Genetic testing has greatly increased prevention for those at risk and treatment for those diagnosed, but timely symptom recognition is still the best available option for everyone else.
More than 1800 people are diagnosed with ovarian cancer in Australia each year. More than 1100 will die from it. Many of these cancer deaths may be prevented by identifying at-risk women through genetic testing, but not through population screening, experts say.
By the time symptoms appear, the cancer has already spread and is usually at stage III and IV. But in fact there is a large window of opportunity prior to the appearance and recognition of symptoms. Ovarian cancers can take 20 years to become invasive. “What we now know is that most of these cancers actually don’t even start in the ovary. They start in the fallopian tube, in the distal end. And as they grow they drop cancer cells onto the ovary, which is why for many years we thought that they originated in the ovary. There’s a number of stages that occur before the time that the invasive cancer develops,” Dr Rachel Delahunty told a recent Gynaecological Cancers and Primary Care meeting hosted by the Victorian Comprehensive Cancer Centre (VCCC) Alliance.
These stages include the development of a p53 mutation in the epithelium, followed by the precursor STIC lesions (serous tubal intra-epithelial carcinoma) in the fallopian tubes, and then finally what we know as an ovarian cancer.
“This is a really important window of opportunity. If we can find women that are at risk of ovarian cancer, and facilitate access to risk reducing interventions, we can prevent cancer from developing,” said Dr Delahunty.
Although only 2.4% of cancers are ovarian, they cause 4.6% of deaths, and have a 46% five-year survival rate. However, the evidence shows that population screening would not prevent them.
Screening
Cancer Australia’s position, last updated in 2021, is that “Ovarian cancers screening or surveillance is not currently recommended, even for women at high or potentially high risk of ovarian cancer”.
University of Melbourne Professor Jon Emery, who is primary care research and education lead at the VCCC, told the symposium that the majority of randomised control trials comparing multimodal screening and no screening showed no difference in mortality at 16 years follow-up, despite a 39% increase in detection of early stage (I or II) disease.
The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) followed over 200,000 women at average risk of ovarian cancer for over 15 years. The outcomes, in terms of deaths and survival times, were the same for the screened and unscreened groups.
“It didn’t translate into any improvements in mortality,” said Professor Emery.
The evidence, in terms of mortality, is not currently there to screen asymptomatic women, Dr Emery said.
In addition to a lack of evidence for efficacy of a population screening program for ovarian cancer, it is not something we could afford to do, Associate Professor Orla McNally, director of Gynaecology Oncology at The Women’s in Victoria and the Gynaecology Tumour Stream at the VCCC, told Oncology Republic.
“We don’t currently have the resources, even for women who are at high risk of ovarian cancer, to have annual ultrasounds and CA125 testing done,” said A/Professor McNally.
A screening program wouldn’t be money well spent, she said. “Health dollars in the gynae cancer world would be much better spent on improved access to weight reduction strategies, such as surgery, because we know that will reduce obesity, which is the main cause of the rising incidence of endometrial cancers in this country.”
A/Professor McNally said she sees many women in private practice who choose to have an annual ultrasound and CA125 test at their own expense, in spite of the evidence.
“They will do it because they feel more reassured doing something rather than doing nothing. I think they get a false sense of security,” she said.
For one thing, CA125 in itself is not very specific. It can be elevated for various reasons, such as fibroids. For another, the test provides just a snapshot in time. There is work going on to determine better, more specific, more predictive tests using different proteins (HE4 and others).
“Specificity is very important here. For example if you have a negative HPV test, you are extremely unlikely to develop cervical cancer in the next five years. If you have a normal CA125 and ultrasound, this does not guarantee that you will not develop ovarian cancer in the next month, year, etc.,” she said.
But A/Professor McNally said the fact that women are asking for these things is positive.
“We know that huge inroads in breast cancer care and outcomes have been made just by the advocacy of breast cancer survivors. With ovarian cancer, it’s really only in the last five years that we’re getting a bit more traction. People are becoming much more aware of it and much more aware that if there are symptoms that tends to indicate advanced disease already.
“So a lot of the messaging that comes out of the advocacy groups is if you have any symptoms at all, go and get an ultrasound; go and get it. Don’t take no for an answer. And to be honest, I don’t think that’s a bad thing because there’s still quite a significant lack of knowledge amongst women about their bodies.”
Preventing ovarian cancer in at-risk patients
Once you know someone is at elevated risk, you can do quite a lot. “What is important is that these cancers are largely preventable with the adoption of risk prevention strategies,” Dr Delahunty told the meeting.
A patient who has no symptoms but has a genetic risk has options for preventing ovarian cancer. But first, they need to know they have a genetic risk.
Figuring out who can and should go for genetic testing can be confusing.
If a patient had a blood relative who’d had ovarian cancer, and that relative had a genetic test and had a mutation, the genetic testing for the patient was covered under Medicare.
If the family member didn’t have genetic testing, or the results of that test weren’t known to the patient, Dr Delahunty said a referral to a familial cancer clinic (FCC) to discuss their risk was still appropriate. “While waiting times in some states can be an issue, the FCC are publicly funded with no cost to attend,” Dr Delahunty told OR.
Sometimes, a test could be performed on the relative’s tumour or banked blood if available. If a test was done, even in another state, the FCC could access the results.
However, if there was no knowledge of genetic mutation for the relative, your patient would have to pay for their own genetic test.
“There is no current funded testing available for [this patient] until she gets cancer, which makes absolutely no sense to anyone and something I am passionate about changing,” Dr Delahunty told OR.
“Equity of access is an issue, but at the same time, having these women engaged with a genetics service is important as it’s the only way to understand risk to facilitate prevention. So even if the family members go along and have a discussion, they can at least receive some counselling.”
A family history of ovarian cancer is still the biggest risk factor. But carrying a BRCA1 or BRCA2 mutation is also significant, conferring a 40%/17% cumulative lifetime risk (long known, but perhaps not in the general community), even when no family member has had ovarian cancer.
In studies of women with ovarian cancer who had a BRCA1/2 mutation, half did not have a family history of ovarian cancer, Dr Delahunty said at the webinar. “Family history was an insensitive marker for the presence of these mutations,” she said.
In addition to BRCA1/2, researchers have also identified deficient DNA repair pathways, including the homologous recombination pathway, which include RAD51C and D genes, deficient mismatch repair genes, when present in the germline resulting in a syndrome known as Lynch syndrome, and single nucleotide polymorphisms (SNPS) as ovarian cancer risk factors.
Germline testing for all of these is now routine for newly diagnosed patients with high grade (2/3) non-mucinous ovarian cancers, and that’s good news for family members, because they can take preventative steps, the best of which is surgery, according to Dr Delahunty.
“If a woman can undergo risk reducing salpingo-oophorectomy at the recommended age, a woman would reduce her risk by more than 96% and improve all-cause mortality. But the big point with this is it does have to be at the recommended age,” she told the meeting. For carriers of BRCA1-PV, that age is 35-40 years; for BRCA2-PV, it’s 40-45 years.
Currently, salpingectomy with deferred oophorectomy is being trialled internationally, to reduce the risk of ovarian cancer developing in the first place but delay menopause where possible, A/Professor McNally told OR.
“We do have a number of women who are at high risk, with a known genetic mutation, who come and say at the age of 35, ‘I’m finished my family. Can you take my tubes out now and I’ll come back at 40 to have my ovaries out?’” In someone who carries a BRCA mutation, we feel that’s appropriate, we can do that,” she said.
While surgery was the most effective risk reduction strategy, weight control also had a role, Dr Delahunty said in the meeting.
“Exercise is really critical and now there is a lot of data to support that. If that could be supported by GPs… including encouragement to undertake formal exercise programs, that would make a big difference. [There are] less clear guidelines on diet but [it is] important to aim for healthy weight and a good balanced diet, avoiding processed foods, etc,” she said.
Preventing ovarian cancer in the general population
The idea of opportunistic salpingectomy as a general population risk reduction strategy is gathering some momentum.
Results from a Canadian cohort study published in 2022 showed that in nearly 26,000 women of average risk who chose to have an opportunistic salpingectomy, there were no serous ovarian cancers (where 5.27 were expected) and five or fewer epithelial ovarian cancers (where 8.68 were expected) during follow-up.
The Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines already recommend offering salpingectomy to patients undergoing hysterectomy for benign indications.
A/Professor McNally and her team are working towards providing another pathway for opportunistic removal of the fallopian tubes in Australia, and that is during a cholecystectomy, which studies from overseas found was feasible, acceptable and effective.
Meanwhile, as with those at risk, weight control was also a prevention strategy in the general population.
“The larger you are, the more estrogen you produce in your fat, and that stimulates the lining of the uterus,” she explained.
There was also plenty of evidence that the pill reduced ovarian cancer risk, she said. “Ovarian cancer is actually falling in incidence in first world countries, and we think that’s because of the use of the pill,” A/Professor McNally told OR.
Symptoms
For those without a family history of cancer, symptom awareness is still the recommended best surveillance option in Australia.
The symptoms of ovarian cancer are non-specific – things like unexplained fatigue and weight change, bloating, abdominal pain and others that are shared with various conditions, including other cancers. “My experience was regrettably like many in my situation – mildish symptoms, many of which were the type of symptoms that you could easily rationalise as being associated with typical female aches and pains,” Ms Christine Crupi, diagnosed with ovarian cancer in 2022, told the VCCC symposium.
“In general practice, ovarian cancer presents quite a diagnostic challenge,” said Professor Emery. Around one in three women with ovarian cancer see their GP at least three times for their symptoms before they’re referred to an oncologist for a diagnosis, and for a quarter it takes more than 160 days to be diagnosed after they first present to their GP.
“Persistence of symptoms and combinations of symptoms are important. It is partly about keeping [ovarian cancer] in mind as a possible diagnosis and considering investigation with [transvaginal ultrasound] and CA125 as part of the work up,” Professor Emery said.
International guidelines suggested a wide range of symptoms, he said, with bloating/abdominal distension the only one common to all.
“Bloating is a very common symptom. The important distinction is that it’s about the permanent nature of that bloating. If it’s fluctuating bloating, then that isn’t associated with ovarian cancer,” he said.
The current (second) edition of the Australian Optimal care pathway for women with ovarian cancer lists 11 symptoms that “should be investigated” if persistent (abdominal bloating, increased abdominal girth, abdominal and or pelvic pain, indigestion, lack of appetite, quick satiety, unexplained weight change, bowel habit change, fatigue, urinary frequency or incontinence, pressure in the abdomen). Multiple symptoms increase the risk.
UK guidelines differentiate a similar list of symptoms by level of risk, with the addition of ascites and pelvic/abdominal mass for high risk and, importantly, first presentation of irritable bowel syndrome, which occurs uncommonly in women 50 and over, and is associated with moderate risk, Professor Emery noted.
“Investigate persistent distension, pelvic and abdominal pain, urinary frequency – if you’ve ruled out other more common causes, such as UTI – and first irritable bowel syndrome presenting in women over 50. Consider ovarian cancer as a possible diagnosis for women presenting with weight loss or fatigue,” he said.
Investigation
Where to after the index of suspicion has been raised?
“CA 125 is a useful test in addition to pelvic ultrasound in general practice. It is not totally specific and can be raised by other cancers so further investigation of other cancers might be appropriate, guided by symptoms,” said Professor Emery.
Some guidelines recommend a transvaginal ultrasound, some a combined CA125 and ultrasound, others an initial CA125 and ultrasound if raised, or a strategy combining pelvic ultrasound, routine testing to rule out other cancers and conditions and CA125 testing.
The Australian pathway recommends a general and pelvic examination, including rectal examination, by a GP; a pelvic ultrasound, preferrable transvaginal, by a practitioner experienced in gynaecological ultrasounds; a CT scan if appropriate, and routine blood and tumour marker tests. These are CA125, CEA and, in younger patients, HCG, AFP and LDH.
“That is contrary to a lot of other international evidence around the value of these tests in primary care where the prevalence of cancer is so low that these tests don’t perform adequately. So I would … question whether or not any of those other tests are actually beneficial and useful in a primary care setting, but certainly CA125 is part of this multi modal strategy,” said Professor Emery.
“The testing strategy is really this combination of more specific tests such as pelvic transvaginal ultrasound and CA125, plus more routine tests that can help you to rule out other differential diagnoses,” said Professor Emery.
Targeted treatment
Genetic testing is improving the outlook for many people with ovarian cancer.
The standard treatment is generally surgery, then chemotherapy and surveillance. In early stages there are fertility preserving options for some women.
“Unfortunately for most of our women, relapse occurs. But I’m pleased to say that through genetics and access to new therapies, including targeted therapies, we are now shifting our paradigm,” Dr Delahunty said.
“We’ve made a big step forward in reducing relapse overall in our women … and that has been facilitated through genetics. This is why genetic testing is an absolute must for all of our women.”
Genetic testing allows the addition of targeted therapies, such as PARP inhibitors, that work on mutated BRCA1 and 2 genes.
“These have been highly effective and improving outcome for women with ovarian cancer. We’ve seen not only improvement in progression free survival, but what is really exciting is that we are increasing cure rate,” said Dr Delahunty.
