Rebecca Lynn Stone, MD, MS, is an associate professor in the Johns Hopkins Medicine Department of Gynecology and Obstetrics in Baltimore. Her area of clinical expertise is gynecologic cancers. She is also the director of the Gynecology Enhanced Recovery after Surgery initiative, director of the Kelly Gynecologic Oncology Service, and co-director of the Johns Hopkins Fertility Preservation and Innovation Center.
Low-grade serous ovarian cancer (LGSOC) is a rare subtype of ovarian cancer, making up only 2% to 5% of all ovarian cancers. One survey found 99% of women had never heard of it before they were diagnosed.
Although LGSOC grows slowly, there's no screening test for it. Once it's found, it's a challenge to treat. WebMD asked Rebecca Lynn Stone, MD, an associate professor of gynecology and obstetrics at Johns Hopkins Medicine, to explain more about LGSOC, including why there are plenty of reasons to be hopeful after a diagnosis.
Q: How does low-grade serous ovarian cancer differ from other types of ovarian cancer?
A: If you Google "ovarian cancer," you'll almost always read about high-grade serous ovarian cancer, which is very aggressive and scary-looking. The statistics really make people despair. And so a lot of times when I see people in the office, they're totally freaked out because they don't realize that not everything is high-grade serous.
High-grade serous is the most common type of what we in medicine have called ovarian cancer. It mostly comes from the fallopian tube … but low-grade serous ovarian cancer, really, truly comes from the ovary.
When you think about the bucket of what is called ovarian cancer, low-grade serous ovarian cancers only make up 5% or less of the bucket.
Q: What causes LGSOC?
A: We really haven't been able to identify solid risk factors, which also makes it different from high-grade serous cancer.
About 25% of high-grade serous cancers are due to hereditary mutations that get passed down from generation to generation. But that's not the case with low-grade serous. A large number come from a borderline tumor, a precancerous cystic growth that occurs in the ovary and can progress into an invasive cancer.
Q: Who is most likely to have LGSOC?
A: Low-grade serous ovarian cancer tends to be diagnosed in younger people. High-grade serous is largely seen in post-menopausal women in their early to mid 60s, whereas we see low-grade serous in 40- and 50-year-olds.
Q: What are common symptoms of LGSOC?
A: The symptoms are very similar to the symptoms that we, as women, train our brains to ignore every month. We train ourselves to be OK with bloating, abdominal pelvic pain, urinary frequency, and nausea. And so our brain doesn't really notice [an LGSOC symptom] until it's getting increasingly severe.
Q: What are some challenges to getting a diagnosis?
A: A lot of us go to a GI doctor because it wouldn't even occur to us that there's anything going on with our gynecologic organs. And then when we go to see these other specialists, like urologists, that delays the diagnosis further. A lot of times, people end up getting scopes or trying medication for irritable bowel disease.
That's the lived experience of just about everybody who ultimately gets diagnosed with [LGSOC]. First, we just don't pay much attention to the symptoms. Then they get bad enough to go to other specialists. Finally, you get a CT scan and see an ovarian mass or a spread of the disease in and around the abdomen and pelvis.
Q: How is LGSOC diagnosed?
A: A CT is great for looking at the body overall, but it actually is not great for imaging the gynecologic organs. So when we see something on a CT that looks concerning for gynecologic cancer, the next appropriate step is a transvaginal ultrasound, getting pictures with a probe that goes into the vagina, because that really is dedicated imaging of the gynecologic tract.
Unfortunately, even though there is this precancerous state for low-grade serous cancers, in terms of a borderline tumor, many [people] are diagnosed at an advanced stage, which means that the cancer has spread from the ovary or the pelvis into the upper abdomen.
Q: What's the treatment for LGSOC?
A: Surgery has really been our mainstay of treatment, just because chemotherapy has not worked well.
Low-grade ovarian cancers tend to have a very low growth fraction, meaning at any given time, not many of the cells are actively dividing. Chemotherapy, no matter what type you're using and what cancer you're treating, works by affecting dividing cells. So if only a small percentage of the cells in the tumor are dividing, you could give someone chemo all day long, but it's not going to kill those cells because they're not actively dividing. That's been really problematic for low-grade serous ovarian cancer.
But now there may be more of a role for medical management than there ever has been. I'm really excited about that.
Q: What recent advances have been made in treating LGSOC?
A: One of the most important discoveries is that low-grade serous cancers tend to express high levels of estrogen and progesterone receptors. Now we know that when we treat these cancers with anti-estrogen therapy, that extends the time and remission by years compared to chemotherapy.
A large trial just finished by one of my colleagues looked at giving a non-chemo regimen called an aromatase inhibitor to people diagnosed with stage II to IV low-grade serous ovarian cancer. Aromatase inhibitors are anti-estrogen therapy. They block aromatase, the enzyme in our blood that converts a variety of hormones into estrogens. It was actually developed in the breast cancer world for hormone-positive breast cancers.
The old standard was giving somebody chemo, followed by an aromatase inhibitor. It's really amazing that young women have an opportunity for something other than chemo, for the first time ever.
The other really interesting new development is that a lot of low-grade serous cancers have mutations. One of the most common is a KRAS mutation. People have really focused on developing drugs that block the KRAS pathway, but what scientists figured out is that if you just block that, there's escape through other pathways. One of the most predominant pathways appears to be focal adhesion kinase, and downstream proteins from there that are very supportive of cancer growth.
Now, we know that we have to combine blockage of the KRAS pathway with something that also blocks focal adhesion kinase. [To do that], we [now] have the combination of avutometinib and defactinib, two oral drugs, not infusions. That's also really exciting.
Q: How do concerns about fertility factor into LGSOC treatment?
A: This mostly comes up for women who have a diagnosis of a borderline tumor, the preinvasive version of this. I feel strongly that you should see a reproductive endocrinologist, because a lot of times, you'll have a cystectomy – the borderline tumor is removed from the existing ovary. But, after cystectomy, there's at least a 30% recurrence risk. And so we really want you to have the opportunity to bank your eggs and embryos well in advance of a recurrence.
In a small percentage of cases, women have their recurrence in the form of a low-grade serous ovarian cancer. At that point, the stakes are higher and the safety of fertility preservation is more uncertain. Some of the most effective treatments are anti-estrogen, and in pregnancy, our hormone levels of estrogen and progesterone are astronomically higher than at any other point in our life. Many patients consider getting multiple opinions in this scenario, and gynecologic oncologists often bring these to their colleagues for case discussion.
Q: Beyond standard care, how can people with LGSOC best take care of their health?
A: We know that this cancer really loves estrogen, so having, or striving for, as close to a healthy weight as possible is really important. We usually tell people to aim for a BMI of under 25, because when we have extra adipose [fatty] tissue from being overweight, it's responsible for extra estrogen production in our body.
A lot of studies are looking at the impact of newer medications for weight loss, in terms of decreasing inflammation, helping people get to a healthy weight, and the impact on cancer incidence and cancer survival. Those may be particularly relevant for this disease.
There's also a lot of work to do in the space of healthy eating. I think we're about to enter this era of eating no processed foods and avoiding carcinogens. … Our advice around healthy diets is going to change a lot.
Exercise is really important, too. Even walking 30 minutes, most days of the week, is incredibly impactful. Not just for our physical health, but for processing and coping with [LGSOC].
Q: Where can you find support when you live with LGSOC?
A: There's a lot [available] nationally. The Ovarian Cancer Research Alliance is great. A lot of cancer centers have a survivorship program. Many have "Woman to Woman" programs where veteran survivors are matched with someone who has a new diagnosis, so they can really support each other.
Q: What else should someone with LGSOC know?
A: The outcomes for treatment of this cancer, even at an advanced stage, are excellent. Time in remission … is easily five-plus years. But that means you'll need to be followed for a long time. At five years, you can't guarantee you're yet cured.
I see a lot of women who have recurrence, even over a decade out from when they finished primary treatment. So just being on the lookout for that in survivorship is really important, because we know if people have a recurrence, the earlier we diagnose it, the more likely we are to be able to re-eradicate the disease with surgery and systemic therapy.
