Encouraging Conversation

Many dermatologists do not refer cutaneous squamous cell carcinoma (cSCC) patients for radiation as frequently as the guidelines indicate we should. When I worked at an academic medical center with radiation oncology as part of our multidisciplinary skin cancer tumor board, it was straightforward to refer patients for conversations about the risks and benefits of postoperative adjuvant radiation. When I transitioned to community practice, I had to develop new relationships with our local radiation oncologists. My colleagues and I have observed that without a strong line of communication, radiation oncologists may assume that every patient referred to them should be radiated, which subsequently leads Mohs surgeons to refrain from referring anyone other than very high-risk patients.

When there is open communication between the patient, Mohs surgeon, and radiation oncologist, the discussion can be tailored to the patient’s individual radiation benefits and risks. 

I am proud to be part of research that is bringing radiation into the conversation by validating the 40-gene expression profile (40-GEP) test to identify patients who would be most likely to benefit from radiation therapy after surgical removal of their tumor. I hope that the population of preventable recurrences or metastases that we miss with current staging systems can be identified with the addition of this test. While we know that radiation benefits patients with very aggressive tumors, there is a population of less aggressive tumors that we are missing. If we add high-risk biology to our referral algorithm, we may actually find those bad actors and prevent their poor outcomes.

Changing practice patterns is challenging, especially for those of us who have been in practice for many years. As dermatologists, we tend to underestimate the incidence of SCC recurrence, because oftentimes when these tumors recur, the patient does not come back to us. They may be referred instead to a head and neck surgeon or academic medical center for their treatment. 

Overall, my hope is that the data from the articles discussed in this supplement will help dermatologists refer thoughtfully for adjuvant radiation, so that we can improve outcomes for our patients with high-risk SCC.

Sarah Arron, MD, PhD

Mohs micrographic surgeon

Palo Alto Foundation Medical Group

Association of a 40-Gene Expression Profile With Risk of Metastatic Disease Progression of Cutaneous Squamous Cell Carcinoma and Specification
of Benefit of Adjuvant Radiation Therapy 

doi.org/10.1016/j.ijrobp.2024.05.022

SUMMARY

This study investigated whether the 40-gene expression profile (40-GEP) could identify patients who would benefit from adjuvant radiation therapy (ART), in terms of reduction of regional or distant metastasis. The study included 920 tumors with at least one high-risk feature by National Comprehensive Cancer Network (NCCN) guidelines. Among those not treated with ART, 496 were Class 1, 335 were Class 2A, and 33 were Class 2B, while among the ART-treated patients, 11 were Class 1, 35 were Class 2A, and 10 were Class 2B. To control for high-risk characteristics and treatment selection bias, randomly sampled pairs of matched ART and non-ART patients comprising 10,000 resampled cohorts (to enable use of all matched patient pairs) were each analyzed for 5-year metastasis-free survival and predicted time to metastatic event.¹

After matching for clinicopathologic risk factors, median 5-year disease progression rates for resampled cohorts demonstrated approximately 50% improvement for Class 2B ART-treated compared with ART-untreated cohorts. The Class 2B cohorts treated with ART had a five-fold delay in predicted time to metastatic event and deceleration of disease progression compared with untreated cohorts (Kolmogorov-Smirnov test, P < .01), though this was not observed for patients with Class 1 or 2A cutaneous squamous cell carcinoma (cSCC) (P > .05 for each). No risk factor or staging system combined with ART status identified groups that would benefit from ART as well as 40-GEP.1 Figure 1 shows the median risk of metastatic disease progression in Class 1, 2A, and 2B cohorts with and without ART.

DR. ARRON’S COMMENTARY

When we published the original validation of the 40-GEP test for predicting metastasis, the primary question that my colleagues asked me was what to do with these new data. What they meant was: Which questions can this information help me answer beyond knowing the prognosis of the patient? The answer is that there are many practical utilities for the test at many stages along the cSCC patient’s journey, ranging from the primary dermatologist trying to assess the best treatment for the patient after biopsy to the surgeon trying to assess which imaging or workup might be appropriate along with the surgery. Personally, the primary question I struggle with is determining which patients would benefit from adjuvant radiation. The guidelines that we have are fairly broad and nonspecific; they simply recommend that patients who are at high risk for metastasis should be referred for consideration of radiation. However, radiation is not an easy treatment. The standard regimen involves 30 sessions over 6 weeks, 5 days a week. For patients who have tumors on the head and neck, the procedure is often at best uncomfortable or at worst traumatic. It is also not available everywhere, so some patients need to travel a long distance. All of that led me to ask myself frequently: When should we be recommending adjuvant radiation after surgery? 

Research has shown that radiation reduces local/regional metastasis in Brigham & Women’s Hospital (BWH) high-stage patients.² However, these data do not address lower-stage patients with other NCCN high-risk features such as immunosuppression or acantholysis. Could this test help determine which high-risk patients will benefit from it, and which patients might have the option to defer radiation? In those patients who are on the borderline of being radiation appropriate, could more information help us identify whether the benefits outweigh the risks? The 40-GEP test initially was not designed or validated to look at radiation, specifically, but in my mind, the utility of the test is in how we apply it to these clinical questions.

It is not only helpful to know when a patient will benefit from radiation. The converse side of the story is when patients want to defer radiation. This is a very common situation that comes up after Mohs surgery: An elderly patient with a clinicopathologically very high-risk tumor is referred for radiation, but they have other circumstances that would make radiation challenging. Perhaps they have other health problems. Some of our elderly patients just do not have sufficient access to transportation, especially if they do not live near a major radiation oncology center. Sometimes, it is just patient preference—especially with older patients, they may say that they really just do not want to undergo adjuvant radiation, even if it would reduce the risk of recurrence. In those situations, I can utilize 40-GEP testing because if they are Castle Class 1 (low risk), that gives me one small piece of reassurance. It does not make the patient any less appropriate for radiation, but I would not push as firmly as if they turned out to be a Castle Class 2B (highest risk). I think a number of doctors are using the test in that nuanced setting of incorporating patient preference in the decision for radiation. 

 1. Arron ST, Cañueto J, et al. Association of a 40-Gene Expression Profile With Risk of Metastatic Disease Progression of Cutaneous Squamous Cell Carcinoma and Specification of Benefit of Adjuvant Radiation Therapy. Int J Radiat Oncol Biol Phys. 2024;120(3):760-771. doi: 10.1016/j.ijrobp.2024.05.022. Epub 2024 May 27.

2. Ruiz ES, Kus KJB, et al. Adjuvant radiation following clear margin resection of high T-stage cutaneous squamous cell carcinoma halves the risk of local and locoregional recurrence: A dual-center retrospective study. J Am Acad Dermatol. 2022 Jul;87(1):87-94. doi:10.1016/j.jaad.2022.03.044.

Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the  40-gene expression profile 

doi.org/10.1080/14796694.2024.2390820

SUMMARY

This study validates the previous paper and expands on the findings. In this study, primary cutaneous squamous cell carcinoma (cSCC) tumors from two academic centers received retrospective 40-gene expression profile (40-GEP) testing and were analyzed for both 5-year metastasis-free survival and projected time to event.¹

A total of 423 tumors from 399 unique patients were included for analysis. Tumors had at least one of the following risk factors: tumor diameter ≥2 cm; poor or moderate differentiated histopathology; >6 mm depth of invasion or invasion into or beyond subcutaneous fat; small or large caliber perineural invasion (PNI); lymphovascular invasion (LVI); or desmoplastic subtype. Fifty-two tumors were treated with adjuvant radiation therapy (ART), and 371 were not treated, with a median follow-up of 3.0 years and 4.15 years, respectively. The 40-GEP results for the ART-treated tumors included 20 Class 1, 24 Class 2A, and eight Class 2B; for the untreated tumors, 208 were Class 1, 144 were Class 2A, and 19 were Class 2B.¹ The overall metastasis rate for the cohort under study was 9.7% (95% CI of 6.9–12.5%; 9.2% for regional/nodal metastases and 2.4% for distant metastases). 

Analysis was performed with the same methods described in the initial paper. This cohort demonstrated a similar 50% decrease in metastatic disease progression in the Class 2B tumors treated with ART, compared to untreated tumors. In addition, the Class 2A tumors treated with ART had a statistically significant, albeit modest, benefit of 16.6% decrease in metastasis compared to untreated tumors. A control analysis demonstrated that Class 2A benefit may be attributed to the regions addressed by ART (nodal basin and/or tumor bed radiation). No significant benefit was detected in Class 1 tumors.¹

DR. ARRON’S COMMENTARY

What is really interesting about this article is the ability to compare and contrast it with the other paper. The previous study had a bigger population, but it was broad; some of those patients never would have been eligible for radiation under any guideline. Fewer of them—approximately 6%—were radiated. The second study had a much higher-risk population, so more of the patients had radiation. Additionally, this study was conducted at two academic medical centers, whereas the previous one was done at 59 centers in different settings. 

The fact that both showed a significant reduction in risks when radiating patients with Castle Class 2B (highest risk) tumors is incredibly encouraging. I cannot stress enough that Castle Class 2B tumors are very high-risk tumors; I have heard anecdotes from many dermatologists observing Class 2B tumors progress rapidly. So, the opportunity to intervene on those is the most important takeaway. 

The difference between these two papers is that the second study detected a smaller but significant benefit to the Class 2A patients.  In the publication, the authors hypothesize that this difference may be due to the type of radiation delivered, but my interpretation is that this is potentially because the tumors in this study were higher risk, and therefore the study was powered to detect this smaller difference. 

My interpretation of these data is that a patient who is Brigham & Women’s Hospital (BWH) stage T2a, or has LVI or moderate differentiation, and is also Castle Class 2A will benefit from adjuvant radiation. This is where we can really move the needle with a larger patient population. Most Mohs surgeons will refer a BWH T2b tumor for ART, but not necessarily a T2a unless there is extensive perineural invasion. By testing BWH T2a tumors, we can identify the Castle Class 2A or B tumors that may be better candidates for radiation. The key is that these two factors—clinicopathologic staging and Castle Class call—both need to be considered, because they are designed to be determined independent of each other and they provide different information to the doctor.

I like to use a three-by-three table that incorporates both BWH T stage and Castle Class call into the metastatic risk calculation. With both sets of data points, I can make one of three recommendations: Definitely refer for radiation, consider radiation, or it is likely not beneficial to radiate.  

I find the utility of this test in the decision-making process invaluable. Even though the test is relatively new and has not yet reached national guidelines, I like to think of a Castle Class 2A/B as another high-risk feature that doctors can integrate into National Comprehensive Cancer Network (NCCN) management or their own personal management. It is completely independent from what we know when we stage a tumor, and now we see it can help with practical decisions that surgeons and radiation oncologists are making frequently. 

In conclusion, 40-GEP testing has become a standard of care in the oncology community, but perhaps not yet in the dermatology community. The cost of testing is not insignificant, but when we are making decisions about radiation—which has not only a significant cost to the healthcare system relative to a genetic test but also a significant cost to the patient—it can really be worthwhile. Radiation is a major step, and we should take that step primarily when it is likely to help the patient. This tool to help determine that likelihood has significant value. 

1.  Ruiz ES, Brito K, et al. Predicting adjuvant radiation therapy benefit in cutaneous squamous cell carcinoma with the 40-gene expression profile. Future Oncol. 2024;20(35):2737-2746. doi:10.1080/14796694.2024.2390820. Epub 2024 Sep 4.