An unusual approach to investigate an unusual disease. On almost every front — symptomatic, diagnostic, treatment, cure — ovarian cancer stubbornly refuses to conform to typical oncological expectations. //

By Victoria Leenders-Cheng

French horns are German in origin, Guinea pigs are not from Guinea… and now it appears that ovarian cancer may not be a cancer of the ovaries after all.

Dr. Lucy Gilbert, who directs the Gynecologic Cancer Service at the Royal Victoria Hospital, has been studying ovarian cancer for more than 20 years and says that it is a disease that has confounded oncologists for decades.

Ovarian cancer is a relatively rare cancer — 1 in 60 women get it, compared to about 1 in 10 women who get breast cancer — but it is much more deadly: only 54 percent of women who get ovarian cancer survive more than five years after diagnosis, compared to 89 percent for breast cancer.

Dr. Lucy Gilbert
Unmasking the great pretender: Lucy Gilbert plans to expand her DOvE study to 12 satellite clinics across Montreal to evaluate 14,000 women at risk for ovarian cancer.

“Every decade, we make so much progress in how we treat many cancers,” Gilbert continues, citing improved cure and prevention rates for uterine and cervical cancer by way of example. “But for ovarian cancer, the cure rate is flat over the last 30 years.

“This really is a disease that just drives you to your knees.”

The symptoms of ovarian cancer, which include feeling bloated or having heartburn, are non-specific and easy to dismiss as general discomfort or, for older women, chalked up to menopause. Current methods of diagnostic testing for the disease — measuring cancer antigen concentrations in the blood or relying on ultrasound images — tend to yield a high number of false-positive results, meaning that many women undergo surgical procedures to remove a cancer that isn’t there.

Even when the cancer is accurately diagnosed, Gilbert says, recurrence rates remain high. “These women come, they do exactly what we tell them, they have huge operations and chemo, and then still the disease is back and causes a great deal of suffering.”

In 2007, in the hopes of raising awareness about ovarian cancer and increasing the likelihood of catching the disease in its early stages, three major American cancer organizations recommended that women experiencing symptoms of bloating, frequent urination or abdominal pain for more than two weeks consult a doctor.

Gilbert wanted to find out whether investigating these symptoms would in fact lead to early detection of ovarian cancer and, in 2008, she obtained a grant from the Canadian Institutes of Health Research to do a pilot study.

“Our hypothesis was, if you educate women about these symptoms and you provide easy access to investigation, you may be able to diagnose ovarian cancer early and remove it completely with surgery.”

Gilbert and her colleagues designed a novel study, named Diagnosing Ovarian Cancer Early (DOvE), and invited women 50 years of age or older who had experienced various symptoms of abdominal discomfort or bloating to undergo testing for ovarian cancer. Almost 2,000 women in Montreal responded to the call for participants and two-thirds of them, or 1,455 women, fulfilled the eligibility criteria for further screening.

Once the women were deemed eligible, they underwent a physical examination, a blood test and a transvaginal ultrasound. The blood test checked patients’ levels of cancer antigen 125 (CA-125), a protein that is often found in elevated levels in patients with certain types of cancer, including ovarian cancer. The ultrasound examined the shape and size of the ovaries, as well as the shape and size of any cysts present in the organ.

In normal test results, there are fewer than 35 units of CA-125 per milliliter of blood and any cysts found in the ovaries are smaller than 60 cm3. If both test results were normal the first time around, Gilbert and her colleagues repeated the blood test after four months; if either of the results were abnormal, they repeated the blood test at intervals of four to eight weeks.

Of the 1,455 women who participated in the study, 11, or 0.756 percent, were diagnosed with ovarian cancer. Other studies conducted in the UK, Japan and the US with women recruited from the general population had yielded ovarian cancer prevalence rates of between 0.06 and 0.084 percent.

Gilbert’s study, in other words, had yielded a prevalence rate that was an astonishing 10 times that of the prevalence rate of studies conducted in the UK, Japan and US.

Her results demonstrated not only that women with symptoms of bloating and abdominal pain were 10 times more at risk for ovarian cancer but also that investigating these symptoms can lead to early detection and successful surgery to eradicate the disease.

More surprising, however, was the study’s unexpected finding that the deadliest subtype of ovarian cancer is essentially not a cancer of the ovary but of the fallopian tubes.

Much of successful cancer treatment is predicated on the importance of catching the disease early, before it spreads. One subtype of ovarian cancer, called high grade serous cancer (HGSC), alone causes 90 percent of deaths from the disease, in part because it is not caught until it is already at an advanced stage.

The results of Gilbert’s pilot study indicated that, in the case of finding and removing this HGSC subtype of ovarian cancer, gynae-oncologists might have been looking in the wrong place all along.

“We kept saying that if we find the cancer early, while it is still on the ovary, we can cure the disease,” Gilbert explains. “But to our surprise, no matter how early [we detected the cancer], in some women there was no cancer in the ovary at all. It had all started in the fallopian tubes.”

The fallopian tubes, responsible for delivering eggs from the ovaries to the uterus, don’t in fact touch the ovaries themselves. Instead, they possess finger-like cells called fimbria that drape gently around the ovaries and that sweep the egg into the tube when prompted by hormone indicators released cyclically by the uterus.

“The ovary is a very complex organ,” Gilbert says, “and the fallopian tubes are these delicate organs with these innocuous-looking fimbriae that just float about in the abdomen and drop cancer all over the abdominal cavity, getting it all over the place fairly early.”

This finding has the potential to revolutionize how ovarian cancer is detected and treated, Gilbert says, noting that everything about the disease, from the name, the staging and the diagnostic testing, needs to be reconsidered to improve early detection as well as cure rates. In thinking about how to present the results of the study, Gilbert, whose two decades in gynae-oncology have given her a poetic appreciation for the organs of the female reproductive system, kept coming back to metaphors of disguise.

“We have unmasked the great pretender,” she declares. “This is a very clever disease. It’s not really a cancer of the ovary — it’s a cancer of the fallopian tubes, which look so innocent and beautiful; to be truthful, the poor ovary is an innocent bystander that gets maligned.”

Earlier studies on patients who carry a gene that makes them susceptible to ovarian cancer — the BRCA mutation — had found that a significant percentage of them had cancer in the fallopian tubes. “But we thought this pattern was peculiar to the BRCA mutation and that it was an academic discussion,” Gilbert explains. “In clinical practice, we continued to look at the ovary.”

The DOvE study is the first to obtain this result in the general population of women, not just those with the BRCA mutation. The finding is so startling that it is being referred to as a paradigm shift for fighting ovarian cancer. “It is rare for us to have been so wrong for so long,” Gilbert admits. “For years and years, we’ve been focusing on the ovaries. To recognize that focusing on the ovary is wrong, to look elsewhere and to think, ‘Abdomen, abdomen,’ early in the course of the disease, is very different…”

In 2012, the Canadian Institutes of Health Research awarded Gilbert and her colleagues a $1.4-million grant to expand DOvE to 12 satellite clinics across Montreal. This expanded phase of the study will evaluate 14,000 women at risk for the cancer, which Gilbert estimates will result in the diagnosis of about 100 cases of cancer, most of them early enough that the cancer can be completely removed with surgery.

“From there, we hope to develop good algorithms to advise people all over Canada and the world on how to identify this disease early enough.”

Gilbert warns, however, against widespread implementation of her study protocol for the time being, noting that the investigations must be done by doctors and technicians who are knowledgeable about the trickster nature of

the disease.

“We are still feeling our way through the fog,” she says. “We don’t have a magic formula that says, ‘Do this and this,’ and you will pick up all the ovarian cancer. We don’t know yet how we get it or what is an efficient way to catch it, but at least we aren’t looking at the wrong thing now.”

This research was supported by grants from the Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedars Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto.