my neck for years. I’d watched all these women in my family get sick. I watched them go bald and suffer from chemo and radiation. I’d watched them not be able to lift their arms after surgeries. And maybe even worst of all, I’d watched them get sick not once but twice. They’d be diagnosed with cancer in one breast, and just as they’d gotten better and built themselves up they’d get knocked down again with a diagnosis two or three years later in the other breast. Close to 60 percent of all inherited breast cancers are bilateral. And, of course, I’d watched them all die, including two of my cousins who were only in their thirties,” Angela says without even a hint of tremor in her voice.
In the Jewish community, the issue of genetic testing – and the fear of being stigmatized – has been a raw subject. Because Jewish women of European descent are so easy to screen for BRCA mutations, the gene is sometimes incorrectly referred to as the Jewish cancer gene.
This is the result of something called the founder effect rather than an increased susceptibility among Jewish women to cancer. Because Ashkenazi Jews have, until very recently, remained a cohesive, essentially closed group that by and large didn’t marry outsiders, certain genetic markers can be traced back several thousand years to a handful of founder families. The same genetic phenomenon has been uncovered in Iceland, for precisely the same reasons; the integrity of the group has not been compromised by marriage to outsiders.
“The stigma issue in the Jewish community is totally misplaced,” Offit says. “Not only does every group have its genetic baggage, but it turns out that in many cases what we thought was baggage is not. In the African-American community, for example, sickle-cell turns out to be the leftover result of the body protecting itself against malaria, which was widespread in certain parts of Africa before there was medication. So there may be a higher reason for BRCA as well that we just don’t know about.”
Once the external issues attached to genetic testing are stripped away, however, what remains is the extraordinary impact on the affected families and individuals. Mothers struggling with guilt over passing the genetic mutation to a child. The dynamic between two sisters when one tests positive and the other is negative. Families where certain relatives don’t talk to one another and consequently can’t communicate test results. Women who find the idea of having to tell anyone else in the family so painful they end up not even getting tested.
“I had an older woman with breast and ovarian cancer,” says Myrna Ben-Yishay, a genetic counselor at Montefiore Medical Center/Albert Einstein College of Medicine, “who was simply unable to tell her two sons she was BRCA-positive. So she wrote them a letter that will be included as part of her will.” (Men can carry and pass on the mutation. Though the impact of BRCA defects in men is uncertain, regular prostate and colon exams are urged.)
“I think that so far we have pretty much been dealing with a self-selecting group,” says Ben-Yishay. “These women are unusual people. They are clearly women who believe that knowledge is power. We don’t really know at this point how the average person will feel about all this because I think they’re the people who haven’t started to come in for genetic counseling yet.”
Those people who should be tested, experts say, are women with multiple cases of breast or ovarian cancer in their families, particularly at an early age, generally defined as either premenopausal or before 50.
olly Ker’s family, riddled with breast and ovarian cancer, certainly fits that description. Sitting in a Park Avenue South patisserie one morning recently, Ker, 27, pushes her fruit salad around in its bowl, sips her tea, and talks about having her ovaries removed.
Though she hasn’t been tested yet, she has a plan. If she finds out she’s positive later this year, when she figures she’ll get tested, she intends to have an oophorectomy by the time she’s 35. She worries about ovarian cancer because it’s so insidious, but feels her regimen of frequent breast exams is sufficient to catch anything early enough to take care of it.
She wants to have kids, but she and her boyfriend aren’t ready. “What worries me is I could be 32 and I won’t feel any more ready and I’ve set this deadline. I’ve been raised in a generation of women who’ve been led to believe they can wait till they’re 40 to have kids,” says Ker.
A couple of weeks later, Ker, who works for an Internet company, sends me an e-mail saying her doctor found an abnormality in one of her breasts. He had her take an ultrasound. In the waiting room at the radiology lab, she thought for the first time about a mastectomy.
“To not do everything I possibly can to lessen my chances of breast cancer just feels irresponsible,” she says.
The ultrasound didn’t turn up anything, and Ker remains determined to get tested even though she’s not at all certain how helpful the results will be.
“What’s going to change?” she says. “It’s not going to tell me I’m going to get cancer. It’s only going to tell me about two genes. But how could I not get tested?”
This, of course, is the quandary. The science is good but not quite good enough. “We don’t have all the answers,” says Lauren Scheuer, a genetics counselor at Sloan-Kettering. “We can give people options, but that’s just what they are, options.”
Though Angela was more resolute about her choice than many of the women in the same precarious position, there was a searing irony in her decision to have a double mastectomy. For years she had been offended, outraged, and disappointed by many of the doctors she’d been to. Stunned by her harrowing family history, one doctor after another delivered a version of the if-you-were-my-wife-or-my-sister speech, which essentially consisted of imploring her, often during a first visit, to have a bilateral mastectomy.
It was one thing to hear this in the dark ages of breast-cancer treatment, that period before the activist movement took hold and forced the medical community to rethink some of its preferred treatment options. But it was inexcusable, Angela believes, to have this advice delivered after doctors were enlightened and even after the introduction of genetic testing.
“My argument is with the doctors who were unaware of the choices I could make,” Angela says. “Those doctors who either didn’t know enough about genetic testing or didn’t give it enough credence. They were recommending – without knowing enough about me or suggesting I get tested – that I go in for a radical surgical procedure I may not have needed, as my cousin who tested negative didn’t.”
But it went deeper than that. There was the doctor who told her she didn’t want to go into Manhattan for treatment; the one who said if she used him she’d be “patient of the week”; the one who refused to say specifically how many mastectomies he’d performed; and the one who told her, when discussing breast reconstruction, “you won’t bounce but you’ll never sag.” He also told her the whole thing was really nothing to worry about because “you go in with breasts and you come out with breasts.”
One doctor even told her to get cancer in one breast first and then he’d “take them both off.” But the worst offense was probably committed by the doctor who assured her he could save her nipples. Most breast cancer starts in the ducts that come out from the back of the nipples, and the most critical part of doing a prophylactic mastectomy is getting every last bit of breast tissue.
“This whole process for me,” Angela says, “has been one step at a time. Do you want to go into Manhattan? Do you want to go to Memorial Sloan-Kettering? People go and die at Memorial, don’t they? Do you want to have the blood test? Do you want to do this? Do you want to do that? But I had to know, before making the final decision about my breasts, that I had found the best surgeon. I knew I needed someone who was trained to get every cell possible and understood how critical that was. Unlike the doctor who was going to leave my nipples. Unless I found a doctor I was comfortable with and confident in, I was not going to have the surgery.”
She shopped for doctors in earnest and stuck to a rigid set of standards. If there was a nurse in the office who was snarky, or anything else at all she didn’t like about the practice, it was eliminated. She talked to other women who’d had their breasts removed. “I was empowered. I knew what I was looking for, I had time, and I felt I was in control of this disease. If I had been diagnosed first, I don’t know if I would have, if I could have, taken so much time. If I’d been frightened, perhaps I would have dealt with the first guy who was looking to help me. I might have allowed some hysterical doctor to perform the surgery. But now I was in control. I chose to lose my breasts. The cancer did not decide that for me.”
The turning point for Angela came when she went to see Dr. Alexandra Heerdt, who heads Sloan-Kettering’s high-risk program for women. Heerdt was patient, informed, and compassionate. But she was also direct. She told Angela that based on her family pedigree, her BRCA status, and film of her breasts, she believed she had an extremely high risk of getting cancer.
After their meeting, Angela sat down next to her husband, who’d gone with her, on the commuter train to go home. They hadn’t said much to one another since they’d left the doctor’s office, and now when she looked at him, he knew what she was about to say. “It’s a go,” she told him. “I’ve found my surgeon.”
Angela then chose a plastic surgeon based on recommendations and one interview, and by the time she met with him, she already knew which of the available reconstruction options she wanted. She decided on saline implants. At the end of the surgery, a temporary device called an expander would be put in her chest and filled with saline in order to gradually stretch the skin to accommodate new breasts.
Angela knew when she left the hospital she’d have small breast mounds without nipples. Each week a little more saline would be added to the expander until she had breasts the size she wanted. Then, in a second surgery, the expander would be removed and the permanent implants put in. In a third procedure, some skin would be taken from her groin to construct a nipple and an areola. Finally, micro-pigmentation would add color to the areola that would hide some of the scarring. The entire four-step process would take about a year.
But before the surgery was scheduled, Angela had to meet with a psychologist and answer some questions. How would her life be different if her breasts were removed? How did her husband feel about this? What interests did the two of them pursue? How would this affect their sex life? What did her sons think?
“My husband was actually more concerned with how this would affect me. And with my family history, these breasts were not thought of as sex objects. I didn’t have the same affinity for my breasts that another woman might have. They were the things that could end my life.”
Nine days after the surgery, when Angela was in the very early stages of physical and emotional recovery, a biopsy report came back. It revealed she had an intraductal carcinoma – the very beginnings of breast cancer.
“I don’t know if my recovery would have been any different if the pathology had come back negative,” Angela says now, thirteen months after the ordeal. “But I feel I made all the right decisions for all the right reasons, and as a result I sleep very well at night. I believe genetic testing saved my life.”