Beyond the Sun: Uncovering the Genetic Risks of Melanoma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and Co-Director of the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Josh Arbesman, a Dermatologist and Director of the Pigmented Lesion Clinic here at Cleveland Clinic. He's here today to discuss genetic risks for developing melanoma. Welcome, Josh.

Joshua Arbesman, MD: Thanks for having me.

Dale Shepard, MD, PhD: Give us a little bit of an idea, I gave your title, but what is the kinds of things you do here at Cleveland Clinic?

Joshua Arbesman, MD: A lot of what I do is thinking about melanoma and inherited predisposition to melanoma, so that affects both what I do in the clinic where I see a lot of people that are higher risk for skin cancer development and screen them for the development of new skin cancers, catching them as early as we can.

Then also I have a research focus, which is trying to understand why certain people are more at risk from an inherited perspective for melanoma. That goes all the way from clinical-based research, which we're going to talk about in a second, into the lab where we're trying to understand how some of those genes that we identify functionally may give you increased risk for cancer with the hope that eventually we can come up with novel prevention therapies for some of these high-risk individuals.

Dale Shepard, MD, PhD: Okay. We're going to think about some of these newer genetic sort of things that we might think about risk for melanoma, but traditionally what do we think about as risk factors?

Joshua Arbesman, MD: The major known risk factor for melanoma has been thought to be sun exposure, ultraviolet radiation exposure in the form of sun or through tanning bed use. That probably within the best characterized studies increases your risk about two to three-fold with the highest level increasing you probably up to maybe three-fold. That is in the form of predominantly intermittent sun exposure when we're younger ages, probably childhood, maybe 20s, but not beyond that. That's been thought to be the major risk factor, but as you can imagine, when a risk factor only increases your risk maybe three-fold, there are probably other things out there that are relevant for development of that cancer.

Dale Shepard, MD, PhD: Again, just as a general, since there are lots of different people might be listening in, that doesn't suggest when you're older you should avoid sunscreen.

Joshua Arbesman, MD: That's correct. I'm not saying don't wear sunscreen. The other factor that I'm not mentioning is there's other forms of skin cancers such as basal cell and squamous cell carcinoma that are differently associated with sun exposure and probably more so with squamous cell carcinoma, that longer term chronic use probably does increase your risk. This is just specifically related to melanoma, understanding why we're trying to understand the genetics a little bit more.

Dale Shepard, MD, PhD: Since you see this coming through your clinic in terms of skin cancers, a very random question. You mentioned tanning bed exposure. I don't see those around much anymore. Are there are very many people still using tanning beds?

Joshua Arbesman, MD: It's definitely not as prevalent. There were laws, especially for minors in a number of states that came through, so I think that the use has gone down. I do see some patients that are probably using tanning beds. They may be denying it to me, but it's still probably happening a little bit-

Dale Shepard, MD, PhD: There you go.

Joshua Arbesman, MD: ... But not to the same extent.

Dale Shepard, MD, PhD: There you go. Well, that's a good thing. Give us a little bit of an idea when you've been looking for these genetic risk factors, what sort of things, how are you looking for it? What are the things you're finding?

Joshua Arbesman, MD: What I would put as sort of the undercurrent is a study that came out, I think it's about eight years ago, where they looked at twins and the rate of concordance, or when one twin had a cancer, what was the rate in the other twin? Looking at both identical and fraternal twins or monozygotic and dizygotic twins to understand how inheritable each cancer was. Based upon the concordance, they actually found that melanoma was the most heritable cancer amongst all those that they studied, higher than traditionally thought of inherited cancers such as breast, ovarian, colon cancer. It came out quite high. That's the backdrop where we were starting to understand, yes, sun is important, but there may be a large portion of heritability there. We wanted to understand how that plays out.

There's two major ways I think we're looking at inherited risk for melanoma. One is larger scale studies where we've enrolled a larger number of patients, which is the study that we'll delve into a little more deeply. Then doing more of a broad-based approach in those patients that we've, in our registry... Our Gross Family Melanoma Registry, we're thankful to the Gross family for their support, we've enrolled close to 600 patients into that registry, and so we're doing more broad-based approach there.

The other thing that we're also doing, and that's more of a laboratory-based understanding, is in patients that have developed a high number of melanomas, say 5, 10, 15 primary melanomas, looking more deeply into their genetics to understand functionally what's going on with those genes that they may have altered that put them at higher risk. Those are the major ways that we study it.

I think also what we found is that there's a lot of high-risk melanoma patients that have developed many melanomas that we don't have an understanding for, despite doing a lot of next-generation sequencing over the last number of years. Then there's also probably more medium penetrance genes that are relevant for melanoma that maybe increase your risk two, three, five-fold rather than 30 or forty-fold that are probably relevant, especially in combination with each other or sun exposure perhaps as well.

Dale Shepard, MD, PhD:  Excellent. Well, lots of different ways you're looking into this, but specifically you mentioned the study. Tell us a little bit about the study that you did.

Joshua Arbesman, MD:  This study that we recently published was talking about the first 400 patients that we enrolled in our registry. What we did was we wanted to understand... This has been done in other cancers more recently as well, what are the rates of known genetic variants that increase your risk for melanoma, but also known variants in cancer susceptibility genes in general. What we did was we took these patients and we tested them for a panel of genes. At the end, it was about 85 genes. It started probably around 80 genes. The company kept on adding a few more cancer susceptibility genes. Then we tested those patients, and then we also explored a few other publicly or collaborative data sets looking at other patients with melanoma based upon a variety of inclusion criteria, which I'll talk about in a second. What we found was that somewhere between 10 and 15% of those patients that were tested had a pathogenic or likely pathogenic variant in one of those cancer susceptibility genes, which means that they had some sort of cancer predisposition.

Within our study, we took patients that had more of a familial component to their melanoma, or personal higher risk where we looked at two or more melanomas in that patient or in their family, or we also looked at if they had melanoma or another cancer, not traditional skin cancers like basal cell and squamous cell, but any sort of other cancers. Traditionally, the rule for a lot of genetic testing with the melanoma was the rule of three. Three melanomas in an individual, three melanomas in a family. We brought in that to more of the rule of two with the thought processes that perhaps we may encompass more individuals. We found that 10 to 15% of those patients that had an inherited predisposition to cancer, interestingly enough, at least specifically in our cohort, we found of those genes that we identified, 2/3 of them had not been previously related to melanoma. Expanding that understanding as well.

Dale Shepard, MD, PhD:  Do those particular genes that seem to go along with melanoma, were there other cancers that were more likely to be linked to those susceptibility genes?

Joshua Arbesman, MD:  Yeah. That's also a very critical point is that even if this doesn't change your management from a skin screening perspective, a lot of these genes, so genes such as BRCA-I, BRCA-II, Lynch syndrome genes increase your risk for other cancers. That will affect, for a lot of those patients and their affected relatives, screening for those cancers.

The other thing that comes into play is we know that some of those variants in the germline side are actually also relevant from a treatment perspective so that we've seen for some of our patients that this has actually affected their management of potentially other cancers that they may develop, or potentially their melanoma in particular.

Dale Shepard, MD, PhD:  Maybe expand a little bit about that, how we can use that genetic information and alter treatments.

Joshua Arbesman, MD:  For example, BRCA-I, and II, the PARP inhibitors that have come out target patients that have a defect in homologous recombination. That can sometimes be helpful in treatment for if they develop, say for example, breast, ovarian cancer and there was a clinical trial looking at it within melanoma. Or for example, if patients have Lynch syndrome genes that are altered, immunotherapy is potentially more relevant in those patients. We've definitely seen some individuals benefit from knowing that fact.

Then we've also, going back to the screening, we've definitely seen some patients benefit from knowing that they're more at risk for cancers such as them or their relatives have been screened more aggressively and found cancers at an earlier stage, prior to it being metastatic.

Dale Shepard, MD, PhD:  Since there's more information coming out about cancer susceptibility genes, likelihood for some people to get cancers, how do you see the world in the future? Do you think that patients will be screened based on... And we look and see, do they have cancer susceptibility genes and then do the appropriate screenings? Or do we wait until somebody develops a cancer, they get a melanoma, and then for the sake of their future risk, family risk, then we look for cancer susceptibility genes?

Joshua Arbesman, MD:  I would say I think we're more moving towards understanding people's risk before they're able to develop cancer. I think that's important because we know if we do a more aggressive screening that it is definitely life-saving for them. I also think what we're starting to understand within a variety of cancers is that inherited predisposition or carrying a variant that is pathogenic in a cancer susceptibility gene is more prevalent than we used to think.

For example, in melanoma, we used to think it was maybe 2 to 2 1/2% of patients with melanoma would have a variant in a cancer susceptibility chain. Obviously that's much higher in our studies. I think what we're seeing is that, for me, the goal for melanoma on some level, we can't screen everyone for skin cancer. That's not feasible. For me, I would want to understand is can we develop a panel of genes that are relevant from a melanoma perspective, screen people, and if they do show a positive result, then they will get cancer screening from the melanoma side or other cancers if they need be. Then we will be more aggressive and tailoring our screening for the patients that are at risk.

I think the challenge is that if you wait until someone gets the cancer, sometimes that may not be caught at the right stage. That's hard for that individual. Yes, the flip side to a lot of genetic testing, which I haven't mentioned, is that it can create a lot of anxiety and worry for those patients knowing they're at risk for a cancer and sort of waiting for it to develop. That being said, I do think in a lot of cancers we have proactive approaches, one from prophylactic treatments, whether it be prophylactic mastectomy, oophorectomy in those situations or for skin cancer screening where we can say you come more frequently such that we can catch a melanoma at a stage where it's curable from a surgical perspective.

Dale Shepard, MD, PhD:  I guess also related to those kind of kinks and how we manage patients, insurance becomes an issue, so I guess there's two factors. One would be insurance coverage for the testing, but then if you find something, someone's insurability.

Joshua Arbesman, MD:  Yeah, so those are very important points. I think the goal from our perspective is building up the literature to show that we exceed that pretest probability that's often used in genetic testing of 5%, so that the idea is that what is the likelihood of finding something. In this patient it's above 5%, then it's worth doing that testing. The hope is by building up that literature, we can encourage insurance companies and guidelines to change what they have been recommending for patients such that it is covered.

To the second point of coverage, post getting a genetic test result that is significant. Primarily from a health insurance perspective there are some degrees of laws that prohibit discrimination in that regard. The flip side is that life insurance, there are no such laws. Typically what I tell patients is practically make sure your life insurance is in order prior to getting the genetic testing, then get your genetic testing, and then we go from there.

Dale Shepard, MD, PhD:  I mean, it's very practical advice. I guess when we think about family history and genetic risk and things like that, I think it always, with all of these cancers, important that patients realize that you might be at increased risk, but you can get it without those and not ignoring symptoms. I mean, do you have patients that come through and say, "Well, I have a melanoma but no one in my family's had it. How could I?" Making sure people don't ignore things because they don't have a history or a genetic risk.

Joshua Arbesman, MD:  I think there's a couple of important points off of that. One is there are a lot of people when they get genetic testing and the genetic testing is negative, they'll say, "Oh, then it was a one-off. There's nothing going on with me that I'm at increased risk." We know that's not the case. They should still be screened closely and made sure that we don't miss any new melanomas or skin cancers.

Then the other factor though, to your point about the only person in the family having melanoma, the lifetime risk in the United States at least is about 2%. The way I think about that is that even if you have a genetic risk that markedly enhances your personal risk of developing melanoma, say it increases your risk 20-fold, you take that lifetime risk of 2%, you multiply it 20-fold, you're still maybe not getting anyone else in the family that's having a melanoma. Obviously in synergy with other environmental risk factors. I think that's important that it still could be genetic in those situations.

What we're also understanding based upon our results is that there's melanoma predominant families where melanoma is the primary cancer that we see that they're at risk for, most illustrated by alterations in CDKN2A. Then there's melanoma subordinate families where melanoma is a part of their general cancer susceptibility, which is why I've started asking more patients about not just skin cancer and melanoma in the family, but other cancers because it often does run in this multi-cancer susceptibility families, which we now understand there are some genes relevant for that as well.

Dale Shepard, MD, PhD:  I guess since we have your insight here, lots of different people might be listening in. Could you maybe just give us a quick reminder, who needs to be checked for potential for melanoma? What are the characteristics? Somebody has a lump or bump, some abnormality. Who should get checked out?

Joshua Arbesman, MD:  I think there's two aspects to that question. One aspect is, should people be getting regular skin cancer screenings, head to toe full body skin exams by a dermatologist? There's not clear guidelines at what age or what should trigger that necessarily. Things that we know for sure that increase your risk are family history of melanoma, so those patients, if you have a first degree relative, they should be getting screened for melanoma once a year. Patients that have had other types of skin cancer should be getting screened as well. Patients that had any sort of transplant, they're at increased risk and they should be getting screened. Then probably broadly speaking, people that have fair skin, fair eyes, fair hair, they're at increased risk for melanoma from some degree from a genetic risk factor as well and they should be getting screened. At least I would say consider getting screened by a dermatologist once and then they can help you decide how frequently you should come back.

In terms of an individual area that is of concern, we talk about melanoma, we talk typically about the ABCDE rules, and this is something that the major important thing is it can be raised, which most people will notice if something has risen up, but it also can be flat. If something is flat and meets those ABCDEs, which I'll go in through in a second, it still is worth getting checked out by your dermatologist.

A stands for asymmetry, one half of the mole not matching the other. B is for border, instead of a nice round border it's more jagged. C is for color, instead of one color oftentimes a mole will be tan or brown. It may be multiple colors or very dark. D is for diameter, which we talk about greater than six millimeters or the size of a pencil eraser with a caveat that a melanoma could be smaller when it starts out. That doesn't mean if it's not that size, you shouldn't necessarily get it checked out. Then there are some benign things, birthmarks that we've had for many, many years that are greater than the size of a pencil eraser. The last one I think is the most critical thing and the most intuitive, and that's E, it stands for evolving, is something changing over time. By very nature, cancer should be growing and so if something is growing, you should be seeing changes, maybe checking it every month. If you continue to see changes, that's when something should be checked out. The other thing that I use E for is what we call the ugly duckling sign. That is a mole that stands out amongst the rest of your moles. It's not talking about the patient, obviously. If something looks different than everything else, that's definitely a sign that something should be checked out.

Those are the rules on some level for melanoma. For other types of skin cancers, basal cell and squamous cell carcinoma being the most common types of skin cancers, those are usually a pimple that doesn't go away, a sore that doesn't heal, a pink scaly spot that's not going away. Those are more intuitively noted because they're typically more raised. Melanoma, we want to make sure even when it's flat, people should get checked because if we do catch it at that early stage, it is much more likely to be treatable with surgery without any recurrence risk.

Dale Shepard, MD, PhD:  Well, I appreciate you covering that because it's important that people remain aware of that.

Joshua Arbesman, MD:  Sure.

Dale Shepard, MD, PhD:  Really interesting work you're doing looking for genetic risks, and hopefully that will help shape our ability to screen people and prevent problems in the future. I appreciate you being with us.

Joshua Arbesman, MD:  Awesome. Thank you for having me.

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