S5 EP09 - Sun Smart: Clinical Insights on Skin Cancer

Melanomas are basically the most deadliest of all skin cancers and their prevalence uh they are mostly in men. Compared to women, and the fourth most common cancers in Australia, and more prevalent usually in Australia and New Zealand compared to other parts of the world.

um birthmark uh at the back of my leg that that obviously went malignant. You don't you just don't want that.

Um there are certain mutations that are um basically uh are germline mutations which are happening in their reproductive cells and they're passed on to the to the generation and the generation after that.

uh sequentially and also we can talk about uh somatic mutations that both happen in melanoma presentations. For example, Um, if you want to focus a little bit on germline mutations, mutations such as uh high-risk melanoma susceptibility genes that are present, and the exam, good example of that would be cyclone-independent kinase inhibitor. uh two A and also C D K four, which is um not that widespread or common, but it does happen. It has been identified, C D K four.

Um, also we're dealing with mutations that are both somatic and germline mutations. These are, for example, BRAF mutations that happen in forty to fifty percent of cases. And recently they have been paying a lot of attention to telomerase and uh telomere um uh related genes. So all of these are involved. The other thing that I would like to mention is uh not to forget about low risk susceptibility genes, and those are the genes that Um they carry allic variations in themselves, but they

That is very low. However, that a small amount will add on to the major genes and major players. And that would be basically part of that polygenic risk score. But uh the other thing that I'll just wanted to add on top of that is the factor that we talk about is uh penetrance. So penetrance is if you have got the gene

uh you carry on and develop that disease because of that penet high penetrance. You've got that high penetrance, the likelihood of developing that disease will increase. So in a situation that we're dealing with um Main genes such as CDK C DKN2A and C DK4, for example. Uh these are the high-risk melanoma uh susceptibility genes and um they are observed in 40% of families. The other thing I was gonna add, which is very important.

is that the low susceptibility, low-risk melanoma susceptibility genes are also important to pay attention to. And these are the for example, MC1R

C DK um N2A mutations in melanoma prone families. And that's something that um uh it has been looked at especially recently in a lot of research and new data that is emerging, they're putting a lot of focus on um polygenic risk factors or risk scores. And these are the example. The other example would be the blonde or red hair colour, for example, would also play a role. As well as history of three or more blistering sunburns prior to the age of twenty, and also history of three or more.

uh years of at or job uh as a teenager. Okay. That's also play a major role. And even presence of actinic keratinos uh keratosis, which is basically a rough scaling precancerous patches caused by Chronic sun exposure. So these are the facts that people need to remember and bear in mind. Because, for example, if you Uh if you have one or two of these risk factors straight away, that will increase your risk by 3.54.

Score more than three, that straightaway increases your risk by twenty fold. Wow. We can see that it's yeah, very important. There are other factors as well. For example, if you live near the equator, that also increases your risk. Or um if you constantly primarily working outdoors. Or if you have um recreational habits that they are outdoor recreational habits, like playing golf, for example. outdoor all the time. Also history of prior melanoma lesion.

if you had any history that can all always increase your risk so to factor it in. And the other thing to remember, which I haven't mentioned yet, is To think about the role of tumor suppressor genes. So if those genes have got mutations in them, for example If there's mutation in P16, obviously that is going to influence how the gene mapping is going and how the genes have been influenced in the right way, because the tumor suppressor gene carries mutation in it.

uh they can increase the risk significantly because they're present. That's why it's important that people pay attention to polygenic uh risk factor or risk school overall look at everything together.

uh gene expression or gene activity. We can talk a little bit about um lifestyle factors, we can talk about environmental and we can talk about biological factors as well. So to give you a few examples of lifestyle factors, um, I can talk a little bit about diet, anti-inflammatory diet nutritionally.

Dense diet, antioxidants, and the role that antioxidants are playing to reduce inflammation in the body overall, as well as Other uh lifestyle recommendations, for example, cessation of smoking if people or individuals in these type of categories with increased risk factors that we covered previously. Um it's very important that they stop alcohol and smoking, cessation of both of these agents, uh, because they increase inflammation significantly in the body and they can uh actually impact.

Gene activity and genetic expression. Also, the other thing that is very important to pay attention to is stress. It's important to lower the stress. As we know, a stress is the mother of all inflammations and chronic stress causes a lot of problems in the body, cancer, autoimmune, and so on and so forth. The other thing is avoid acute uh sun exposure that results in sunburns, as we discussed earlier in regards to outdoor habits and recreational habits.

uh avoid the use of tanning beds. It's another important fact. And also um Routine a clinical skin check and examination. So the individuals is preferred if they can routinely check their skin, check the scalp, uh the soles of the feet and even the nails. and also um pay a visit to a specialist to dermatologist uh on a regular base, three or two six monthly, depending on the family history also. The other thing to remember is that

Early detection is very, very important. So you're highly vigilant. You can detect if there is any subtle changes that you can identify.

Um so these are sort of summing up the lifestyle recommendations. As far as the environmental recommendations are concerned, they mainly worry about pollutants. We worry about environmental toxins and also not to mention the pharmaceuticals. And a lot of people are on multi pharmacy and there are chemicals. That can, after being broken down in the body, then they can actually pose a risk and increase the individual's risk of developing.

situations and certain conditions. Also in regards to health and biological factors, um, age, infection are important to be mentioned. Um also maternal health, pregnancy, for example, gestational diabetes, these risk factors as well as obesity are all risk factors that need to be considered.

Triathlon, which of course uh requires lots and lots of training out in the sun. I mean you can do it indoors, but um obviously you're swimming, you're riding and you're running, and sometimes for hours and hours on end, and the actual event itself

takes twelve hours to complete so it's impossible actually um while you're in the middle of a race to kind of re lather yourself with uh with sunscreen so it can be really problematic um when it comes to you know getting burnt and obviously damage to the skin.

quite vigilant after that. I mean that may not have been um, you know, necessarily d directly related to the sun, uh, but it could have been. So I have been really, really vigilant about that. But it was about three years ago, so it was post COVID, uh, that I went for a regular skin checkup, which is what I have been doing, you know, for the past number of years. And that's when he basically uh identified the first

invasive BCC on my nose. Um and then a couple of years later uh there was one on one side of my nose and then one on the other side of my nose. And six months after that I had two further BCCs. All of them were invasive and all of them needed quite rapid um treatment. And obviously, you know, it's just one nose, so to have four of them um over a short period of time was was quite intense actually.

um and that had a period of healing, uh, it's very important it in s in any skin graft for that skin not to move at all, otherwise it doesn't necessarily graft or take. And so that was the very first one that I had and I was just following doctor's orders I suppose um for that one. The second one was discovered, as I mentioned, not that long after, but that was uh more on the tip to the other side of my nose.

and um that one was was quite aggressive and they recommended um another type of surgery. It was called Moe's surgery and I had like a flat um which is quite a specialised cosmetic surgery procedure. And um I must say that I didn't realise, probably didn't get the full uh understanding of what that involved because I all I remember was waking up from the anaesthetic. It was a general anesthetic to get that done.

and I had this enormous um wound on my nose with literally looked like hundreds of stitches. Um and uh yet was quite very unsightly. So I must say that was uh quite a surprise.

And then i it was the the the final time when they discovered two further B C Cs and they were all seemed to be the same type of BCCs um on my nose and basically they cut them out and then the skin doctor recommended that after having four of these in such a short space of time in a s in a small area that um just a a six week radiation treatment was gonna need to um

within a day or two. And unfortunately in that particular instance the surgeon had uh decided that, you know, addressing on the wound was not was not, you know, the best course of action. So you kind of have to walk around with this horrible looking wound on your nose, knowing full well that

you know, it's it's very unsightly and obviously, you know, um people probably don't want to look away rather than look at you sort of thing. So, you know, that that's never a never a pleasant uh thing. So y you've got to sort of deal with that. Um equally, you know, throughout my life I've I remained very active um and throughout all the surgeries you've got to be

you've you probably have to tone your activity down a little bit. Um so, you know, instead of getting up and doing my exercise in the mornings, I you know, while I was going through treatment or what have you, I'd have to tone that down a lot.

And, you know, for me that's where I get a lot of my energy, for example, is getting out, exercising, getting fresh air, you know, pushing my body a little bit'cause that really gets my adrenaline and everything else going for the day. So I suppose from that perspective it affected me in that um y you obviously like anything when you're undergoing treatment for anything, you have to kind of change your daily life

your your normal habits and what have you. So it was a matter of uh yeah, just I I guess realising that it was it was something that I had to go through. Many people have to go through the the you know, similar sort of things and that

the outcome for me obviously was gonna be um was gonna be qu quite positive. But no, there's no there's no doubt. And there there was one um situation where I um it was actually right at the end of, you know, my sort of radiation treatment when my nose looked particularly bad, it was looking very raw. and not very nice at all. And um I went to to go and do some shopping at Woolley's. Um and I was just in the aisle trying to get some chicken, I think it was, and there was a

a small child in a in a trolley in front of me, um, and a as soon as he saw me he burst into tears and he wanted to run away. So I I realised then that I actually you know, I was actually scaring children, so Not ideal. Anything particularly on your face, you know, obviously you know, people do get different, you know, skin cancers on different parts of their body, but I think anything on your face and particularly on your

knows. Um, you know, you do feel very self-conscious. Um, but by the same token, um certainly, you know, in my working environment, my home environment and other other than scaring the poor child in wool. Everybody was really, you know, obviously just realised it was something that I had to go through at the time and he was ultimately going to heal.

Certain integrative approaches that can uh offset the side effects of the treatment at the same time be synergist with the treatment to make sure they get the best benefit with that treatment that that's been offered. So for example, a treatment. Immunotherapy treatment might offer them 40% response rate. And if you add on top of that, that holistic approach, you're going to increase that percentage significantly to a much higher percent.

Yeah it's important to take all of that into consideration.

from the immune system. So immune system would be on high alert. So for example, um the two examples of that I can mention would be Nivolumap and Epilumap. So These two will be targeting specific molecules on the T cells and remove the brakes. By targeting those molecules they basically remove the brakes

on the immune system. So the immune system will be attacking on the attack mode at all times. Okay. What they might do, they might add on targeted therapy on top of immunotherapy. Targeted therapy Basically, when we talked about earlier we talked about breath mutations. If they want to try to block breath They use specific um medicines such as, for example, debrofenib or trametinib, these agents will specifically block breath mutations.

And we call them targeted therapy because they touch on map kinase pathways which are fueling that cell proliferation and survival. In essence, they might have immunotherapy on its own, for example nivolumap, epidumumap. as immune checkpoint uh checkpoint inhibitors, or they might add them together to targeted therapies. Bring targeted therapies alongside immune checkpoint inhibitors in the presence or absence of radiotherapy. But the other thing you have to remember is that if you bring in more

more therapies together to be used as combined therapies, obviously you need to factor in the side effects. Yeah. Because a lot of people would suffer unfortunately um in certain settings up to fifty three percent they suffer grade three and grade four toxicities and that's huge. Mm. And some of them they have to leave the treatment because they can't continue and some trials that they run, they have to stop the trial because of the

toxicity and some of these toxicity, for example, it might we might be dealing with colonic perforation. We might be dealing with sepsis, you know, they're full full on heavy. So we have to remember all of these. Melanoma is the best example of immunogenic tumor. So because of that, they are developing more and more immune therapies to attack melanoma. So the last option that uh conventional medicine treatment will consider would be chemotherapy.

Chemotherapy will offer you about twenty-five percent response rate and they might use single agents, such as for example, timidol or tumosolamide is the same drug, tomosolamide slash timidol. or they might use um for example um docarosin or they might use these agents in a combination of other drugs and call them um a name which is uh the name for that cocktail, for example.

bold. Bold is uh Bellomyosin bin Christensis platinum so they might use other combination of so it all depends but Immunotherapy seems to be um the one that is giving you the best response rate in regards to a melanoma sofa.

So why ketone bodies are important? Because ketone bodies basically try to alter that system, that tumor system, and make that environment less desirable for these cells to proliferate and to thrive. So that's one thing that is very important for us. Also, ketone bodies that are generated through ketogenic diet not only affect the glucose metabolism, they also alter amino acid metabolism. And one other thing that I would like to mention is that

They um bring sensitivity to radiotherapy and chemotherapy uh and also they interfere with oncogenic signaling. So that's based on research. Now why is this important in melanoma setting is because The melanormal cancer cells, they have got their metabolic flexibility, which can range from being lipolytic to glycolytic to glutaminolytic. So they can shift.

And use these agents, all of these agents to generate that fuel that they want. So if we can block the glucose and glutamine metabolism, blocking two major sources of the fuel for these cells. So and that will put them under a lot of stress. Yeah. So that's based on research. However, research on that field is still evolving and there are uh clinical trials that are still um uh on ongoing. So these the research is still emerging.

Um some of the research in regards to diet, they have proposed that Mediterranean diet will actually increase progression-free survival in these patients and That's because mainly because of the fiber and omega-3 fatty acids that um are important in generating, for example Butyrate um butyrate producing microbiome pathways and chain fatty acids also. um help with um managing the immune system and bringing homeostasis uh and keeping the gut integrity intact.

And so um there's some proposition uh around the Mediterranean diet as well, but In regards to nutrition, definitely um anti inflammatory diet, loads of antioxidants and as well as um the um other factors that we have to consider, for example Dysbiosis, um fact that microbiome could be under stress, these play major roles.

These agents are stimulating the immune system significantly. So you don't want to give a patient a supplement per se that is going to add on top of that and stimulate the immune system further because what you will do ultimately you will increase the sound effects for that patient. These are the things that you have to monitor based on research. Everything has to be checked to the letter, make sure that the

patient is getting desirable effects, not undesirable effects. You certainly don't want to give a supplement or product that is contraindicated in this setting. That that'd be that would be very dangerous and negligent.

or have influence on breath signaling. So this is how these things need to work together. You need to find the key nutraceuticals or key herbs. That you can directly align it with those faults in the genome and genetic pathways to be able to restore some um expression or restore some function to assist. in in those settings, you know, comprehensively. And the other thing I would like to mention, for example, is vitamin D. So

People overlook vitamin D. Vitamin D is very important. Actually the research has shown that high levels of vitamin D are associated with lower levels of recurrence of melanoma. So if you look at these little things, they're very, very important. Um or if I want to talk a little bit more about other nutracyticals, for example omega-3 fatty acids that we discussed earlier a little bit and we talked about them. So they affect

specifically not only affecting the butyrate producing microbiome pathways, they also reduce inflammation. So those would be uh key players as well. The other thing to mention is that um we don't want to forget about gut skin access. If there is dysregulation in gut skin axis that can straightaway um influence the immunity. And it will make the environment permissive for the tumors to thrive and to grow and be happy. So it's very important to

mention these things. And one other thing, for example, there are specific strains of bacteria that reside in the microbiome, for example, acumensia or ifidose. bifidos, acumencias, research has shown that people ha who have got more of these restrains in their microbiome, they actually are responding better.

to immunotherapy actually not having these agents these strains of probiotics so microbiome is paramount to be considered um and the fact that you need to make sure that uh you're helping the repopulation of certain uh strains of these probiotics is fundamental.

patient is already been educated on that code. Also the handheld devices such as dermoscopy or dermatoscopy, um, so they basically help with identifying and viewing their skin lesions in a magnified view and that reveals some uh pattern of pigmentation and vascular structure and that's a beautiful non-invasive measure that people use.

Also um confocal microscopy um and that will allow the optimal um optical imaging that uh gives the cellular detail and that can help reduce the unnecessary biopsy, for example. Um and it gives a better margin assessment and use it's very useful for uncertain lesions because when you look with naked eye you can't decide whether this is something you need to worry about or not. So why not?

um visualize it on the Lacon focal microscopy to give you a much better idea as to what's happening. Also, other tools that you can use is the 3D total body imaging and sequential monitoring of that. So that would also be of importance. Or if for people who live in remote areas, a smartphone uh would be of importance because they can just take a shot. and send it to the specialist for evaluat evaluation if there's something that is suspicious.

Finally, OCTs or optical coherence tomography to capture cross sectional views or slice images. of skin and that can reach deeper levels of the skin. And it gives you much better reading and much better ideas of uh of how things

can't reiterate enough. Like you don't realise how damaging it can be until it's like anything, you don't realise how damaging it can be until you are personally affected by it. So and also understand that it's that early stage in life where you probably are gonna be um most affected, but you won't know until later on in life. So

There's there's nothing healthy about the sun. I mean the sun will just literally um it'll it'll burn your skin, it'll damage your skin, it'll you know, you know, make you age a lot earlier than you potentially should and then ultimately you can get skin cancers uh you can obviously get BCCs, SCCs, but you can also get melanomas. And if you don't pick them up sometimes melanomas can be really, really tiny. Obviously I had that birthmark at the back of my leg that that obviously went malignant.

You don't you just don't want that m you know, you you don't want the option of that because clearly that's, you know, when your life is endangered and you you you don't want that. So just think about that as a young as a young person or for me now, looking back as a as my younger self, I was bulletproof. I I was gonna be fine. Why wouldn't I be in the sun and

That's okay, I'll deal with it later when I get older, which is a really silly attitude, unfortunately. Now I'm sort of paying the price a little bit, and uh yeah, it's definitely, definitely not worth it.

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