Opportunistic Salpingectomy: High-Risk Ovarian Cancer Preemptive Treatment

[Rebecca Stone MD]
When we think about ovarian cancer, by far and large, you're talking about epithelial ovarian cancer. That comprises about 80% to 90% of ovarian cancers. Then the other small percentage is made up of germ cell tumors and stromal tumors. When we think about epithelial ovarian cancer as a group relative to germ cell and stromal tumors, epithelial cancers really are the most lethal group of cancers. In that group of cancers, you may have heard of cancers like clear cell, endometrioid, mucinous. Then, of course, the most infamous one, high-grade serous ovarian cancer.

High-grade serous ovarian cancer is in the group of epithelial ovarian cancers and is, by far, the most common. It's a very lethal type of ovarian cancer. Somewhere on the order of 20,000 women are diagnosed with that type of cancer in the United States every year. It really is the histologic type of ovarian cancer that we think we have the most chance of preventing with opportunistic salpingectomy.

[Mark Hoffman MD]
What makes it so difficult to treat?

[Kara Long Roche MD]
I think most of us know that there are no symptoms of high-grade serous carcinoma when it is in its early stages or early phases. I think we don't even really understand whether the stage progression is how the disease disseminates, or whether it disseminates immediately to advanced stage, when it's in its early form. There's no symptoms, there's no effective screening tests.

There's been wide-scale, massive studies that have been undertaken to look at screening tools such as ultrasound, CA 125. While there was some signal that we might be able to find it at a slightly earlier stage, that never translated to a reduction in cancer death. What we have is a disease with no symptoms, no screening test, and unfortunately, as we've all seen these patients come in with widespread advanced disease. I think it's still a unique cancer because, even though the cancer is widespread, we do still treat it with curative intent. With some of the newer developments, there are patients who are long-term survivors, and some who are cured.
Unfortunately, the majority of patients undergo hours-long surgery, months and months of chemotherapy, and unfortunately, will still recur and die of their disease. I think it's not so much that the biology of the disease makes the cells resistant to treatment, but that we have no way to find it before it's widely metastatic. That's really what makes it more challenging.

[Rebecca Stone MD]
I just wanted to just say that I remember reading “that” The Gray Journal article that laid out the whole rationale of why ovarian cancer, and I'm doing that in quotes right now, is disseminated tubal cancer. It was fascinating because all of this evolved over the course of my training. Not to date myself too much, but I graduated from medical school in 2002, and it's now 2023. We did all these things like ovarian cancer screening with pelvic ultrasound, and checking CA 125, and then there's the PLCO study. Nothing helped, and actually, we hurt patients by going in and trying to take out these cysts.

[Amy Park MD]
It was such a great article because it laid out the biologic plausibility and rationale for SIN and its existence because nobody really paid attention to the tubes. It was like a passive actor to get the sperm and the oocyte together, do you know what I mean? Can you just tell our listeners a little bit more about that whole journey of understanding? I think that's really crucial. I'm in the stands, but you guys are in the front seats of all these developments. It's a complete change in our understanding, mindset, and paradigm shift. Just tell us a little bit more about that.

[Kara Long Roche MD]
I think Becky should explain it because she does the best job of it. I tell patients all the time that when someone finally looked in the fallopian tube, and realized that this was the origin of serous carcinoma, everything made sense. That's why there's no symptoms, that's why screening doesn't work. This discovery actually made all of those trials of hundreds of thousands of women where screening didn't prevent deaths, it made it all make sense.

[Rebecca Stone MD]
If you really think about it, I agree, Kara. It was like a light bulb. Amy, your point about these screening trials, all these screening trials have been structured around ultrasounds. Things like CA 125, or maybe even some thinking about more sexy blood tests we can do in this day and age. When you really stop and think about it, there's no medical grade imaging that we have that can even see the fallopian tube. I think that it's essentially time that we accept that the biology of ovarian cancer is different from that of other solid cancers.

We've done screening tests in other solid cancers, like cervix cancer and lung cancer, where screening results in a stage shift that is life-saving. That just hasn't been shown to be the case with ovarian cancer. That may be because there really isn't an early hematogenous phase to the cancer where we could pick it up in the blood. The early phase is this widespread dissemination that occurs in the peritoneal cavity and a blood test just is not going to be able to detect that. The history of this is exactly what you say, which is that the BRCA genes were sequenced in the mid-1990s when sequencing was really clunky and hard and expensive. People like Kara and my personal hero, Mary Claire King really led that charge. We're so grateful to her.

Once that was discovered, that really created some biologic rationale for what we know as risk reducing surgery; this idea that you can reduce a high risk patient's lifetime risk of developing ovarian cancer by removing the ovaries. When we take out the ovaries, there's no point in keeping the tube because the person can't get pregnant and the blood supply of the tube and the ovary are heavily intertwined, so the tubes came out with the ovaries. You're right, I think people were really focused on the ovary.

Then one day in the early 2000s, people began looking at the fallopian tube under the microscope. They found that there was a lot of dysplasia and that dysplasia really looked very similar to invasive high grade serous cancer. Then people started to look at larger cohorts of BRCA patients and started to find these abnormalities in the fallopian tubes. Then there was a pile on, lots of scientific data and even epidemiologic data and population data that showed taking out a fallopian tube for ectopic pregnancy or taking out the fallopian tubes for surgical sterilization in large populations of people resulted in a decrease incidence of ovarian cancer.

[Mark Hoffman MD]
I've been doing this now for a decade. I don't think I've done a tubal banding or a clip in probably a decade. Every single hysterectomy, the tubes come out. I've also talked to some other senior surgeons over the years and as this was starting up, they're like, "Wait till you see the damage to the ovary and other things." Can you talk about other possible risks? We talked a little bit about the surgical risks, but are there any downsides for a 30 year old woman who's done having kids and wants it out to the ovaries, to ovarian function, to menopause coming early, things like that?

[Kara Long Roche MD]
I'm happy to answer this. I think that the question has been raised in many different instances of whether removing the fallopian tube somehow damages the vascular supply to the ovaries, which could then damage ovarian reserve and ovarian function and result in early menopause. There are some anecdotal reports of this. There have been many studies, some of them prospective studies, some of them retrospective that have looked at the incidence of menopausal symptoms after salpingectomy or looking at hormonal signals, AMH.

I would say that the overwhelming summary of the data is that salpingectomy does not damage ovarian function and does not result in early menopause. However, I do think that if salpingectomy is done correctly, it will not impair ovarian function. Which leads me to actually, what I think is one of the major potential pitfalls that we have to think about, which is one, how do we make sure that people are doing this procedure correctly? It goes back to your questions about technique.

I do think that someone who's not familiar or comfortable operating around the adnexa and around the IP could potentially damage the IP in taking the fallopian tube out. That, we know, could damage the ovary, especially if they're having a concurrent hysterectomy. Then I think that one thing, and Mark, maybe this isn't what you were asking, but for Becky and I who are thinking about how to expand this in a population, how do we make sure that patients aren't becoming sterilized before they're ready? We know that in this country there's a very dark history of sterilization practices in patients, especially in vulnerable patients.

How do we make sure that if we put this message out there that patients are not having this procedure done before they're absolutely ready? How do we make sure that patients are getting educated, providers are getting educated and we're teaching providers how to communicate this to patients, ensuring that they're done with childbearing. I think, yes, ovarian function, but more than that is making sure that it's being done in the appropriate patient.

[Mark Hoffman MD]
That's such a great point. That's such an important point.

[Amy Park MD]
I was going to also ask, you had alluded to the Canadian data on decreasing the incidence of ovarian cancer by performing opportunistic salpingectomy, I'm assuming that people get the majority of their hysterectomies 40 to 60 or whatever, and then that overlaps with the ovarian cancer incidents. We would anticipate, maybe, a 10-year timeline of when you would see the incidents decrease.

[Rebecca Stone MD]
I think that's probably right. I think that when they published that data in February last year, there was just a short follow up of a few years for a large portion of those patients. I think all of us are really interested in seeing the longer term follow up data, not just in terms of mortality, but also confirming that. It really does decrease population-level incidents of high grade serous cancer. Also going back to earlier in our conversation, we're also interested to know what happens to the other histologic subtypes of ovarian cancer. Does it also decrease endometrioid and clear cells? What about mucinous cancer? We still have no idea where mucinous ovarian cancer comes from.

[Kara Long Roche MD]
This question, we look at the timeline, we said 2013 and 2015 were when ACOG and SGO put out their guidelines. We're really just coming up on a decade of this being done in this country. There is an immense amount of data that I think will come out. Maybe it will not be the end-all, be-all answer, but will, at least shed some light on looking at how often we find high-grade serous carcinoma in someone who's had these procedures. We know even after bilateral salpingo-oophorectomy that you can still get high grade serous carcinoma. Now as we're doing these operations younger, I think in the next 10 years, we're going to learn much more.

[Rebecca Stone MD]
Yes, I think to your point, Kara, it probably will matter at what time in a person's life the procedure is performed. Going back to what we were saying about the fallopian tube accumulating all this P 53 mutation burden in the fimbriated end, the earlier it's performed-- as opposed to like you think about the bladder cancer patient population, I was talking about, neurology, those women are 60 to 70 years old. They've had their fallopian tubes for a long time. They probably have a higher P 53 mutation burden, maybe even a higher number of precancerous lesions.

Really I think if we're going to really maximize the benefit of salpingectomy, probably, it's performing it in women in their 40s, before those fallopian tubes have hung around and had a chance to develop pre-cancerous change. We actually think now that from the time that a pre-cancer forms in the fallopian tube, like a STEC serous tubal epithelial carcinoma, there may be as much as 7 to 10 years before a patient develops clinical symptoms and diagnosis of high-grade serous cancer, as we know it now. There is a time where the disease can be intercepted.

[Mark Hoffman MD]
To follow that up, do you expect that this will evolve and that this will become more than opportunistic? I do a lot of laparoscopy, I do a lot of super complex stuff but also the easy ones are getting in and out of the belly, that's the risk, but once you're in, the risk of major injury from these surgeries is very low, especially in the hands of experienced high-volume surgeons. Is this something that you think will become indicated for everybody? Certainly, BRCA patients, there are high-risk patients, but for the general population, where do you see that going?

[Kara Long Roche MD]
It's actually interesting because there's been a lot of press in the lay media and the New York Times and the Washington Post where some statements have been made advocating for this without too much explanation to follow. Becky and I have both had a huge influx of phone calls to our practices asking just for salpingectomies without any other indicated surgery going on.

I hesitate to say that I think that will become standard practice, because, I do think, anyone who does a lot of surgery knows that surgery is serious business. Even minor surgeries can have major complications, whether they be blood clots or bleeding or infection. I think that we are a long way from telling people to call their doctor and ask for surgery in the setting of average risk.

I think we have so much work to do in the OBGYN OR, to make sure that this is being done all the time. Then we have all these other opportunities that we need to safely expand access in. Only after that can we think about this as a standalone procedure. I hesitate to say I think that's going to happen but maybe. Maybe if we really show that this is preventative, then it will be a safe option, but I think we're far from there.

[Rebecca Stone MD]
I do think one scenario where we may see practice change is that, we know that for high-grade serous cancer, about 20% of it is related to hereditary gene mutation, like BRCA for instance, Lynch, RAD 51, CD, PALB2. That means that 80% of it, we haven't been able to really identify the genetic underpinning. Maybe we'll learn more about genetics, maybe we won't. But that means that the patients that Kara and I take care of, these patients have sisters, they have daughters who have been with us in taking care of these women for 5, 10 years. Who've been at the bedside when they died, and the genetic testing is negative.
Yet we know that if you look at the data on these people who have a family history of a first or second-degree relative who had ovarian cancer, they have a bit elevated risk compared to the general population, in lifetime risk. For them to be able to do something that might decrease their risk of having what their mom had or their sister or what have you, really is very significant. That they can make a decision, that they can take control, that they can do something that is preventative.

I have several of these families and patients in my practice and it's very meaningful to them. I do think that this is one pocket where we may be able to, or we have opportunity to change practice and potentially affect or impact, positively, not the highest risk patients who are at genetic risk but patients who have some increased risk, who have watched or been with a family member who died of it.

[Kara Long Roche MD]
I couldn't agree more with that. I think that strong family history of ovarian cancer or ovarian cancer in a first-degree relative, these patients don't fit anywhere in the guidelines neatly. We tell them they probably have a higher risk, maybe up to 5% of their lifetime and yet there's no place where they fall and I totally agree that salpingectomy as a standalone procedure may be the perfect middle ground for these patients to act on risk reduction without the supply of a premenopausal BSO.