In this interview, Dr Vishal Patel discusses recent advances in high-risk cutaneous squamous cell carcinoma (CSCC), focusing on gene expression profiling (GEP) and promising treatment approaches. He highlights the evolving role of GEP in risk assessment and treatment decision-making, emphasizing the need for personalized approaches based on genetics, disease characteristics, and patient factors.

Vishal A. Patel, MD, FAAD, FACMS is an associate professor of Dermatology and Medicine/Oncology at the School of Medicine & Health Sciences, George Washington University in Washington D.C.

Transcript:

The Dermatologist: What recent advances have you seen in high-risk CSCC gene expression profiling (GEP)? How do these impact diagnosis and treatment?

Dr Patel: Great question. Genetic expression profiling and personalized risk stratification is becoming more commonplace across all cancers and all tumor types and high-risk cutaneous squamous cell carcinoma is not any different. It certainly is one of the newer malignancies that are seeing the incorporation of genetic expression profiling. And it's one that clinicians should be thinking about and potentially be incorporating that into their workup.

Now, it's very early on in the journey of cutaneous squamous cell carcinoma and gene expression profiling. You know, we're in the early phase where we are just really beginning to understand the types of genes that play a role in the behavior of the tumor and how we can measure and then make actionable decisions based on that.

There is currently a commercially available gene expression profiling test and there's a number of other tests being developed and this is an area that I believe the next 5 to 10 years is going to see robust attention and development in as we get a better understanding of how we can utilize gene expression profiling with our patients.

Specifically, I utilize a number of different ways to think about genetics and genetic expression profiling. What I'm most excited about is recently there's been the development with colleagues based in the Netherlands at Erasmus Medical Center in Rotterdam who have developed an online simple calculator with a number of risk factors that you can input and get a quantifiable risk of your patients, risk of metastases at one, three, and five years.

Dr Marlies Wakkee and the group at Erasmus medical center have published and now this online calculator is easy to access, is free for all clinicians, and if you're in front of a patient and just quickly trying to understand the risk of a patient right in front of you, rather than ordering any type of test that you have to wait for, this is a really useful tool to just help provide some concrete, quantifiable risk numbers to think about how you might treat a patient.

Now, other more formalized gene expression profiling tests, including ones that you can order are on the market. And while that data is very robust and helpful as we predict the risk of metastases at three years, we're only beginning to understand how to incorporate that into the decision-making process. Specifically, there are not clinical trials that have been done to evaluate whether specific decisions made based on the test result score positively or negatively impact the patient.

And so that should be still mindful within the mind, be kept in the mind of the clinician as we think about what to do with that test result score. If you have a high-risk profile score, does that mean the patient needs to come back more frequently have radiologic imaging, or would even consider doing more aggressive therapies such as radiation therapy, or all ideas that have been proposed, but we clearly need more concrete evidence before we can generalize that on a large -scale level.

That being said, I do consider and utilize these tests to help me understand a patient's risk if a patient, say, lives far away and can't come in frequently for a very long time or if we're trying to decide whether or not to add radiation to the patient. And in those specific scenarios, the test can be very useful. But as a whole, I don't think we're in prime time yet to be widely utilizing gene expression profiling for most, if not all, of our patients, because we do have a good understanding of risk for the vast majority of patients that dermatologists do see and that most of the cutaneous squamous cell carcinoma malignant are low risk. And those that are high risk, we often are already deciding and convinced that we need to do surgery plus potentially radiation at that point and it may not change our decision pattern.

So a lot still to come from this, but certainly this is where the future is going and we're moving from the analog representation of just staging a tumor with just three or four risk factors to thinking about a more dynamic digital version of how that tumor is going to behave and predicting that risk and as a result be able to offer personalized treatment for them.

The Dermatologist: Could you discuss promising new treatment approaches for CSCC? How do they compare with standard therapies in terms of effectiveness and safety?

Dr Patel: It's an exciting time for squamous cell carcinoma because there's been recent developments both on the prognostics side, we've talked about the gene expression profile, but also very exciting data on the treatment side. One of the most new exciting pieces is the use of neoadjuvant immunotherapy prior to surgery for high-risk resectable cutaneous squamous cell carcinoma or borderline resectable. And it really has changed, it's a game changer for how we think about these diseases, these disease presentation at this stage.

Traditionally, these are, this is the gamut of high-risk tumors, large tumors, deeply invasive, or tumors that are presenting with nodal metastases at the same time. We know these are gonna be difficult to manage and require multidisciplinary care, but traditionally we've managed them with large and disfiguring surgeries, plus the combination of radiation therapy, since these tumors have a notably increased risk and surgery alone is unlikely to cure to them. Well, what's most exciting is the data in the last 18 months, recent publications showing the use of neoadjuvant, meaning before surgery, immunotherapy, up to four doses of cemiplimab, IV therapy, can lead to a remarkable, remarkable response of the tumors. And in fact, greater than 50% of tumors had complete responses and almost two-thirds of patients were major pathologic responders, so less than 10% viable cells.

And this is really remarkable results for just four doses. of immunotherapy. What's more remarkable is that the patients, the way the trial was designed, they still needed to undergo surgery so that we can assess the level of response, and how much of the tumor had completely shrunk on a histologic level. Of those patients that were either major responders or complete responders, the durable response, the event-free survival, and the metastatic-free event rate is dramatic. Over 90%, 95% depending on which specific group you're looking at, and these are unheard of numbers as we think about this really high and aggressive and risky disease at this stage.

This has really changed our mindset, at least my mindset and the approach for how to manage these tumors and now thinking about these tumors when they present at that advanced stage, we're considering whether they are candidates for this neoadjuvant immunotherapy approach of systemic therapy first and then surgery to help us determine whether or not the patient needs more systemic therapy afterwards, or maybe they do not and they don't need radiation therapy and only that surgery and few doses of immunotherapy is sufficient to have that long-lasting cure type of response that we look for in oncology.

This is also changing how we think about risk stratification because we may not need to predict what's going to happen down the line if we're getting such a robust responses from a small initial therapy that a lot of the patients present at this point where the horse is out of the barn. We know it's an advanced disease already. We're not worried about predicting whether or not they'll recur. We're trying to get that deepest response from the first surgical get-go. And we now really are seeing data that supports that.

And I know in the next few years, there's already so much work being focused on perfecting that neoadjuvant regiment that they're really is going to become part of the place for most providers and patients.

The Dermatologist: How do you incorporate genomic information like GEP into your clinical decisions for patients with high-risk CSCC? What challenges do you face, and how do you address them?

Dr Patel: As I mentioned previously, it really is paramount for any clinician to stage a risk stratify tumors, aggressiveness, and risk. And traditionally we've done that with staging systems and then in the last decade, we've put so much work on improving the cutaneous squamous cell carcinoma staging system, both with the advent of the alternative Brigham Women's Hospital staging system as well as the improved AJCC 8^th edition.

Those staging systems are certainly useful at identifying the low-risk tumors and does identify a number of the high-risk tumor cohorts. And on first pass, for most tumors that the clinicians will see, this can be a sufficient approach for risk stratification. There's still work going on refining those systems. And in fact, both those systems in the last 12 months or so are undergoing refinement as those risk factors are better defined as how they can predict risk, but we still have gaps in our knowledge of how a tumor is going to behave. Those are not perfect systems and that's where gene expression profiling really fits in.

It provides a more dynamic picture of the tumor and the tumor's genetic expression to help predict how risky that tumor will behave and whether it will recur or not only metastasize or distantly metastasize at different time points.

But those tumors, for my standpoint, are the ones that fall into that gray zone. It's a small cohort where they're on the border line of not the obvious high -risk tumors or the obvious low-risk tumors. And those tumors in that, in-between gray zone, this is a useful extra data point. It helps push those tumors either downstage or upstage them by more complete looking at that genetic expression and that's where I utilize them. So we're talking about Brigham and Women's T2A tumors or T2B tumors. Those risk factors that maybe are not included in Brigham and Women's Stating Systems or the AJCC T2 or T3 tumors as well as those risk factors, for example, lymphovascular invasion, or quarterly differentiated tumors that are AJCC T2, because that risk factor is not included in that staging system.

This is a prime place to utilize GEP because we know that's where the staging systems are incomplete in their risk assessment. And when the clinician is worried rapidly growing immunosuppressed patients, we just have a belief, you know, our clinical judgment tells us something is wrong. Certainly think that is a useful place to utilize gene expression profiling.

The difficulty, however, is that we're still early in the phase of knowing what to do with that data. And there are not concrete trials to tell us, should we provide radiation? should we provide systemic therapy, should we more aggressively radiologically image those gene expression profile scores that are high risk, or can we do the converse for those that are low risk? We're beginning to get, and there's in the last 12 months or so, great literature showing that there is data that corroborates that the risk protection is accurate and we may be able to make treatment decisions based on that.

Dr Sarah Arron has lectured and spoken about some new and exciting data that's coming out and we're really excited to see that there is potentially data that shows that those patients that are high risk on the gene expression profiling scores may benefit from the radiation therapy and that other patients on the gene expression profiling score potentially don't have a benefit and this may help us decide to not radiate a patient or to radiate a patient based on these scores.

I specifically am not using the test rather sparingly because I don't have that concrete information of what to do with the test result, and I asked myself first, is this test going to change my treatment decision? And if I'm looking for that information, say I'm looking for a reason to not radiate a patient because they're old and frail and may not be able to tolerate it, then I think this test is really useful because we have that data that shows that that low risk score really does help us predict that they're likely not to do poorly.

But on the other hand, as I mentioned earlier, because we've seen this field move so rapidly and neoadjuvant immunotherapies entering in the field, it's really beginning to make me think about if this is the way that we are approaching treating these tumors, whether or not this risk prediction is as critical and important at that time point. It's really just too early to see and figuring that out is still going to take us a little bit of time, but I'm excited that in the next few years, I think we will have that kind of data that helps us really clearly say, maybe these are the patients who need to be seen every three months and get a PET scan or a CT scan every four to six months, whereas the lower risk patients don't need that. And if patients do recur, and maybe we can avoid radiation therapy and the patients do recur, well, we're going to move straight towards systemic immunotherapy because we have such a strong response and durable response rate in those patients and can truly save them that way.

The Dermatologist: When choosing treatments for CSCC, how do you tailor them to individual patients based on factors like genetics and disease characteristics?

Dr Patel: Just like with any tumor, it's critical to tailor the treatment based on the risk of a patient. That risk stratification is key. Whether you use that first filter pass as staging, and then you add it in genetic expression profiling to help give you further data points, understanding that risk is only half of the picture. The other half is just understanding the patient's tolerability and their goals. And so thinking about this as a whole, because we do have for cutaneous squamous cell carcinoma, a fairly limited number of treatment options, surgery, radiation, immunotherapy, and then when systemic immunotherapy fails, then we go back to the treatments of chemotherapy, either platinum-based or targeted chemotherapy. And so our treatment options are fairly limited in comparison to other tumor types, so to speak. That we really have to think about the patient as a whole. a whole and that risk stratification and understanding that risk helps us really determine whether or not a patient should have multimodal therapy depending on the risk of that tumor.

The other caveat to consider when thinking about how we provide a personalized approach for patients is also understanding that this is not just one tumor that they deal with oftentimes, cutaneous squamous cell carcinoma patients have a field effect across their skin and the risk relates not just to the one tumor you're seeing, but they oftentimes have multiple tumors and multiple tumors over many, many years. And so we're thinking about that whole journey as a whole. And so it's not just the surgical treatment of the tumor in front of you, but thinking about that whole patient, whether the patient is immunosuppressed and we need to think about their immunosuppression as well as what strategy we can invoke for prevention from a field cancerization treatment and management standpoint and thinking about either systemic or topical or light based therapies to help prevent that risk as well as prevent the risk of occurrence of the high risk tumor in front of us. But it certainly is a complex interplay. And the reality is, is that because we've lagged behind melanoma for so many years, that our risk stratification has not been as robust. And as a result, we don't have as many concrete trials that have looked at the specific question of does radiation help in what specific subset of patients? Do patient need to send a lymph node biopsy or not? Or when systemic therapy needs to be initiated at what time point to have the best outcomes? But hopefully that in the next few years we'll have a lot more clarity on that.

The Dermatologist: How do you stay updated on the latest research and guidelines for CSCC treatment, and how have you applied new evidence-based practices in your practice?

Dr Patel: Certainly, it's challenging to stay up to date on the guidelines, especially in a field that's evolving so rapidly. It feels like new data is coming out before you can fully digest and even apply the data that you've just absorbed or seen, heard about, or read.

One thing that I think is certainly helpful, other than the traditional conferences and meetings where you go to and see experts provide input of their approaches or lecture on the latest and greatest data that's coming out. I've found it really helpful that there are a number of nice high-quality CME, either symposium or online discussions of experts, multidisciplinary experts, medical oncologists, surgical oncologists, dermatologists or dermatological surgeons, most surgeons discussing this topic because high-risk uterine squamous cell carcinoma does not live within one specialty. It certainly is a disease process that is brought across the medical, surgical, dermatologic specialties.

And as a result, having all those experts together and discuss cases and new advances in a very comprehensive but succinct fashion, I think has been really great. And it's also great even as experts where we're comfortable with or we might be learning about this information in real time to see what our colleagues are doing and are there regional differences, geographic pattern differences that we may not consider based on where we are. So I urge you to if you don't have a chance to maybe learn about this topic or not going to a meeting where it's being discussed, then some of these really great CME programs, such as can be found on The Dermatologist or other sister organizations have convened the experts to provide a 45 minute or 60 minute in-depth discussion on this topic, really is a great way to stay up to date and then be able to apply that in your practice.

The Dermatologist: Are there any tips or insights you would like to share with your dermatology colleagues regarding GEP and high-risk CSCC?

Dr Patel: Yes, I mean, melanoma and nonmelanoma skin cancer for so many years have kind of been treated separately as two different disease processes.

What we're learning is that they're very, very similar and the types of approaches and responses we see with melanoma is what we are, applying and seeing that it works in squamous cell carcinoma and slightly, maybe slightly less so in basal cell carcinoma, but along the same way and also in merkel cell carcinoma. And so I think about this field of skin cancers, cutaneous oncology is all combined. And as I mentioned earlier, being able to see CME programs or have resources where experts are providing succinct updates is a great way to apply that across those fields.

And so it may not be relevant if you're not taking care of melanoma patients, but sometimes 30 minutes, 45 minutes in the car listening to either a podcast or a program, you'll begin to realize how that applies to non-melanoma skin cancer and vice versa. And these are really digestible bites of information, these CME programs.

So I really urge you that if you're interested in that to seek some of those out, because there really are some really wonderful programs across multi-specialty, multi-disciplinary experts discussing those topics.