“It was a four-year ordeal,” Lewis recounts, sitting beside her husband one autumn morning in a sandwich shop north of Houston. Her own breast cancer risk, always a nagging worry, didn’t assume center stage until 2013 when, then 42 and a mother herself, she had a series of breast-imaging callbacks. Her routine screening mammogram was abnormal, which led first to an ultrasound, then a MRI and then a biopsy of several worrisome areas before cancer ultimately was ruled out. “God, it felt like forever,” she says.
Determined to no longer live in a cancer limbo, Lewis got tested later that year for the BRCA gene mutations that can run in families and significantly raise a woman’s risk of developing breast or ovarian cancer. And when the results came back positive, she moved quickly. In early 2014, a surgeon removed both of her breasts and she recovered with the help of her husband, Jerry, and her mother, who recently celebrated 23 years free of cancer.
But the thornier dilemma – whether to relinquish her ovaries as well – was just emerging.
“For me, I feel quite a ways away from menopause,” says Lewis, who has two young daughters. “Although we were pretty confident that we were finished having children, I didn’t want to prematurely be thrown into menopause. I was more afraid of that actually than the double mastectomy, because of the hormonal changes it can cause and the imbalance in your body.”
Now there may be an alternative surgery, an experimental approach that’s built upon intriguing science. A small cadre of doctors are exploring whether removing the fallopian tubes but sparing the ovaries – for a stretch at least – will enable women like Lewis to preserve their hormonal balance a bit longer, and perhaps provide some buffer against ovarian cancer.
As testing for BRCA mutations becomes more common, clinicians are meeting with more and more women like Lewis, who have been blindsided in the prime of their reproductive life by the knowledge that they carry a potentially life-threatening mutation.
But these women can dramatically reduce their risk of cancer – by removing their breasts and ovaries and, along with them, the tissue and estrogen supply that fuel the vast majority of these malignancies.
Consider these daunting stats: women with BRCA mutations face a lifetime ovarian cancer risk that can be as high as 40 percent, compared with 1.3 percent in the general population. No reliable screening test has been developed. Nearly two-thirds of ovarian cancers aren’t caught until they’ve spread beyond the lymph nodes to elsewhere in the body. By then, the five-year survival rate is 27 percent.
Some women, though, flat out refuse to shut down their childbearing options or be thrown into menopause prematurely, says Denise Nebgen, a gynecologist at the MD Anderson Cancer Center in Houston. Psychology also can play a role, she says, as some patients are “glass-half-full types”. So they will flip, say, a 27 percent lifetime risk of ovarian cancer upside down, instead focusing on the 73 percent likelihood that cancer won’t ever flare. Emphasizing the inadequacies of early detection with screening “until you are blue in the face” won’t change their minds, she says.
Nebgen is the principal investigator of a pilot research study led by MD Anderson, one of several research efforts now in the works that are looking at alternative surgery: taking out the fallopian tubes of BRCA carriers who decline the recommended approach of removing both ovaries and tubes.
This controversial procedure is built upon research suggesting that the fallopian tubes may be responsible for a good proportion of the most common form of ovarian cancer – between 40 per cent and 70 per cent, depending on the studies cited.
The hypothesis that the tubes are implicated in many cases of ovarian cancer represents a sea-change in thinking, says Douglas Levine, MD, a gynecologic oncologist at New York City’s Memorial Sloan Kettering Cancer Center, who counts himself among the early skeptics. “For about 30 years, almost everyone thought that it [ovarian cancer] came from the surface of the ovary.”
The MD Anderson study began enrolling patients in late 2013. In France, a different study is looking at tube removal in a small group of BRCA mutation carriers, with the plan to monitor cancer rates in the years ahead. Meanwhile, a coalition of US medical centers is developing a clinical trial, which will be submitted for approval to the National Cancer Institute, to study tube removal in roughly 250 pre-menopausal BRCA mutation carriers aged 30 to 49, says Levine, who would be the principal investigator.
Depending upon the perspective, this emerging research is either investigating a risk-reduction alternative for those BRCA mutation carriers who would otherwise avoid ovarian surgery entirely, or it is throwing women onto the third rail of experimental uncertainty.
These women are “guinea pigs” assuming an unknown degree of risk, says Christopher Crum, a Boston pathologist considered one of the pioneers in making the connection between fallopian tubes and ovarian cancer.
Crum worries that he hasn’t been able to trace some advanced malignancies back to the tubes, at least so far. One possibility is that there is another route to seeding ovarian cancer, one that doesn’t involve the tubes. “There could be things happening that we don’t understand,” he says.
“If you have BRCA, and somebody made a mistake [about the tubal connection], you’re not going to see your grandchildren,” he says. “That is to me the issue.”
There are two BRCA genes: BRCA1 and BRCA2. The proteins they encode help repair damaged DNA in cells. People with mutations in either of these genes are believed to be more vulnerable to cancer because the ability to repair errors in cellular DNA is impaired.
Women who carry these mutations face stark choices, as the actress Angelina Jolie highlighted in 2013 when she underwent a double mastectomy after testing positive for BRCA1. And Lewis, despite years of trying not to fret about her familial risk, recalls the shock of seeing her own BRCA2 mutation stated in black and white on the letter from the genetic testing company Myriad. To drive the results home, it said in capital letters near the top: “POSITIVE FOR A DELETERIOUS MUTATION”.
Amy Starr, who also lives near Houston, hoped against hope for a negative test result. Sitting in her living room, the 39-year-old surgical nurse pulls a family photo album down from a shelf. She runs her finger along the faces, as she describes which of her father’s siblings have developed cancers linked to a BRCA mutation.
Beginning with her grandmother’s generation, cancer, primarily breast and ovarian, has been diagnosed at least seven times, taking four lives. Most recently, her Aunt Susie died in 2011 at age 61 from a form of ovarian cancer, primary peritoneal, after testing positive for BRCA1 nearly a decade before.
"I thought, ‘I’m going to put my mind to rest’,” Starr says. “‘I’m just going to prove to myself that I don’t have it.’ That was the goal,” she says, with a nervous laugh. “But that didn’t work.”
In 2010, she tested positive for BRCA1.
Lewis and Starr are among at least 1,100 women, most of them BRCA mutation carriers, who have visited MD Anderson’s high-risk ovarian screening clinic since 2010. On an autumn morning, the clinicians there meet with a steady stream of patients with turnstile efficiency, reviewing ultrasounds and blood work results, and discussing the significant benefits of ovarian surgery against cancer.
In one room sits a young woman in her early 30s, her head wrapped in a pink scarf, partway through treatment for breast cancer. In another, a 34-year-old without a history of cancer describes how she’d prefer to postpone any surgery, to keep her options open until she’s found the right guy. “I’d like to have one or two more kids,” she tells Nebgen.
As testing for these mutations increases, clinicians are encountering more women in their 20s and 30s. While ovary removal is not recommended until at least the mid-30s, Nebgen says, some of these younger women seek counselling earlier on, as they start to weigh the excruciating dilemmas involved.
“It’s life-changing to have your breasts and your ovaries removed 10 to 15 years before that [menopause] would happen naturally,” says gynecologic oncologist Karen Lu. One frequently voiced fear, she says, is loss of libido.
That possibility haunts Starr. “It’s hard to give up your sexuality,” she says. “Who knows how bad it’s going to be?” These days Starr pursues a vegan diet, a change she made while waiting for her genetic results; the slim mother of two boys, aged 5 and 12, she stays active with walking and running.
Although it seems drastic, the current recommendation to remove the ovaries and adjacent fallopian tubes has a well-established track record. The operation slashes the risk of ovarian, fallopian and peritoneal cancer, according to a recent study that followed nearly 5,800 BRCA mutation carriers from Canada, Europe and the United States.
And the protective payoff doesn’t stop there: removing the ovaries also shuts down the estrogen supply that fosters the growth of some other cancers, including those of the breast. Women who had the procedure were 77 per cent less likely to die by the age of 70.
But Lewis and Starr aren’t the only holdouts. Just 46 per cent of women with a BRCA mutation but no history of breast or ovarian cancer consented to the ovarian surgery within five years of learning their genetic risk, according to a 2012 study which followed 700 women from England.
Lewis and Starr enrolled in the MD Anderson study, keeping their ovaries for now, but getting their fallopian tubes taken out last year. The cancer centre’s goal is to follow 40 BRCA mutation carriers who will choose one of three paths: screening only, the recommended ovarian removal, or the experimental tube removal followed by ovarian surgery three years later.
Starr says she understands the risks she’s running, and emphasizes that the MD Anderson researchers didn’t promise anything specific in terms of the benefits of tube removal. “I didn’t want to have my ovaries out yet,” she says. “But I wanted to feel like I was doing something as far as reducing my risk.”
The fallopian tubes, which measure no more than 13 centimeters long each, are the tissue pipeline through which the egg travels each month from ovary to uterus.
It’s a remarkable journey, beginning when the egg is first spat out of the almond-shaped ovary, sliding through a minuscule hole that appears in the outer lining. From there, if all goes well, the released egg is captured by the nearby fallopian tube, with the help of moving finger-like tendrils that extend over the ovary.
Called the fimbria, these tendrils look somewhat “like a chrysanthemum flower”, Lu says. Sitting in her MD Anderson office, Lu sketches out an informal anatomical drawing showing how the tubes, and specifically that fimbriated end, play a crucial role in the reproductive process. “It has to catch the egg every month,” she says. “Like a baseball mitt.”
Detecting ovarian cancer early has proved difficult because it seems to emerge full force from nowhere. By the time cancerous signs are spotted from blood work or a vaginal ultrasound, the cancer has more than likely spread beyond the ovaries. So where does ovarian cancer begin?
Until recently, the most common form, high-grade serous carcinoma, was believed to stem from some breakdown related to the egg’s release each month, Lu says. As that egg emerges through the outer skin of the ovary, the minuscule tear has to be repaired.
“When that happens, you have little pockets that form,” she says. “And so the original thinking was that ovarian cancer developed when there was a kind of a pocket of epithelial cells [cells from the outer surface] that got stuck inside the ovary. And then those cells within the ovary became cancerous.”
It was the first waves of ovarian surgeries on BRCA mutation carriers, beginning in the late 1990s, that provided a front-row view of cancer’s development. Pathologists began to stumble across early cancers in the nearby tubes, says Christopher Crum, the pathologist at Boston’s Brigham and Women’s Hospital. Crum was struck by several papers published between 2000 and 2004, some of the first to postulate that at least some of these high-grade serous cancers originated in the nearby tubes.
The underlying theory, according to Crum, is that if tumors emerged in the tubes, they would be more likely to appear in that fimbriated end nearest the ovaries as they’re rarely found in the tube’s mid-section. Soon after reading the papers, Crum developed a pivotal dissection technique – dubbed the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end) – that continues to be used today.
The technique fillets the fimbriated end of each slender tube into numerous tiny sections, reducing the likelihood of missing a cancer, even if it’s just 1 to 2 millimeters in size, Crum says.
A series of studies followed, published by Crum and other researchers. They showed cancers in the tubes, with sometimes no signs in the ovaries, typically appearing in the fimbria. Another breakthrough, which involved genetics, began to link pre-malignant cellular changes in the tubes, called precursors, to later malignancies.
Crum, who played a key role in that work, stained hundreds of fallopian tubes, looking for mutations in a different gene that had already been found in high-grade serous ovarian cancers. Was the mutation also present in the fimbriated ends of the tubes?
He stained the tissue with a biomarker that would highlight the protein product of the gene in question. The view down the microscope started to light up as small stretches of benign epithelial tissue stained strongly, showing evidence of the mutation, and possibly the earliest stages of what might eventually become cancer. Crum remembers turning to a researcher nearby: “I said, ‘That looks pretty important.’ And he said, ‘No shit.’”
As they counsel patients about the new study, clinicians at the MD Anderson clinic walk a fine line of educating the women about the tubal research without overstating its potential. “Is that a theory or is that a fact?” one articulate 36-year-old woman keeps asking as clinicians outline the evidence to date. “Is that for sure going to reduce my ovarian cancer risk or not?”
The evidence is “pretty strong”, Nebgen tells the woman. Along with outlining some of the pre-cancerous changes that have been identified during dissections, Nebgen also cites the benefits that women already reap when they get their tubes tied – technically called tubal ligation – once they’ve finished having children.
That common procedure, which damages some of the tubal tissue, reduces the rate of later ovarian cancer by 34 per cent, according to a review of studies. Taking the tubes out completely could reduce your risk by at least that much, and hopefully more, Nebgen tells the woman and her husband, who is sitting nearby and intently listening.
Given the number of women who have routine pelvic surgery, such as a hysterectomy or getting their tubes tied, why not just take out the tubes completely during the procedure? A group of Canadian researchers have been pursuing that line of thinking in a large initiative in Vancouver, dating back to 2010, which focuses on women at normal ovarian cancer risk. More than 11,000 women to date have had their fallopian tubes removed during common pelvic surgeries.
Crum says he has no problem with that preventive step, given that those women aren’t genetically vulnerable to breast or ovarian cancer. But the equation is much different for mutation carriers, given their genetic risk and other uncertainties, he says.
For one thing, studies don’t agree regarding what percentage of these common ovarian malignancies can be linked back to the tubes. Physicians in Canada cite data showing that at least 70 per cent of all high-grade serous cancers are seeded in the tubes. Crum provides a table listing half a dozen recent studies, with findings ranging from 19 to 59 per cent of all cases, and an average of 42 per cent.
Another conundrum: when do these risky cells migrate beyond the tube? Most women start menstruating in their early teens, MD Anderson’s Lu notes. “It may be that the at-risk cells that are at the end of the fallopian tube drop into the ovary – they are probably getting shed – and they become incorporated into the ovary at a very young age, let’s say in the teens or the 20s,” she says. “So if that happens, removing the fallopian tubes at 30 may be too late.”
Despite the uncertainties, Lu and Nebgen fall into the camp thinking that it’s better to offer BRCA carriers this option if they would otherwise stall on ovarian surgery, perhaps indefinitely.
Steven Narod, a Canadian physician who authored the recent study showing a 77 percent reduction in the overall death rate by age 70, is critical of that stance. He argues that even suggesting the tubes-only option allows at-risk women to equivocate about having their ovaries out.
In his practice, he estimates that 90 percent of women with a BRCA mutation consent to the traditional surgery. “Why don’t you send me the patients that chose not to have it, and I’ll see damn well that they have it,” he says. “In other words, if they chose not to have it, you can be sure the doctor is not giving them full disclosure of the benefits.”
Starr flares at a recounting of Narod’s comments, calling that attitude paternalistic. She recalls a particularly tone-deaf comment about her ovaries, tossed off by the first gynecologic oncologist she consulted prior to visiting the MD Anderson clinic. “He said something like, I’d be better off when they were in a jar. And that was just a horrendous thought. I had just had a baby the year before. I never went back to him ever again.”
Lewis, who thought she had bought herself a stay from menopause, learned several weeks after her tubal surgery that the window might be closing anyway. “It’s kind of heavy,” she says, sitting in the booth at the Houston sandwich shop. Earlier this morning, Nebgen called with her pathology results. The tubal dissection had revealed precancerous changes, albeit so early that they have scarcely advanced beyond normal, as Nebgen explained it.
At this point, there’s considerable debate in the medical community regarding what these precancerous changes mean, and to what extent they’ll progress, if at all. So Nebgen took the pathology report to MD Anderson’s multidisciplinary conference, which recommended that Lewis’s best option was to get her ovaries removed.
Now, the Lewises are processing the news, husband Jerry alternately pulling up relevant articles on his phone and rubbing his wife’s back as she talks. “They are not even cancer cells right now – it’s a precursor thing,” he reminds her.
For women like Lewis and Starr, women who live in the shadow of cancer risk, time is not on their side. One of the handouts that the clinicians at MD Anderson provide is a grid-like chart that details risk based upon mutation and current age. The numbers increase at age 40, and more sharply for those with BRCA1 mutations than those with BRCA2. A BRCA1 carrier aged 40 faces a 20 percent risk of developing breast cancer, and a 6.7 percent risk of ovarian cancer, before she turns 50.
Perhaps most unsettling, Lewis’s experience has illustrated, more than once, how these highly personal decisions are constructed upon the shifting sands of scientific knowledge, where even highly experienced and respected experts do not necessarily agree upon the best path.
After she and her husband have met with Nebgen to talk things over, Lewis seems resigned to ovarian surgery – possibly in late 2015, after her body has fully recovered from the battery of 2014 surgeries. “I certainly didn’t go through a double mastectomy and the fallopian tube removal just to get ovarian cancer,” she says.
Then another curveball struck shortly before year’s end. Nebgen unexpectedly called while Lewis was out shopping. Her case had been reviewed by another group of experts, this one with a pathology focus, and they didn’t feel that surgery was necessary so soon. “That the irregularities in my cell work were not enough to cause alarm, or to at this time warrant removing my ovaries,” Lewis says.
Yet another group will take a look this spring. While Lewis describes the shifting guidance as frustrating, she is relieved that she might be able to push back the surgery for another year or two. She’ll continue to get screening ultrasounds, although she acknowledges their limitations, adding: “I’m just not up for going into menopause right now.”
Neither does Lewis regret her decision to choose the experimental tube removal, even if she does end up returning to the operating room sooner than she’d prefer. If the traditional ovarian removal had been the only surgical option, she remains convinced that she would have stuck with screening for some indeterminable stretch of time. Thus, she would have missed out on the precancerous insights that she now possesses, knowledge that will help her make potentially life-changing decisions in the years to come.
Starr, who has seen various risk charts, continues to struggle with her own heart. As part of the research study, she’s agreed to have her ovaries removed by 2017, the year she turns 42. “I’m supposed to,” she says, her brown eyes steady behind wire-rimmed glasses. “I think I will. I want to live.”
This story first appeared on Mosaic and is republished here under a Creative Commons license. Written by Charlotte Huff, a Texas-based journalist and recovering newspaper staffer, whose features have appeared in various publications, including American Way, Genome, Medical Economics, Slate and Women’s Health. Charlotte tweets @Charlotte_Huff. Top image: Michael Krainer, Medical University of Vienna