New research opens the door to better treatment and prevention options for ovarian cancer

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Ovarian cancer is one of the top 10 killers of Australian women. Every day in Australia, four women are diagnosed with ovarian cancer and three will die from the disease. Unfortunately, this has not changed in 30 years, but newly published research could open the door to more effective treatment and prevention options.

The silent killer

More women are dying from ovarian cancer than any other gynaecological cancer, as hard-to-detect symptoms are making early detection difficult. Over 60% of ovarian cancer cases are diagnosed after the cancer has already spread. While five-year survival rates for uterine cancer, the most common gynaecological cancer, is around 84% in Queensland, ovarian cancer survival rates are significantly lower. Around 280 women are diagnosed with ovarian cancer annually in Queensland, yet only 48% of those women will survive five years. This year an estimated 190 women will die from the disease. Ovarian cancer is more commonly diagnosed in women over 50, but all ages need to stay vigilant.

It’s usually not until after a patient endures persistent gastrointestinal symptoms that they will receive a screening that reveals the cancer. Symptoms are vague and easily confused with other conditions, which is why it is often called the "silent" killer. It may include increased abdominal size or bloating, unexplained abdominal or pelvic pain, loss of appetite, unexplained weight gain or loss, back pain, indigestion, nausea or excessive fatigue. 

Ovarian cancer linked to an X chromosome mutation passed down through dad

If your grandmother on your dad's side of the family had ovarian cancer, you and your sisters may have a greater risk of developing the condition than if your maternal grandmother had it, a new 30-year study suggests. The research paper, Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study, published February 15th in PLoS Genetics (available on CKN), indicates that women may inherit ovarian cancer through the X chromosome passed down from their father, independently of genes on other chromosomes already associated with the disease. Kunle Odunsi, Kevin H. Eng and colleagues at Roswell Park Comprehensive Cancer Center in Buffalo, New York, report that the mutation on the X chromosome may advance ovarian cancer's age of onset by more than 6 years

In earlier studies, researchers noticed that when a woman develops ovarian cancer, her sister faces a higher risk of also developing the disease than her mother, an observation they found difficult to explain. This observation led Eng and colleagues to investigate whether genes on the X chromosome, potentially passed down through the father, may contribute to his daughters' risk of ovarian cancer.

Dr. Eng’s team examined data that had been collected over 30 years on the Familial Ovarian Cancer Registry and identified more than 890 grandmothers with ovarian cancer who had granddaughters with the condition. About a quarter of this group (229 women) were the paternal grandmother of a woman with ovarian cancer. Around 28.4% of the paternal granddaughters had ovarian cancer, compared to 13.9% of those with a maternal grandmother. "The chance the granddaughter has ovarian cancer doubles if the disease pattern transmits through dad's side of the family," Dr. Eng said.

The researchers also observed that fathers were more likely to have prostate cancer if their mother and daughters had ovarian cancer. 

To look at this pattern further, the researchers sequenced the X chromosome of 157 BRCA-negative women with ovarian cancer. The sequencing identified a gene called MACEC3. Women who had inherited this gene were diagnosed on average more than six years earlier than those without it, independently of other known susceptibility genes, such as the BRCA genes. Future studies will be needed, however, to confirm the identity and function of this gene. This observation suggests that there may be many cases of seemingly sporadic ovarian cancer that are actually inherited, and may lead to improved cancer screening and better genetic risk assessment.

Dr. Eng said "our study may explain why we find families with multiple affected daughters: because a dad's chromosomes determine the sex of his children, all of his daughters have to carry the same X-chromosome genes. What we have to do next is make sure we have the right gene by sequencing more families.”

Paul James, director of the Familial Cancer Centre at the Peter MacCallum Cancer Centre in Melbourne, said the research could, "potentially help us with the process of personalising women's risk in the future. It may help us understand the biology by pointing out this gene, but you can't say, 'Oh that's like another BRCA gene we could use to detect women and work out their risk'. But what they have done is opened a new direction that further research might produce that kind of information."

Widespread screening for ovarian cancer is not recommended

While the prognosis for ovarian cancer sufferers is serious, in the general population ovarian cancer is still a relatively rare disease. A just-released report from the US Preventive Services Task Force (USPSTF), published in JAMA, recommends that women who are not at a genetic risk should not undergo screening for ovarian cancer if they don’t have signs or symptoms of the disease. The evidence showed that current screening methods do not prevent women from dying of ovarian cancer, and that screening can lead to unnecessary surgery and related complications in women without cancer. The researchers examined 1,381 titles and abstracts and 74 articles from medical databases such as Medline and Cochrane. The studies considered were published over a period of 14 years, between 2003 and 2017, and most of them were randomised clinical trials of screening versus no screening in asymptomatic women aged 45 and above. This category is seen as "average-risk."

Among the outcomes measured were ovarian cancer-related mortality, false-positives, surgery and surgical complications, and psychological effects of screening and their results. After carrying out their analysis, the team concluded that "ovarian cancer mortality did not significantly differ between screened women and those with no screening or in usual care." However, screening harms included surgery, with major surgical complications, in women found to not have cancer, the authors add. 

Given these new findings, the USPSTF conclude with "moderate certainty" that there are more disadvantages and potential harms to women who are not at increased genetic risk for ovarian cancer in having screening than there are benefits. 

“Technically it’s fallopian tube cancer even though we’re not going to change the name.”

A growing body of evidence is pointing to ovarian cancer beginning in the fallopian tubes and not the ovaries, giving researchers hope for developing better strategies to prevent and detect the deadly cancer.

Two studies published last October in the journal Nature Communications (available via CKN) focused on high-grade serous ovarian carcinoma (HGSOC), the most common and serious type with only 15% of those diagnosed surviving beyond five years. The studies have confirmed previous claims that the deadly disease actually starts in the fallopian tubes. The discovery simultaneously gives researchers hope for developing better detection and prevention methods and highlights the alarming reality that very little is actually known about the disease.

Douglas Levine, director of gynaecologic oncology at the Perlmutter Cancer Center at NYU Langone Health in New York City, along with a team of co-researchers, examined precursor lesions, which are an abundance of abnormal cells, and the genetic profiles of tumours from 96 women with ovarian cancer. In their study, Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma the researchers took collections of tissue from a separate group of healthy women and looked at their fallopian tubes, ovaries and the lining inside the abdomen. They developed molecular bar codes, or “signatures,” to see which tissue the cancerous cells were more genetically similar to.

The finding: in almost every case, the cancerous cells were most similar to the fallopian tube tissue.

“Ovarian cancer really comes from the fallopian tube,” says Dr. Levine. “Technically it’s fallopian tube cancer even though we’re not going to change the name.”

About 15% to 20% of ovarian cancers are inherited. BRCA1 and BRCA2 are the most well-known cancer-causing genes for ovarian and breast cancer, and women who test positive for genetic mutations in the genes have a substantially increased risk of developing ovarian cancer. In fact for BRCA1 mutation carriers that risk of developing either breast or ovarian cancer in their lifetime is overwhelming. The likelihood of developing breast cancer before the age of 80 is estimated to be about 72%, while about 44% will be diagnosed with ovarian cancer – with a survival rate of less than 50%.

In Australia women with a family history of breast and ovarian cancer now have access to free BRCA1 and BRCA2 genetic testing, after the federal government introduced new Medicare rebates on November 1 last year. If someone has breast and ovarian cancer and has the mutations, all their relatives will also be able to have the test for free. Women with a history of ovarian or breast cancer are also urged to talk to their families about their breast cancer history and to use Cancer Australia's Risk Calculator to assess whether they would benefit from genetic testing.

For women with BRCA mutations doctors usually recommend preventive surgery between ages 35 and 40, when a woman has decided to have no more children or 10 years before the earliest ovarian cancer death in her family. It is thought their risk of cancer reduces by about 90% by undergoing a mastectomy, as well as having her ovaries and fallopian tubes removed, resulting in premature menopause. 

A growing number of at-risk Australian women are now choosing to take the drastic preventative measure of having radical risk reduction surgery, including a double mastectomy and full hysterectomy, including removal of their ovaries, fallopian tubes and uterus. In 10 years, the number of women undergoing surgical removal of the ovaries and or their fallopian tubes at Melbourne’s Royal Women’s Hospital has rocketed from 19 a year to 106.

Doctors put much of the increase in awareness and genetic testing down to the impact of Hollywood actress Angelina Jolie, who in 2013 revealed that she had undergone a double mastectomy because she carried the BRCA1 gene. Later, Jolie announced she had undergone further surgery to have her ovaries and fallopian tubes removed.

Given that the average age of menopause is 52, going through it 12 or more years early can significantly reduce a women’s quality of life. Dr. Levine is part of a clinical trial led by researchers from MD Anderson Cancer Center in Houston that is comparing the standard treatment, removing ovaries and fallopian tubes at the same time, with an experimental treatment, removing only the fallopian tubes at a younger age and saving the ovary removal until closer to the natural time of menopause.

Karen Lu, senior vice president and chief clinical officer at MD Anderson Cancer Center in Houston and lead investigator of the clinical trial, said, “Surgical menopause is no walk in the park. It’s a much more rapid decrease in oestrogen,” she says. "That can result in rapid onset of symptoms such as night sweats and hot flashes. Some symptoms can be counteracted with hormone replacement therapy. But many women surveyed have complained of a decrease in sex drive," she says.

Surgeon and gynaecologist David Wrede, at the Familial Cancer Centre at the Royal Melbourne Hospital and Royal Women's Hospital said “we understand the anxiety about retaining ovaries when you have this knowledge, but a normal hormonal cycle is highly beneficial for women, so making someone menopausal at 35 is a very big deal."

Researchers will evaluate several quality of life measures from 270 women in the study, including sex drive and menopausal symptoms. They also are looking at the number of cancers that develop in each group to evaluate the risk of developing cancer.

Investigating the genetic link

In the second study in Nature Communications, High grade serous ovarian carcinomas originate in the fallopian tube, researchers examined multiple tumour samples from women with high-grade serous ovarian cancer.

The team looked at small lesions in the fallopian tube; fallopian tube tumours; ovarian cancers; and metastases. They sequenced the genomes of the tumours from each individual to identify the order in which the lesions arose. The researchers estimate that seven years elapsed between development of the early fallopian tube lesions and ovarian cancer. Then, within a year, the cancer quickly spread.

One of the study’s lead researchers, Dr Ron Drapkin, an associate professor of pathology in obstetrics and gynaecology at the University of Pennsylvania, has been studying ovarian cancer for nearly two decades. “It’s been about 10 years since the first research came out about ovarian cancer starting in the fallopian tube,” he said.

He said these two studies were “the last nails in the coffin.”

“Before 2006 or 2007 no one had thoroughly looked in the fallopian tubes, so researchers kind of just stumbled upon all of the precursors to ovarian cancer. Since then we’ve been trying to understand what makes the fallopian tubes susceptible to the cancer. We already basically knew that ovarian cancer began in the fallopian tube, but this study gave us the genomic evidence to support that idea,” Dr Drapkin said.

Going forward, Dr Drapkin says that the most valuable research will deal with prevention and early detection, both of which can benefit from the findings of the study. “There are two new early detection methods in the works right now that are heavily based on our findings,” he said. One is a scope that travels up into the fallopian tubes to collect cells for testing.

A second is a test similar to a pap smear that could take cells from the uterus and detect changes coming down from the fallopian tubes. “This method is based on the menstrual cycle and the idea that everything flows through the same path, so by testing downstream from the fallopian tubes we could detect potential signs," he said.

Looking to the future

Internationally work continues on prevention and treatment options, with immunotherapy combinations slated as a way forward with several phase III studies under way. 

Federal Labor has pledged $12 million towards ovarian cancer research if it wins the next election. The Federal Health Minister Greg Hunt has already committed to providing $3 million to the Traceback gene screening program at the Peter MacCallum Cancer Centre in Melbourne. Test tissue samples of 11,000 women diagnosed between 2001 and 2016 will be screened to see if they are carriers of the BRCA gene mutations, and identifying if there is a genetic risk for other family members.

There is also promising work being done to develop a screening tool for earlier detection of ovarian cancer.

With regard to treatment, all cases of ovarian cancer are currently treated with the same chemotherapy. In most cases, there are good results early on, but the cancer usually recurs and becomes resistant to the chemo. Applying the genomic research from Dr Drapkin's study could allow for more individualised and effective treatments. Dr Drapkin said that it will be several years before significant changes are seen in the field of ovarian cancer, and it could be 15 to 20 years before new treatments are available, but that these recent studies are a big first step in a field that had very little research as recently as a decade ago.

February is Ovarian Cancer Awareness Month and Cancer Council Queensland is urging women to understand the potential symptoms as early detection helps survival. “If detected early, between 80% and 100% of women diagnosed will survive at least five years,” said Cancer Council Queensland CEO, Ms Chris McMillan. “The simplest way we can start to address this is to urge women to get to know the signs and symptoms of the disease, and speak to their GP when they notice changes to their body that are new and persist for a few weeks.”