All Things Considered

Family Struggles With Ambiguity Of Genetic Testing

By Deborah Franklin

Published December 30, 2008 11:41 AM

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"Information is power," has become a common mantra. But for many people seeking answers through genetic testing, all the DNA probing ends in this twist: Less certainty, not more.

This sometimes leads to tough personal decisions amid ambiguity. Nashville novelist Susan Gregg Gilmore learned this lesson the hard way.

Gilmore, a happily married, 47-year-old mother of three daughters, sought testing for flaws in two long genes known as BRCA 1 and BRCA 2. A number of mutations in those genes, first identified in the mid-1990s, have been strongly associated with an increased risk of breast and ovarian cancers.

The risk is particularly elevated for women; having one of the harmful mutations increases the lifetime risk of breast cancer to somewhere between 36 percent and 85 percent, according to the National Cancer Institute. The range reflects the differing risk estimates that have turned up in different studies. A BRCA mutation increases the ovarian cancer risk to between 16 percent and 60 percent.

The Gilmore family, from left, Josephine, Susan, Alice, Dan and Claudia.(David Deal for NPR)

Though she had heard of the test, Gilmore says, she never thought much about it before getting a call from her mother-in-law, Martha, a few years ago. Eighteen months after defeating breast cancer, Martha Gilmore, a Methodist minister, was diagnosed with ovarian cancer, at age 63. Though most cases of breast and ovarian cancer are not inherited, Martha and her doctors wondered if a BRCA mutation might be behind both diseases in her case. She had called to tell Susan that she was considering taking the test so that her children and grandchildren would have more information.

The Power Of Information

Susan Gregg Gilmore and her husband, Dan, struggled with major health decisions after receiving genetic testing results.(David Deal for NPR)

Susan was very close to her mother-in-law, and was encouraging that day.

"I remember saying 'Martha, you've got to do this. I mean information is knowledge and power. We have three daughters … Yes, yes. We need to know.' But in no way did I realize at the time what kind of impact that test would have on my life," she recalls.

Claudia, 21, (right) has already chosen to have genetic testing. Josephine, 17, and Alice, 14, will make this decision when they get older.(David Deal for NPR)

Martha did turn out to have one of the mutations in BRCA 1 that's been tied to cancer. Eventually, she died of the illness, with Susan and other family members at her bedside. And not long after Martha's funeral, further testing showed that her son Dan Gilmore — Susan's husband — had also inherited the mutation.

Susan was out of town that day, and when Dan called from the clinic to tell her the bad news, she fell apart.

"It really threw us for a loop," he says. "We were not as emotionally prepared for it as we should have been."

Now, you could argue that Dan's genetic test result really had implications only for him and his three daughters, who are now in their teens and early 20s. But as Dan and Susan started scrambling to get more information, Susan started worrying about her own DNA.

One aunt, she recalled, had suffered a chronic disease of the ovaries, and eventually died of ovarian cancer. To Susan, who was still reeling from her mother-in-law's terrible illness, the aunt's death seemed ominous. And that wasn't all.

"As we're sitting there with a genetic counselor plotting out our family tree — Dan's family tree — I'm kind of looking at the tree and putting my own family members on the branches," says Susan, "and realizing that there are some missing branches!"

She had the sort of gaps that are common in an extended family's medical history. "My mother's mother had died at a very young age, in her early 30s," Susan says. "And no one seemed to know why."

According to family lore, Susan's grandmother might have died of a botched abortion. Others said it could have been cancer. Such vagueness isn't unusual.

"But it puzzled me and terrified me," Susan says.

Taking It A Step Further

The best solution, she decided, would be to get tested herself for BRCA mutations. It would put her mind at rest, and give her daughters "a more complete medical history on both sides of our family." Susan's mother is still alive and healthy, and Susan has lots of middle-aged female cousins and sisters who are all cancer-free. The doctors told her it was extremely unlikely she had a BRCA mutation. All the more reason to get tested, she thought.

"I wanted to bring some good news to the table," she says.

Dan, a pragmatic attorney and marathon-running former Marine, was initially worried that this time the test was just inviting more trouble. But he eventually came around to Susan's view.

"Chances are she doesn't have it," Dan figured. "This'll sure be nice to rule this out."

So Susan got tested, and remembers exactly where she was, a week or so later, when she got the news.

"I walked out of the Y that day," she says. "It was a beautiful day. It was crisp, it was clear. And I remember standing in the parking lot thinking, 'I feel good.' And for the first time in months I do not feel like cancer is going to control my life, or even the thought of cancer. Or the fear of cancer. And not even five minutes later, I get a call on my cell phone."

It was the genetic counselor. Susan still winces remembering the words that came next.

"She started talking about this variant, this variant of 'undetermined significance,'" Susan says, "and how it shouldn't change my life or my medical plan. But, you know, all I could hear was variant …and it wasn't really making any sense. And it felt … it felt overwhelmingly gray."

Susan and her family had been counting on good news — or at least a clear thumbs up or thumbs down. But, as the counselor explained, a variant mutation of "undetermined significance" turns up in roughly 10 percent of all case of BRCA tests, and even more often among African-American families. It means there is definitely a mutation, but one that hasn't been linked to illness, in all the research that's been done so far. Susan's "variant" could turn out to be harmless … or not. At this point, no one can say for sure.

Determining Where To Go From Here

Susan was far from comforted.

"I thought, 'Can we not catch a break here in this genetics game? And what is this variant? And quit telling me that it's of undetermined significance, because I can tell you right now, it is feeling extremely significant," she says.

What she really wanted to know, she says, was whether she should she have her ovaries removed, "just in case." She consulted several doctors and genetic counselors, but, much to Susan's frustration, they all stopped short of direct advice.

"I totally relate to the frustration," says Beth Peshkin, a genetic counselor the family consulted at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, D.C. "Because I think, as clinicians, we would like to have more definitive answers as well."

As Peshkin explained to Susan, the BRCA test has proved to be quite helpful over the years, particularly to families who have a widespread family history of ovarian and breast cancer across several generations. Once the particular mutation has been identified that's behind a family's cancer, any member who tests negative for that mutation can be considered truly negative. That's the good news result. The risk of that person getting cancer is no higher than the risk among the general population, and those who get that news can be certain they won't pass the family cancer gene on to their children.

Even a "bad news" test result — knowing that they have a harmful mutation — feels empowering to many people, Peshkin says, because it prompts them to get more frequent screening for breast cancer. Any tumors subsequently discovered are likely to have been caught at an earlier, more treatable stage. Some women in that situation choose prophylactic mastectomies as a further hedge against disease. And, because there are no good screening tools yet for ovarian cancer, some women who discover they have harmful BRCA mutations are choosing to have healthy ovaries removed in their mid-30s, once they are done with childbirth. Though never an easy choice, such surgery does greatly reduce the risk of cancer.

But the catch is this: Increasingly, with more healthy people from healthy families seeking testing than ever before, the results coming back are often much harder to interpret.

"Today," Peshkin says, "maybe half the people seeking BRCA testing get back results that are uninformative for one reason or another."

Letting Tolerance Level For Risk Be The Guide

Some, like Susan, have an ambiguous variant that may or may not be normal. Others are told they are "negative" for all known BRCA mutations, but because they have many cases of cancer in their family, it seems likely that a different flawed bit of genetic machinery that has yet to be identified is to blame for the family's disease. In these cases, patients are told that their test result is negative, but not necessarily a "true negative."

Whatever the cause of the uncertainty, research studies have shown that such ambiguous news is often at least as distressing to hear as bad news, at least in the beginning. As Peshkin tried to help Susan work out what to do next, she advised the anxious patient to let her own tolerance for risk serve as a guide.

"In this case," Peshkin says, "it really came down to, 'It doesn't look based on your family history or your test result that you're at increased risk for ovarian cancer. But you're very worried about this disease; there isn't good screening for this disease; we can't tell you conclusively what your risk is.' So, it really did have to be her decision."

Susan says that even if the science suggests her cancer risk is minimal, those statistics can't wash away her experience of her mother-in-law's final days.

"Doctors can tell me that ovarian cancer is very rare," she says. "But then I can say, you know, I've known more people with ovarian cancer than breast cancer. I have held the hand of a woman dying of ovarian cancer. So, in my reality, ovarian cancer is very present."

So, last June, Susan decided to have her healthy ovaries removed. Dan supported his wife's decision, and Susan says she doesn't regret the surgery for a minute. She now knows she's done everything she can to eliminate any risk of ovarian cancer.

Peshkin agrees that, for Susan, the surgery was justifiable. But is she better for having taken the genetic test in the first place?

"I don't know," says Peshkin. "In some ways probably yes, in some ways probably no. But this is what it is to live with uncertainty. And some people have a harder time living with uncertainty than others."

Looking At Their Daughters' Futures

Through it all, Susan and Dan believe they've been good role models for their children. They were supportive when, earlier this fall, their 21-year-old daughter Claudia, the eldest, decided to get tested. Claudia has inherited Dan's mutation.

In many ways, Susan says, that was the hardest news to get of all.

"Knowing that from the time she's 25, every six months she'll have to have … a mammogram or MRI … and biopsies whenever they pick something up … all that testing anxiety and decisions. Do I have my breasts removed? My ovaries removed? Sure, it's life-saving information, but it's a lot of muck, and there's a sadness to that," Susan says.

"As a parent, you know bad things are going to happen to your kids," she says. "But it's a very different feeling when you are the ones handing them the muck. It's an unnerving feeling to have to say, 'Here — we know what this is, and we're giving it to you. Now make something of it.'"

For now, that new knowledge just means extra breast exams for Claudia. Dan says that genetic testing for the two younger girls, who are still in their teens, can wait.

"There's the whole ethical issue of them having a choice in it," he says. "We really felt like they needed to be old enough to decide on their own, to make it a fully informed decision on their own."

Susan says she's content with all the family's decisions so far. Still, she's in no big rush to sign up for further genetic testing for other diseases.

"I mean, this year alone ya know, all the genetic testing that my husband's done—my mother, my daughter, myself—I'm kinda done. I mean, I want a year off from empowering knowledge. At some point, you've just got to get out there and live life," Susan says.

Deborah Franklin reported this story during her time as a Kaiser Family Foundation fellow.

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ROBERT SIEGEL, host:

From NPR News, it's All Things Considered. I'm Robert Siegel.

MELISSA BLOCK, host:

And I'm Melissa Block. We often hear that knowledge is power. Well, today, we have the story of a family that found the saying is not always true. The Gilmore family rushed into genetic testing, which can determine whether you are at risk of cancer, only to find that each test result raised new, unsettling questions. NPR's Deborah Franklin met this family while she was a fellow with the Kaiser Family Foundation. As she reports, even the best genetic tests can produce uncertain results, and that knowledge can force some tough personal decisions.

DEBORAH FRANKLIN: Susan Gregg Gilmore was never all that interested in science. She's 47 years old and healthy, a successful novelist, married to the man she loves, mother of three healthy girls. Genetic testing wasn't even on her radar.

Ms. SUSAN GREGG GILMORE (Author): I was very happy living in this world of words and, you know, feelings and emotions and color, and that was more my schtick. And I just honestly didn't think about it much, not until my mother-in-law was diagnosed with breast cancer.

FRANKLIN: And then, just 18 months later, with ovarian cancer. Now, Susan loved her mother-in-law very much. Martha Gilmore was curious about the world and a great listener. She was one of the first women ordained as a minister in the state of Texas.

Ms. GILMORE: She was always a pioneer. And I was very drawn to her from the beginning, and we just shared a lot of things - very close, free emotional relationship. I never - and I told her this - I never once felt like your daughter-in-law, I always felt like your daughter.

FRANKLIN: One day, between visits to the doctor for chemotherapy, Martha called to talk about a medical test that wouldn't change her own treatment, but maybe the outlook for her granddaughters. It was a genetic test, kind of pricey - about $3,000. Still, Martha was considering taking it.

She explained to Susan, the test looks for certain mutations in two long genes, known as BRCA1 and BRCA2. If you have a bad mutation, the gene doesn't work right, and you're more likely to get breast cancer or ovarian cancer or both. If Martha had inherited this faulty gene, there was a 50-50 chance that she had passed it along to her son and maybe, through him, to her granddaughters. Susan was convinced.

Ms. GILMORE: I actually remember talking to her on the phone and saying, Martha, you've got to do this. I mean, information is knowledge and power, and we have three daughters. We need to know. So, I was very encouraging. Go, go, yes, yes, we need to know.

FRANKLIN: Susan's mother-in-law got the test. And she did turn out to have one of the mutations in the BRCA1 gene that's been strongly linked to cancer.

Ms. GILMORE: And when she called, she was just devastated, in tears, and her sadness was for her granddaughters.

FRANKLIN: Still, the girls were only in their teens and might not even have the gene. It didn't seem the time to be anxious about their future. Though Martha had survived her battle with breast cancer, the ovarian cancer was killing her. Susan was at her mother-in-law's bedside when Martha died.

Ms. GILMORE: It got to the point where we really could only communicate by looking at each other. And then, in the last day, I hoped that she knew that we were all there and surrounding her. I believe she did, but, you know, you don't really know for sure at that point.

FRANKLIN: You could say that's when Susan inherited a fear of ovarian cancer from her mother-in-law, along with a determination never to get the disease and to keep her daughters safe. Though already slim, she started swimming several times a week to help with the stress and pushed the family to eat better, hoping that would reduce their risk. Her husband was dragging his feet about genetic testing, but soon after the funeral, Susan went to the doctor herself and got a preview of what they would face once her husband was tested.

Ms. GILMORE: I remember her saying, well, have him tested first. If he doesn't have it, then you don't have to worry about it. If he has it, then you'll need to have the girls tested at some point. And then, well, you know, if they have it, they just will need to have a complete hysterectomy and a double mastectomy by the time they're 40. And then I left and came home in tears, and said to my husband, who I'd been begging for months now, have this testing done, you must do this genetic testing. Look, this is what we're dealing with.

FRANKLIN: Her husband, Dan Gilmore, is a lawyer, a marathon-running former marine, handsome and steady. Dan says he hadn't hurried off to get tested because he was still raw from his mom's illness and death.

Mr. DAN GILMORE (Attorney): For the longest time, I just didn't want to even consider the fact, this is something I need to deal with. And I think a lot of that was not wanting to face the potential of having to deal with this with my daughters for the rest of my life and their life.

FRANKLIN: In hindsight, everybody agrees that they should not have gotten into genetic testing so soon after Martha died. Dan did get tested, and he got the results a few weeks later. Susan was out of town.

Mr. GILMORE: I called from the clinic and told her, and she just fell apart.

FRANKLIN: Dan told her he had inherited his mother's mutation.

Mr. GILMORE: It really threw us for a loop. We were not prepared, I think, emotionally, for it as well as we should have been.

FRANKLIN: Susan started running the numbers. The news meant that Dan's risk of getting breast cancer was only about seven percent. But if the girls had inherited the faulty gene, their risk of breast cancer could jump as high as 85 percent, with as much as a 50 percent risk of getting ovarian cancer. Susan started questioning everything, and Dan focused on holding his family together.

Mr. GILMORE: My tendency is to kind of jump in and say OK, I have to be functional for both of us. I have to maintain my normal routine and have to just, you know, keep going to work and just stay in my routine, then I'm kind of insulated from this new turn in our lives.

FRANKLIN: Now, you could argue that Dan's test result really only had implications for him and his daughters. But as the couple reached out for more information, Susan started wondering about her own DNA.

Ms. GILMORE: You know, as we're sitting there with a genetic counselor plotting out our family tree - his family tree, his family tree - I'm kind of looking, you know, at that tree and putting my own family members on the branches and realizing that there's some missing branches.

FRANKLIN: And something else that terrified her. Susan had one aunt who'd suffered a chronic disease of the ovaries and eventually died of ovarian cancer. As for gaps in the family medical history...

Ms. GILMORE: My mother's mother had died at a very young age, in her early 30s, and no one seemed to know why. To be so vague about how someone in our family, I mean, my mother's mother died, that puzzled me and bothered me.

FRANKLIN: According to family lore, she may have died from a botched abortion. Others said it could have been cancer. The counselor tried to reassure Susan it was extremely unlike that she'd inherited a worrisome mutation, but Susan wanted to take the BRCA test, just to be sure. Dan was hesitant.

Mr. GILMORE: My first thought was, does she really need to? And are the chances of her having the mutation - are they significant enough to warrant it? And pretty soon after that, my thought was, this is a good thing because chances are she doesn't have it. This will sure be nice to be able to rule this out.

FRANKLIN: Susan says she wanted the girls to have their full medical history, plus...

Ms. GILMORE: Maybe somewhere hidden there was a little bit of I want to prove that, you know, from my side of the family…(Laughing)…we're perfect. You know, there's a lot of crazy emotions that are flying around when you're dealing with all this.

FRANKLIN: So, she got the test and a week or two passed by.

Ms. GILMORE: I walked out of the Y that day. It was a beautiful day. It was crisp. It was clear. And I remember standing in the parking lot thinking, I feel good. And for once, in months, I do not feel like cancer is going to control my life, or even the thought of cancer or the fear of cancer. And not even five minutes later, I get a phone call.

FRANKLIN: It was her test results. Susan still winces just remembering the genetic counselor's words.

Ms. GILMORE: Hi, Susan, how are you? Where are you? And I just - then she started talking about this variant - this variant of undetermined significance and how it shouldn't change my life or my medical plan. But, you know, all I could hear was variant, variant, and it wasn't really making sense. And it felt overwhelmingly gray.

FRANKLIN: She'd been counting on good news or at least a clear thumbs up or thumbs down. But as the counselor explained, a mutation of undetermined significance turns up maybe 10 percent of the time among people who get this test. It could be harmless or not. At this point, nobody knows.

Ms. GILMORE: And I thought, can we not catch a break here in this genetics game? What is this variant? And quit telling me it's of undetermined significance, because I can tell you right now, it is feeling extremely significant.

FRANKLIN: What she really wanted to know was should she have her ovaries out? Searching for an expert who would tell her yes or no, Susan called Beth Peshkin. She's a genetic counselor and researcher at Georgetown University's Lombardi Comprehensive Cancer Center.

Ms. BETH PESHKIN (Senior Genetic Counselor and Associate Professor, Oncology, Lombardi Comprehensive Cancer Center, Georgetown University): I totally relate to the frustration because I think, as clinicians, we would like to have more definitive answers as well.

FRANKLIN: Peshkin told Susan that, these days, many people have to deal with a BRCA test result that is ambiguous, for one reason or another.

Ms. PESHKIN: In this case, it really came down to it doesn't look as though, based on your family history or your test result, that you're at increased risk for ovarian cancer. But you're very worried about this disease. There isn't good screening for this disease. We can't tell you conclusively what your risk is, so it really did have to be her decision.

FRANKLIN: Susan wasn't comforted by the statistics about the disease, either.

Ms. GILMORE: Doctors can tell me ovarian cancer is very rare. But then I can say, you know, I've known more people with ovarian cancer than breast cancer. I have held the hand of a woman dying of ovarian cancer. So - and in my reality, ovarian cancer is very present.

FRANKLIN: So last June, Susan had her healthy ovaries removed. Dan supported his wife's decision, and Susan says she doesn't regret the surgery for a minute. She's not at risk for ovarian cancer anymore. Genetic counselor Beth Peshkin...

Ms. PESHKIN: In the end, is she better off for having gotten the testing? I don't know. In some ways, probably yes; in some ways, probably no. But this is what it is to live with uncertainty, and some people have more of a difficult time dealing with the uncertainty than other people.

FRANKLIN: Susan and Dan believe they've been good role models for their daughters. They were supportive when, earlier this fall, their eldest, 21-year-old Claudia decided to get tested. She has inherited Dan's mutation. For now, that just means extra breast exams for her. Dan says genetic testing for the other girls can wait.

Mr. GILMORE: There's a whole ethical issue of them having a choice in it, and we really felt like they need to have - be old enough to decide on their own, to make a fully informed decision on their own.

FRANKLIN: Susan says she's content with all the decisions so far, but she's in no big rush to sign up for genetic tests for other diseases.

Ms. GILMORE: I mean, this year alone, you know, all the genetic testing that my husband's done, my mother, my daughter, myself - I'm kind of done. I mean, I want a year off from empowering knowledge. At some point, you've got to go out there and live life.

FRANKLIN: Deborah Franklin, NPR News.

(Soundbite of music)

BLOCK: It's not uncommon for people to get genetic testing and find themselves, like the Gilmore family, with more questions than answers. Well, we'd like to hear your questions about genetic testing for breast and ovarian cancer, and we'll get you some answers. You can send your questions by going to npr.org. Click on contact us at the top of the page. Please be sure to put the phrase "genetic testing" in the subject line. And tomorrow, we'll put some of your questions to an expert from the Dana-Farber Cancer Institute. Transcript provided by NPR, Copyright National Public Radio.

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