Rare but Urgent: Emerging Targets and Biomarkers in Vulvar Cancer

New GOSH episode out now! 🎙️ On this episode, we are joined by Dr. Madeline Rhind, a medical oncology fellow at BC Cancer, to discuss her work on druggable targets and prognostic biomarkers in vulvar squamous cell carcinoma. The conversation highlights challenges in rare cancer research and the importance of translating molecular discoveries into clinical care. Tune in now at the link in our bio! #vulvarcancer #gynecancer #bccancer 

For more information on the Gynecologic Cancer Initiative, please visit https://gynecancerinitiative.ca/ or email us at info@gynecancerinitiative.ca

Where to learn more about us:
Twitter – @GCI_Cluster
Instagram – @gynecancerinitiative
Facebook – facebook.com/gynecancerinitiative
TikTok – @gci_gosh

Transcript

00:00:02 Intro 

Thanks for listening to the GOSH Podcast, the Gynecologic Oncology Sharing Hub. We share real, evidence-based discussions on gynecologic cancers featuring stories from patients, survivors, researchers, and clinicians. Our podcast is produced and recorded on traditional unceded territories of the Musqueam, Squamish, and Tsleil-Waututh Nations. It is produced by the Gynecologic Cancer Initiative, a BC-wide effort to advance research and care for gynecologic cancers. 

00:00:35 Carly 

All right, well, welcome everyone to the latest episode of the GOSH Podcast. My name is Carly and I will be your host today, interviewing Dr. Madeline Rhind. Welcome. 

00:00:48 Madeline 

Thank you for having me. 

00:00:49 Carly 

It's great to hear such a beautiful tone in your voice for our people who are in Canada listening, because you are from New Zealand. 

00:00:56 Madeline 

Yes, that's correct. 

00:00:57 Carly 

What part of New Zealand are you from? 

00:01:00 Madeline 

So I grew up in Palmerston North, which is a town kind of a couple of hours from Wellington. 

00:01:05 Carly 

Okay, perfect. I've been to New Zealand, but not on that side. 

00:01:08 Madeline 

Yeah. Most of my training in Auckland, so I was living there for the last 10 years or so. 

00:01:14 Carly 

Right. And so that's where you did your medical oncology is going on now at BC Cancer and you completed the rest of your medical training in New Zealand and Australia. 

00:01:25 Madeline 

Correct. 

00:01:26 Carly 

So how did that bring you out to Vancouver, Canada, when you were doing most of your training out that way? 

00:01:32 Madeline 

So I came here for a fellowship opportunity, essentially. So BC Cancer has a, you know, excellent international reputation. And I also really liked the idea of a little adventure to Vancouver. So that's kind of how I ended up here. 

00:01:47 Carly 

Oh, perfect. We love that. So we're going to talk a little bit more on the depth of the work and the identification of druggable targets and prognostic biomarkers in vulvar squamous... Do I say it right? Squamous cell carcinoma. 

00:02:04 Madeline 

Yeah. It's a mouthful. 

00:02:07 Carly 

And I mean, I don't know if you know, but I'm a two time vulvar cancer survivor myself, and I still can't pronounce that properly. So, you know, it's not an easy one. So why don't you start it off and kind of explain what vulvar squamous cell carcinoma is and why it's an important area of research that people may not hear about very often? 

00:02:27 Madeline 

Of course. So vulvar squamous cell carcinoma is essentially just the most common form of vulvar cancer. And squamous cells, they're like the lining cells of the body. So we have them on the surface of our skin, but we've also got them in, say, like the lining of the lungs or the esophagus or the bladder. So the squamous cell is just the cell that this particular type of cancer starts from. And the cancer can really form from two different pathways. So one of those can be associated with the human papillomavirus or HPV virus. So that is also the virus people might have heard of as associated with cervical cancer. And, you know, the hope is that as we start to see the effects of HPV vaccination, all of these kind of HPV associated cancers will become less prevalent. So that type of vulvar squamous cell carcinoma that's associated with HPV tends to affect younger women. And it's actually associated with a better prognosis. And then we have the other form of vulvar squamous cell carcinoma that isn't associated with HPV. And that type is more commonly associated with underlying inflammatory skin conditions like lichen sclerosus. So that's something that tends to affect older women. So they both start from the squamous cells, but they're just driven by different pathways. And you mentioned that your listeners might not have heard of this cancer before, and that's because, fortunately, it's a rare cancer. And what's even rarer is for this cancer to be diagnosed at a point where it has spread and metastasized to other places in the body. And that kind of makes sense because The vulvar is like the external genital area. And so if you have a cancer there, you're likely to notice some changes. You might kind of feel a lump or a bump. So fortunately it gets usually detected early and then we can give treatments like surgery and radiation to cure women of this cancer. What that means though, is for those like unfortunate women whose cancer has spread to other places in the body, is that it's so rare that it doesn't get a lot of attention, it doesn't get a lot of research funding, and then we don't have evidence to even guide our treatment. So instead, we borrow treatment protocols from cervical cancer, and that results in our patients having worse long-term outcomes. And actually, you know, metastatic disease in this setting is associated with very poor outcomes. So that's why I think it's an important area of research. 

00:05:05 Carly 

Absolutely. And it, I obviously know more about it now as a cancer survivor, a vulvar cancer survivor. I didn't really even, to be honest, know too much about my vulva before I got, I got this cancer, but I am finding more people with this cancer than I ever have and since I was diagnosed in 2014 and mine was not HPV related. Like you talked about different pathways, but it is out there more and pain is our friend. Like you mentioned, you feel that bump and that's what alerted me to mine and ultimately saved my life because the cancers that don't give those types of warnings sometimes are diagnosed too late. 

00:05:44 Madeline 

Yeah, absolutely right. Yeah. 

00:05:46 Carly 

Yeah. So when you talk about druggable targets, what are you looking for at the molecular level and how could that translate into new treatments? 

00:05:56 Madeline 

Sure. So I guess when I'm talking about druggable targets, it's helpful to kind of think about what we do in medical oncology and what treatments that we give. So if you came to see a medical oncologist, you know, 15 years ago, the only tool I've got in my toolbox is probably chemotherapy. And chemotherapy's great and there's a real time and a place for it, but it's a very blunt tool. So all it does is it targets cells that are turning over and dividing rapidly. So we can kill those bad cancer cells, but we're also gonna kill the good cells. So things like the cells that are made in your bone marrow that are turning over and dividing rapidly. They're gonna produce these like infection fighting cells. And that's why you're going to be immunosuppressed when you have chemotherapy. So there's a lot of toxicity and side effects. So we're trying more and more to make our treatments more targeted and more personalized. So for this study, what we were specifically looking at is we were looking at targets for a new type of therapy that we're increasingly using in medical oncology. And that therapy, the drugs are called antibody drug conjugates, or ADCs for short. It's still chemo, but it's chemo that's attached to a special antibody. And the antibody acts a bit like a key to a cancer cell. So the cancer cell has to have the lock on the outside, and that's a receptor or a protein. And so when the antibody drug conjugate enters the bloodstream, circulates all through the body, and it acts a bit like a missile. And it only attaches to the cells that express that receptor. And then the whole complex, the chemotherapy and the lock and key can get internalized into the cancer cell and deliver the chemotherapy specifically to those cells. So it's a really targeted delivery of chemotherapy. So you can imagine like the perfect ADC would be targeting a receptor that's just expressed on cancer cells and not anywhere else in the body, and ideally on all of the cancer cells. Yeah, so I hope that makes sense. 

00:08:03 Carly 

It does, it does, yeah. 

00:08:05 Madeline 

So what we looked at for this study is we actually looked at six receptors that already have antibody drug conjugates approved for use in other cancers. So there's already drugs available. And we just wanted to see, does vulvar cancer express those receptors? So that's kind of the druggable targets that we were looking for with the study. 

00:08:25 Carly 

Right. That is so interesting. Where was this study in 2014 when my cancer was diagnosed? Because that's not what I went through. What types of biomarkers are most useful in vulvar cancer right now, like prognostic, predictive, or both? And what role do they play in patient care? 

00:08:47 Madeline 

Sure. So I think maybe it'd be useful just to kind of step back and say what a biomarker actually is. 

00:08:53 Carly 

Oh, yeah. 

00:08:54 Madeline 

So a biomarker is just something that we can measure. So you could have a biomarker that's measured from a blood test, or you could have a biomarker that's measured from looking at your tumor biopsy. And then when we have a biomarker, we can say it's a prognostic biomarker or a predictive biomarker. Prognostic biomarker is really just telling us how aggressive the cancer is. So it's not telling us anything about the treatment. It's just saying, look, women who have this biomarker, their cancer tends to act in a more aggressive way and this is more indolent. And then the other type is a predictive biomarker. And that's telling us something about response to treatment. So it's saying patients who have this biomarker are more likely to respond to this specific treatment. So at the moment in vulvar cancer, we definitely... we certainly do have some prognostic biomarkers. We talked a little bit about the importance of HPV status. We can actually measure HPV status quite easily, looking at the tumor tissue to see if it expresses a protein called P16. So that can be used as a surrogate for HPV infection. And then we can say, look, women who have a P16 expressing tumor have a improved prognosis. We can also look at the flip side of that and say within the group that don't express p16, do they have abnormal p53 expression? And unfortunately, abnormal p53 expression, which is most of the non-HPV associated tumors, tend to act a little bit more aggressively. So that's prognostic. There's a slight predictive element as well in that the HPV associated tumors can often be more responsive to radiation treatment. But I would say that's not as well validated as some other predictive biomarkers. We do not have any predictive biomarkers currently that would guide our systemic treatment. So there's nothing that I could test that would say, this shows me that this drug is going to work really well for you or not work really well for you. 

00:11:04 Carly 

Wow, there's so much like deep digging, diving to figure out, because each patient will also be so different. So you need to vary the treatments for those patients, right? 

00:11:15 Madeline 

Absolutely. So those biomarkers are essentially guiding the care that that patient's going to receive. And sometimes we have to make sure that they're really well validated before they get to that point, for sure. 

00:11:27 Carly 

Gotcha. Wow. And so with vulvar cancer being, you know, very quite relatively rare. How does that rarity come to affect the research progress, the clinical trials, and ultimately patient outcomes? 

00:11:43 Madeline 

So I think the rarity has a huge impact. If you look even at just gynecological cancers in general and the amount of funding that they get and compare that to some other forms of cancer like prostate cancer, gynecological cancer is getting less funding. And then, you know, vulvar cancer on top of that is a rare cancer. And that means it doesn't have the public attention. People don't know about it. There's no campaigns for it. So it's getting less money. And then less money leads to less clinical trials. On top of that, even if you had the money for a clinical trial, how are you going to recruit patients for a large randomized phase three clinical trial with such a rare cancer? It's going to be impossible. So we don't have these big trials, and I can't say, you know, I mean give 500 women this treatment and 500 women placebo, and then do some really robust statistics to show the survival advantage. So we're never going to get that level of evidence. And then you can take that a step further than say, you know, if a government is looking at how they're gonna allocate money to drugs, it's much easier to justify allocating money to a drug that's got this huge phase three trial. So it has a big knock-on effect. And I think we can see that directly in our outcomes for our patients, particularly with those patients with metastatic disease. 

00:13:06 Carly 

Absolutely. Because you need to have the amount of patients to do the proper trial to get the proper results. And with a rarely diagnosed cancer, you're not going to have all these women to pick from because they're just not there like other cancers that are more prevalent would be. Right? Yeah, that's crazy. So what do you think are the biggest challenges in making those discoveries a little, you know, more talked about, known about, or like the biomarkers and the drug targets from the lab into the real world clinical care? 

00:13:38 Madeline 

Yeah, so the pathway from, you know, finding something in the lab to then making it applicable for clinical practice is long, and there's a good reason for that, and we need to make sure that it's really well validated. So you could take the study that we have done, just as an example and say, look, you've found that there's three of these six receptors are highly expressed in vulvar cancer. You've tested the primary tissue and you've tested the lymph nodes, but I haven't tested distant metastatic sites like the lung, the liver to see is there a difference in the expression of the receptor in those sites? Because I don't have that tissue because people haven't gone and done these unnecessary biopsies. So, you know, I could find when I tried to do a clinical trial that actually the receptor is not expressed as highly in those distant sites and therefore the drug wouldn't work as well there. Other issues might be just because the receptor is expressed doesn't actually mean that the drug's going to work. So I could have a drug that works really well in like, say, bladder cancer, enfortamab vedotion for Nectin-4, that's one of the receptors, It might not work in vulvar cancer. It might not, even if the receptor was highly expressed, maybe when the lock and key bind together, maybe there's an issue internalizing it into the cell that we didn't anticipate. So those are the kind of things that you could find when you go and you design your clinical trial and you're really optimistic and hopeful that these drugs are gonna help patients, maybe they won't. So these are all kind of hypothesis generating studies and they're the first step, of many steps until making something that actually changes day-to-day care. Yeah. 

00:15:23 Carly 

And just like a little side note to that is like, I remember during treatment, they asked me if they could keep my tissue and they could use it for research and like all these things. And at the time I was like, yeah, sure, I'm just trying to stay alive. I didn't really understand the why. But as I've gotten more involved with this podcast and other advocacy type platforms, I understand now that that's what we need to help the next person to get these trials to, biopsy. I'm not a doctor, but whatever research that tissue helps is what we need to find out more solutions for the next one coming down the road. 

00:15:58 Madeline 

Absolutely. It's where a lot of our first kind of steps come from in the science. So it makes a huge difference. And having patients like you volunteer to be part of this is massive. I may have actually included a bit of your tumor in this. 

00:16:12 Carly 

You got to look me up in the files. My file is really big at BC Cancer. Like you cannot miss it. It is very big. I am very visible there for sure. Oh my word, that's too funny. So if we were to kind of like close out this chat right now, if we were to think about like one thing that you really wanted to point on for research priority that could most improve outcomes for patients like myself and other people currently going through vulvar, I can never say it, squamous cell carcinoma, what would it be and what would your reasonings be for that? 

00:16:49 Madeline 

So I think specifically for vulvar squamous cell carcinoma, where I see the biggest gap in terms of outcomes would be our patients with metastatic disease. And I think what we really need with these rare cancers is more kind of innovative approaches to trials. So we need huge amounts of international collaboration, which we're really good at. And then, you know, it's things like, if we can't do a randomized phase three trial, could we do like a basket trial where we take everyone who's got this biomarker, regardless of where their cancer started from. So gastric cancer, a rare vulvar cancer, and actually just in the kind of like a, we call it tumor agnostic way. Just see, does this drug work for cancers that express its biomarker? Or we just want to focus on vulvar cancer, we could do like an umbrella trial and say, I'm only going to recruit women with vulvar cancer, but I know only 40% express this receptor, 30% express this receptor, and I'm going to test multiple different drugs within the same trial. Logistically really challenging and comes with its own issues, but I think, Until we can kind of include these patients in trials, we're just not going to have the evidence to guide our care. Absolutely. We don't want to see this cancer grow and get more aggressive, but as it does, the research will only get better because we're going to have more people that have gone through it and we can do it to do this type of research with, right? 

00:18:17 Carly 

Double-edged sword, yes. 

00:18:19 Madeline 

Yeah, I know, very double-edged, for sure. 

00:18:21 Carly 

Yeah, well, thank you so much for taking your time. I hope that you're enjoying Vancouver. I mean, I've never been to your part of New Zealand, but when I was in New Zealand, just almost a year ago, I found it very similar landscape-wise to BC, right, to the Vancouver vibe. Same thing with Australia. So I hope we give you a little bit of sense of home here because you're coming here to help BC Cancer and also helping you. It's only going to help the next cancer patient. So from a survivor, I'd like to thank you. And too bad I didn't get to meet you at my last checkup, you know, because you're not in the rooms like you mentioned to me before this. You're doing more in the treatment type size of things with patients, right? 

00:19:01 Madeline 

Yeah, well, it was lovely to meet you and thank you. I have felt very welcome here in Vancouver. 

00:19:05 Carly 

Yes, well, thank you so much for your time and everything you do for the patients out there. 

00:19:09 Madeline 

You're so welcome. Thank you. 

00:19:13 Outro 

Thanks for joining us on the GOSH Podcast. To learn more about the Gynecologic Cancer Initiative and our podcast, make sure to check out our website at gynecancerinitiative.ca.