MolDX: Molecular Biomarker Testing for Risk Stratification of Cutaneous Squamous Cell Carcinoma Open Public Meeting - July 18, 2023 - JE Part B

Kari DuPreez:
Well, welcome to the Open Public Meeting for the proposed LCD MolDx Molecular Biomarker Testing for Risk Stratification of Cutaneous Squamous Cell Carcinoma DL39589 for JE DL39594 for JF.

Before we begin the meeting, I would like to make the following announcements. This meeting will be recorded. The recording and written transcript will be posted on our website following today's meeting. All lines are currently being muted and will remain muted throughout the meeting.

Only those who registered to present, will be allowed to comment on the proposed LCDs today. For the presenters, you are being allotted 10 minutes to make comments. Your line will be opened when it is your turn to speak. Make sure you are not on mute within your system, or we will not be able to hear your comments. You should be prepared to begin your presentation immediately when called upon and we'll hear on the moderator's voice when one minute remains.

By signing in today, you are giving consent to the use of your recorded voice and your comments. Please be mindful of sharing any personal health information during your presentation. In addition to comments that are made today, all comments should also be submitted in writing. All written comments received will be recorded in the response to comments article.

I will now turn this meeting over to Dr. Barry White. Dr. Whites you may begin.

Dr. Barry Whites:
Thank you so much and I do appreciate the attendance and the comments and the presentations that we are going to be receiving today. This policy is one that will be part of the MolDx genre of policies as we members of that cooperative workgroup.

So, this policy drives and then from MolDx amd then comes to us for review and acceptance. This policy has been accepted, and it is a noncoverage policy as written and I'm not aware of any great changes or any changes in the policy versus the original MolDX proposed policy.

The summary of evidence on this, and first of all an introduction to those who are listening, and I'm sure the experts know this by heart, this is an epidermal keratinocyte-derived malignancy. It is the second most common skin cancer behind basal cell. It has higher incidence in areas of the greatest sun exposure, such as here in Mississippi, where I'm located.

Each year there are approximately 700,000 new cases that are diagnosed, with 5,600 to 12,600 patients developing nodal metastases. The incidence is highest in non-Hispanic white population, males greater than females. Mean age of diagnosis is seventy-one right in the middle of our Medicare population, and chronic sun exposure is the most important environmental risk factor in less-pigmented skin types.

The summary of evidence shows that a highly pigmented skin individual, they're more frequently found and non-exposed areas, in contrast to those who have light skin often associated with chronic inflammation, chronic wounds, or scarring.

The etiology is more difficult in this type of squamous cell carcinoma is more difficult to treat and exhibits a higher recurrence rate than in lighter skin individuals.

The overall prognosis five-year survival is about 98%. The risk of nodal metastasis varies on the study and tumor registry but between 1.2 to 5.8% is the nodal metastasis and the risk of death is approximately 2%. This is not considering those patients who have had Mohs surgery, with the local recurrence rate is that of about 2.5%.

Metastatic disease down to 1.9%, in contrast to a death rate of 2%, with Mohs surgery's death rate of about 0.5%, so, it does make a difference with appropriate restrictions.

The approach to risk stratification in staging, have currently have limited positive predictive value on the studies that were reviewed at the time of this publication. The most utilized staging and system guidelines include, I'm sure all of our presenters are familiar with the NCCN the National Comprehensive Cancer Network, AJCC which is the American Joint Committee on Cancer 8^th Edition Staging System for head and neck tumors and the BWH, Brigham and Women's Hospital staging system.

The data to date suggested that the AJCC suggested to upstage low risk disease whereas the Brigham Women's Hospital is superior in identifying those low risk patients.

The predictive biomarkers in any present profile have been used to improve risk prognostication and clinical decision-making in other types of cancers. Several are in development to improve risk stratification for cutaneous squamous cell carcinoma with the goal of bolstering the information provided by the various staging systems.

Further studies have felt to be required to determine clinical validity and clinical utility, particularly clinical utility, with the definition of clinical validity is how well the genetic variants are being analyzed is related to the presence, absence, or risk of a specific disease. Clinic utility is whether or not if a test can provide instrumental information about diagnosis, treatment, management, or prevention of a disease. Announcement of the evidence show that [unrecognizable] is capable of metastatic risk stratification, but it's unclear how the results can be consistently and accurately interpreted in the context of baseline clinicopathologic risk of the comprehensive risk assessment to change patient management. In otherwise, clinical utility is lacking in what we have seen. Test performance has not convincingly demonstrated superiority to currently available staging tools and clinicopathologic factors in the intended use population.

Currently available published literature, again at the time of this publication, does not describe test performance in a patient population with the exclusion criteria proposed by the test manufacturer. Inclusion on this proposed LCD is, although this clinical utility need for molecular markers to improve risk stratifications, the currently evaluated test at the time of drafting this policy have not yet demonstrated definitive value above a combination of the available clinical, pathological, and staging criteria that is currently used to assess risk.

Therefore, clinical validity and utility have not yet been established for this type molecular risk stratification for cutaneous squamous cell carcinoma. Contractors will continue to monitor the evidence and may modify coverage based on new information in the pertinent literature and society recommendations.

Another reason today for this open meeting is to get others' opinions as we don't always get all the information that we think we have. So at this time, I'm going to ask that we begin our presentations from our speakers.

Our first speaker is Dr. Aaron Farberg from University of North Texas Health Science Center in Bare Dermatology in Dallas, Texas. Dr. Farberg please go ahead.

Can you unmute yourself?

Dr. Aaron Farberg:
Can you hear me now?

Sorry, I was forced unmuted by, I believe the system, can you all hear me?

Dr. Barry Whites:
Yes, sir. We got you now. Thank you very much for being persistent.

Dr. Aaron Farberg:
Yes.

Ah, you know, technology nowadays. So, first of all, I want to thank, start by thanking the Noridian Medical Directors , and you, of course, Dr. Whites, for the opportunity to provide my comments. Clinical utility, you gave me the perfect segue. But my name is Aaron Farberg. I'm a board-certified dermatologist, and most certain here in Dallas, Texas I'm also an assistant professor at UNT, where I'm core faculty with the residency training program we have this year. As well as assistant program director, now, I have participated in research both independent and collaboratively with the company Castle Biosciences and have acted in a paid advisory role. But I am not conflicted and providing these comments today or participating in today's discussion.

Next slide, please.

So, don't see it advancing.

There we go. All right, so, you know, the current draft LCD that non covers, DecisionDX-SCC test, the 40 GEP, it misses the mark in several areas. And I'm going to provide my reasons as to why this test should be covered for the sake of our high-risk squamous cell patients. First, while reading this draft LCD, one of the areas that stood out to me as incomplete was really the literature review.The draft here incompletely evaluates and it doesn't even site several publications that actually articulate consistent management algorithm incorporating the decision DecisionDX-SCC test, the 40 GEP test results, into the context of staging information and then we can make specific management changing recommendations for those patients. So, you know, the statement that the LCD states here, that quote, "it is unclear how GEP results", I believe you said this to Dr. Whites, as "it is unclear how GEP results can be consistently or accurately be interpreted" is the result of incomplete and, you know, in my opinion, flawed evidence review and is simply unfounded.

Let's go to the next slide, please.

So, this next slide continues with additional limitations, in the same LCD section here. There's a brief summary of the NCCN guidelines that it does not capture the full range of management considerations for these high-risk squamous cell patients. You know, our Doctor's metastatic risk assessment really informs a broad range of management changes for these SCC patients with high-risk and even very high-risk factor tumors. There's also some confusion within the draft LCD about the efficacy of specific management strategies. Specifically, there are statements that, for example, sentinel node or adjuvant radiation therapy may not improve outcomes, which is in direct contrast to the broad use of these interventions in patients and really, the fact that these interventions are covered by you, covered by Medicare today.

These statements conflict directly, with other aspects of the LCD that describe a consensus from academic centers on the use of imaging sentinel node, radiation, follow up, and the current management strategies outlined in the NCCN guidelines, are I'd say firstly they are aligned to the patient's risk of poor outcomes. including the risk of metastasis, which the 40 GEP helps us with, and second, they're included in guidelines based on really their ability to improve these patient outcomes.

Next slide.

All right. So, a critical limitation of the LCD is that it focuses/references exclusively to academic medical centers but really misses the fact that most clinicians actually use risk factor-based stratification in addition to formal staging and really more than half of this section discusses a single survey published by Patel,et al. of 156 physicians. However, really important results were omitted from this review. The survey is used really by the LCD to establish that most dermatologists and cancer specialists use staging, but they admitted that very important data point that a large number of respondents reported that they do not, they do not use staging systems to help consider whether or not to perform imaging, sentinel node, radiation, all others are of management and that was from the paper.

Next slide.

So, a published counterpoint to this this academic only perspective from Patel could be found in a clinical impact study with a survey, which is by the way, very similar to Patels that was not cited in the draft LCD and it's this paper from Dr. Litchman that was published 2022 and included 162 dermatologists who made relative importance of the GEP results with other clinical and pathologic risk factors and importantly here the class 2B was found to be the most important risk factor. Just says, doctors use clinical and pathologic risk factors to evaluate our patient's risk of having a poor outcome. The 40-GEP test result can also be included as one of those risk factors to inform our risk aligned management decisions.

Next slide, please.

So, as it relates to the clinical utility of the 40-GEP test, it's really clear from the published literature exactly how GEP results can and are being used in the context of these clinic pathologic risk factors that result in changes in our management. So, the LCD has mentioned earlier, asserts that well, it is quote "it is unclear how GEP results can be consistently or accurately interpreted" but this statement is just difficult to justify, is actually the answer is readily available, available in my own paper. Farberg, et.al., published in CMRO in 2020. The proposed LCD reviews this paper, but they dismiss it as being quote out of date based simply on the fact that, well, we use the NCCN high-risk, instead of high-risk and very high-risk criteria.

So, you know first it's important to point out here that the NCCN high-risk, it was the current NCCN competitor or comparator at that time, when this paper was peer reviewed and published and yeah, there was a three-year delay in the evaluation of the test, and this should not allow for the dismissal of the clinical utility evidence. Also, the changes in the NCCN guidelines do not negate the actual clinical utility findings in that manuscript. The only difference is how NCCN further subdivided the categories of high- risk and the treatment, by the way, of both of these high-risk and very high-risk is the same.

Next slide, please.

So, in addition to the consistent clinical utility evidence around this minor shift in the guidelines there is also consistency in the clinical validity test and here Ibrahim 2021, there's additional clinical validity analyzes that confirm this and the maintenance of this stratification and independence of the 40-GEP within the NCCN high-risk and very high-risk subsets.

Next slide, please.

Now, the consistency from clinical impact studies and expert panels really does demonstrate that this 40-GEP can be interpreted in the context of our known risk factors and these next few slides, which I'll go through quickly, point out the specific publications. You know, here's the figure from Farberg, et.al. which directly answers the medical directors' questions here, about how the results can be consistently and accurately interpret this this figure essentially bins the various management recommendations and recommendations from the NCCN guidelines and splits it into low, moderate, and high intensity plans.

Next slide, please.

All right.

And, you know, there's consistency in this or approach as it was also [inaudible] there's been another article by Dr. Sinh, and the management algorithm is fairly similar and is updated to include those new

NCCN high-risk and very high-risk groups.

Next slide.

And here's another expert panel coming up here that was published, recommendations for high-risk results and are nearly identical to the preceding two publications with their management algorithms. Again, they take several management recommendations from our guidelines, and they match them to the outcomes of the 40-GEP for that risk aligned treatment plan.

Next slide, please.

And, again, the published clinical utility data, it demonstrates clinical use is consistent with algorithms and other expert panels here, specifically that their test results are interpreted appropriately and consistently. So, a patient that's BWH T2A SCC, a class 1 result, from the 40-GEP is associated with a decrease management intensity and T2b is associated with an increased management intensity.

Next slide, please.

Now, another study that I believe is not completely reviewed was the for the LCD was this one from Hooper. The LCD sites the real-world data from this paper, but it really doesn't discuss the impactful clinical utility aspect of the manuscript. This paper evaluates both in the overall management strategy changes, as well as the specific management changes for 6 real-world cases of patients that were treated with the 40-GEP and oh, by the way, the management changes by the GEP changes by the GEP results and Brigham Women's T stage. They align with the management algorithm in my paper Farberg, et.al. CMRO in 2020.

Next slide.

And on this, on this last slide, covering specific data reviews for the final LCD. I want to highlight that there's another recent manuscript and is in final preparations, so not submitted quite yet, but it comes from the recently convened Skin Cancer Prevention Working Group, which is a group of dermatologists, who all spent at least one year in additional fellowship, focused entirely on skin cancer, and the expert panel achieved an evidenced based consensus statements in supporting the use of the 40-GEP test after there was a structured review of the published literature, as well as both, you know, the SCC management in general, and then that recently developed molecular tests, in this case, the 40-GEP, once, it's completed and submitted for review I'll gladly submit the manuscript to the medical directors.

Next slide, please.

All right, we made it to the end. Here's my conclusion slide highlighting the main points I just laid out. I'm not going to um, you know, take up your time being repetitive here.

But I do hope that the medical directors can consider positive coverages, we all continue to try to do what is best for our patients diagnosed with high-risk squamous cell carcinoma. Thank you again so much for your time and appreciate your comments.

Dr. Barry Whites:
Thank you so much for your presentation.

The points that you make, please put that in writing for us, that you mentioned at the beginning, also copies full copies of the article that you mentioned that were not appropriately represented in the draft LCD. All of those will be answered by MolDX group considering your comments as well as others that will be submitting today. I did not, I heard briefly when you first presented a statement about no conflicts of interest [inaudible]…

Dr. Aaron Farberg:
Can you repeat yourself, your microphone blanked out there.

It's been going in and out. Hello?

Dr. Barry Whites:
Dr. Farberg, could you hear me?

Dr. Aaron Farberg:
Nope. You sounded very faded away. Like the far distance.

Dr. Barry Whites:
I'm sorry.

Is it better now?

Dr. Aaron Farberg:
Yes. Perfect.

Dr. Barry Whites:
O.k., good, yeah. Please submit your comments, your recommendations, as well as the full article that you referenced that you feel were not represented in our current review and those who are presented to the MolDx group itself and all of these will be answered in our file document. The other thing is that I had heard you mention very briefly something about conflict of interest, but that could not understand. Would you, would you please restate again any conflicts you may have?

Dr. Aaron Farberg:
Yes, absolutely. I have participated in research both independently and along with collaboratively with the company Castle Biosciences, which is the maker of the 40-GEP tests. And I have acted in a paid advisory role, but for my comments today and my participation today, I'm not getting paid. I'm not conflicted in any way, that way.

Dr. Barry Whites:
Thank you so much. I really appreciate the presentation. Thank you, sir.

Dr. Aaron Farberg:
Always, no, thank you so much, sir for your time.

Dr. Barry Whites:
Next, will be Dr. Matthew Goldberg, Senior Vice President of Medical Castle Biosciences. Please state your, which I think is an obvious one, but please state your conflict of interest before beginning your presentation, if you wouldn't mind.

Dr. Matthew Goldberg:
Absolutely. Can you all hear me?

Dr. Barry Whites:
Yes. Sir.

Dr. Matthew Goldberg:
So, before I begin, I plan here to provide about just under 15 minutes of comments. Here, I just wanted to verify with the organizers that that's still OK on timing here before I get started.

Kari DuPreez:
Yes, Dr. Goldberg. That's fine. Thank you.

Dr. Matthew Goldberg:
OK. Thank you so much. I appreciate that and Dr. Whites, I'll start with my conflicts of interest here. So, as listed here on the slide, I'm Senior Vice President of Medical here at Castle Biosciences. where I'm a full-time employee and stockholder.

By way of introduction as well, I'm also a board-certified dermatologist and dermatopathologist. And my comments this afternoon here on behalf of Castle Biosciences support our assertion that the DecisionDX-SCC Gene Expression Profile test, or GEP test has met criteria of medical reasonableness and necessity for Medicare coverage, and we believe should be included, therefore, as a covered test, in the final policy.

Next slide, please, if you don't mind.

OK, we'll move on to the next slide, and also just, I started with conflicts, but I really should've started with, thank you, thank you all, for the opportunity to speak here at the public meeting and provide these comments.

By way of brief background, Dr. Whites, you started with a discussion of the disease state.

The DecisionDX-SCC test really addresses limitations of risk stratification approaches that are currently used by skin cancer experts across the country. It helps physicians navigate the wide range of management options that are available to all patients after they've been diagnosed with a high-risk squamous cell carcinoma.

Risk stratification approaches rely on the presence or absence of clinical or pathologic factors alone actually misclassify a significant number of patients with cutaneous squamous cell carcinoma.

At least 30% of patients who go on to experience regional and distant metastasis are actually found to be at low stage at initial diagnosis, and on the flip side, not all patients who present, initially with high stage disease will actually go on to experience poor outcomes. Like regional and distant metastases.

DecisionDX squamous cell carcinoma is clinically validated solution to these well-known limitations of staging approaches.

Next slide, please.

So, the draft LCD contain statements that reflected incomplete understanding for how high-risk SCCs [inaudible] today by skin cancer experts. At a high level, the LCD contains multiple inaccuracies that invalidate the conclusions of the draft policy.

These include misconceptions that high-risk SCC are treated solely in academic settings and really misses the fact that patients are also treated in community practices across the United States (U.S.) where methods of risk assessment vary widely from practice to practice, due to, again, they're known limited accuracy.

It's critically important to note that the test DecisionDX-SCC should be used with available staging approaches, and risk assessment systems, and does not replace these systems, as is suggested in the LCD.

The LCD also demonstrates misunderstanding of Adjuvant Radiation Therapy or ART, as I'll call it today. Which is indicated for patients who have a high risk of metastasis with a demonstrated improvement in their health outcomes.

What's more is ART is currently recommended considered for a broad range of high-risk SCC tumors, all of which are currently covered by Medicare.

The problem is that skin cancer experts don't know, based on the clinical and pathologic factors alone, which patients have highest risk of metastasis and therefore benefit from Adjuvant Radiation Therapy.

This presentation will focus on the perspective of clinicians, treating patients with SCC today, and with a focus on ART. Again, a specific management decision informed by the DecisionDX-SCC test result that has demonstrated improvement in health outcomes when it's provided to patients with the high -risk of metastasis.

Next slide, please.

Will submit formal comments that address MolDX requests for additional clinical validity data during the open comment period. These don't impact the conclusion that the test is medically reasonable and necessary, and I won't discuss them here in this brief presentation, but rather, in written comments, which will follow this presentation.

Next slide, please.

For brief background, again, the Decision DX-SCC test was developed and validated to predict metastatic risk regional and distant metastasis for SCC patients with one, or more clinical or pathologic risk factor. This is a 40 gene expression profile test that produces 1 of 3 results here on the right: Class 1, Class 2A or Class 2B.

Next slide, please.

In an independent validation study for DecisionDX-SCC, by Ibrahim and colleagues in 2021, within a group of 420 patients with squamous cell carcinoma in one or more risk factors, the test identified three discrete risk groups, and what does a consisten, has been consistent across validation studies, Class 1 results in green are associated with half the risk as the overall cohort. In class 2B results in red is associated with nearly three times the risk is the overall cohort. This fold decrease and increase in risk compared to baseline respectively is consistent across validation cohorts and various subset analysis.

Next slide, please.

A multi variable analysis from the same study demonstrated the statistical independence of the Class 2A and Class 2B results from the risk factors that are incorporated into staging.

Decision DX-SCC adds prognostic information that is formerly not obtainable from risk factors or staging and can be added to other known risk factors for more complete assessment of metastatic risk.

Next slide please.

Continuing that thought Decision DX-SCC validation studies have shown comparison to every current clinical and pathologic based risk stratification approach. The Kaplan-Meier curve here show how DecisionDX-SCC stratified risk with an NCCN high risk and very high-risk patient groups. Adding information and risk assessment to the current NCCN risk assessment system.

Next slide please.

Multivariable analyzes with all other staging systems included, currently in use in United States, DecisionDX-SCC provides independent prognostic information. Here the, Class 2A and Class 2B results are statistically independent of the metastatic risk describing each of these three stratification approaches seen in their respective columns.

So, the assertion in the draft LCD that it is unclear how the test adds value to clinical and pathological information is simply unfounded in the face of this published clinical validity data.

Next slide, please.

To unpack how the test sets information to current risk stratification, this table provides accuracy metrics when DecisionDX-SCC is used in the context of BWH staging, again, these are calculated from the Ibrahim al Study from 2021.

Here, the test significantly improves the accuracy and addresses current limitations in staging approaches. For example, all low stage patients, T1/T2a patients are not truly at low risk of metastasis.

Here are the lowest Class 1 patients with T1 and T2a tumors have an improved negative predictive value compared to all T1/T2a tumors and all patients identified by Class 2 or Class 2B results here, are actually all missed by stage. They are all predicted to have favorable outcomes by staging.

On the other hand, all high stage patients, these Brigham and Women's T2b patients do not all benefit from higher intensity management and the positive predictive value of the Class 2 result here is excellent within the BWH T2b tumors, significant improvement from the overall cohort at Brigham Women's T2b.

Dr. Cook will go through this even more granular approach with a validity data and in the next presentation and it's in this way and combining DecisionDX-SCC, with existing risk stratification systems like BWH here on this slide, that significantly improves the accuracy of risk prediction.

Next slide, please.

To further emphasize this point from, again, a published reference, here on this arrow chart from the Ibrahim, at.el. study, the DecisionDX-SCC tests provide stratification within the BWH stages. Again, this emphasizes that the published clinical validation of the test is to enhance the accuracy of staging but does not replace staging approaches.

The prospective multi-center clinical utility study from [inaudible] demonstrates the DecisionDX-SCC leads to a change in management of 24% of patients tested with DecisionDX-SCC. Which is comparable to other Medicare covered molecular tests for cancer patients. We focus on specific management changes such as ART decision specifically, the bar graph on the right, from Hooper, at el. it's a clinical utility study that confirms that clinician management changes are not made in a vacuum, as the LCD suggests but rather in the context of the clinical and pathologic risk factors and each real-world case. This analysis from Hooper, at el. was not included in the draft LCD.

Next slide, please.

On a high-level, based on broad management strategies, which are available to patients who have been diagnosed with high-risk SCC. ART is considered as a therapeutic option for all patients and the intended use population for DecisionDX-SCC and is covered by Medicare when ART is provided to those patients.

More detail would be provided and written comments, but the cost of ART is significant and for every Medicare beneficiary who receives this treatment, it's a significant cost.

ART is also associated with substantial morbidity and there's a need to better identify patients, most likely to have their outcomes improved by ART that essentially balances the risk benefit ratio for each patient.

The ability to inform more risk aligned to ART therapy also unlock significant cost savings.

Next slide please.

One study not referenced are considered in the LCD from Dr. Ruiz, at.el., demonstrates that ART is associated with a 50% reduction in poor outcomes in patients with high risk of regional and distant metastases. Essentially, with the study demonstrates that ART is beneficial in patients with elevated metastatic risks. If there is a need for improved risk stratification in a population which includes patients within the intended use DecisionDX-SCC test.

What we see here in these three cam curves, is that ART is beneficial in patients with elevated metastatic risk and the benefit of ART is greatest in cohorts with the highest risk of metastasis from the central cam curve. But that there's a need to improve risk stratification in the cam curve on the right, in patients with a slightly lower risk by clinical and pathologic risk factors, and again, this aligns with DecisionDX-SCC test population.

Next slide please.

In this slide, the combination of BWH stage and DecisionDX-SCC test results impacts that predicted metastatic risk and crosses meaningful thresholds that are clinically actionable.

When you use staging alone, only T2b tumors cross the threshold for ART scene in the horizontal line across the slide. Specifically, the addition of GEP identifies patients with the Class 1 result who fall below the threshold and patients with a Class 2b result who rise above the threshold for ART across all stages of tumors. Because DecisionDX-SCC provides independent risk, stratification, the addition of GEP results can identify patient populations not found by clinical and pathologic factors alone that have a higher or lower risk of metastasis then would be predicted by their stage alone.

Essentially, when using GEP in combination with staging approaches, the DecisionDX-SCC test can identify Brigham and women's T1, and T2a tumors that have T2b like levels of risk and the other side of the respective can identify T2b tumors. Brigham and women's T2b tumors with more T2a like risk that crosses, again, these clinically actionable thresholds for ART.

Next slide, please.

This is also true for approaches that look to count NCCN risk factors.

Next slide, please.

So, we looked at next that the combined validation cohorts of 954 patients in a matched control analysis to evaluate DecisionDX-SCCs ability to identify patients who will benefit from agilent radiation therapy. While all of these patients in this cohort are eligible for consideration of the ART, based on the broad guidelines for management strategies, the DecisionDX-SCC test is able to find a group of patients who will significantly benefit from ART. When you look at the Class 2B graph on the right, ARTs associated with a marked improvement in metastatic rate, as seen by the blue curve on the bottom right.

This aligns with published literature that ART benefits patients the most when they have an elevated risk of regional or distant metastasis. Here identified by the Class2B gene expression profile test result.

Notably, there's a steep rise and the red curve with metastatic events in this Class 2B cohort, which corresponds to the rapid rate of metastasis in these patients not treated with ART who have a Class 2B test result. This, again, highlights the urgency to act on this Class 2B result where most metastatic events are seen within the first two years following diagnosis. So, putting this ART discussion together, ART is a costly intervention known to improve patient outcomes when it's directed to patients with the highest risk of metastasis from published literature, not cited in the draft LCD.

For high-risk SCC, clinical and pathologic risk factors alone are insufficient to accurately guiding our decision making. And the DecisionDX-SCC test provides clinically actionable risk stratification that identifies SCC patients in any stage who can considered for, and who benefits from ART with a Class 2B result.

In addition, Class 1 results identify patients who can avoid ART as they are unlikely to benefit from this intervention, which leads to significant cost savings.

Next slide, please.

It's important to emphasize that skin cancer experts ordering DecisionDX-SCC are appropriately using this test within the intended use population.

Most clinically tested patients have an average of 2.7 risk factors, with a predominance of BWH T1 to T2b tumors by staging. Clinicians are ordering the test in patients when they can make risk aligned management decisions after surgery, including whether or not to recommend or consider ART.

And, again, this is in addition to other specific interventions that are outlined in the published clinical utility studies.

Next slide, please.

For prognostic tests, clinical utility of the test is demonstrated by improvement in risk stratification that informs treatment modalities that are included in guideline recommendations and that are known to impact patient outcomes.

This is the standard clearly articulated another MolDX LCDs for similar prognostic tests in prostate cancer, breast, cancer, and bladder cancer, which have positive coverage under Medicare LCDs.

DecisionDX-SCC has clearly met this level of evidence.

Next slide, please.

So, in conclusion, the draft LCD should take into consideration how high-risk SCC is currently managed in the U.S., have a more complete understanding of the scope of practice in academic and community settings.

Clinicians treating SCC or skin cancer experts adapted incorporating multiple clinical, pathologic, and now genetic risk factors to inform risk align treatment plants.

That demonstrated both in practice and clinical utility studies that test results are being used appropriately with staging information to make individual patient management decisions that are risk aligned.

DecisionDX-SCC can be used to guide ART decisions that have proven impact on health outcomes for patients with a high risk of regional and distant metastasis.

Therefore, improvement in the accuracy of risk prediction, for patients with SCC, tested with DecisionDX-SCC, has inherent improvement in patient outcomes as this test directs those with high-risk of metastasis to a therapy known to improve outcomes.

Further, data presented today confirms the ability of the Class 2B result to identify patients who benefit from ajuvant radiation therapy.

Finally, the broad clinical adoption of DecisionDX-SCC stands in stark contrast to the analysis of evidence in the draft LCDs DL39589 and DL39594 with Noridian.

Over 3,600 clinicians experienced in treating patients with high risk-SCC have determined that the DecisionDX-SCC test is medical necessary for more than 7000 patients to inform their management decisions. We therefore urge the Noridian medical directors to work closely with Palmetto CMDs to consider the rationale for determination.

Reviewed new evidence will be submitted during this open comment period and written comments and finalize this LCD with positive coverage for DecisionDX-SCC for the benefit of Medicare beneficiaries diagnosed with this impactful cutaneous malignancy.

Again, I appreciate your attention today and the opportunity to provide these comments. I'd be happy to answer any additional questions.

Dr. Barry Whites:
Thank you so much for your informative presentation. You said these will be submitted, be sure that you do submit them in writing. That you would have your comments referenced, if you could, to the best that you can, to the areas that you feel in the draft policy that are in error or incomplete and it would certainly help in our evaluation of the literature that you are submitting. Thank you.

Dr. Barry Whites:
Next, we have Dr. Rob Cook.

Dr. Robert Cook:
President, thank you again, sir.

Dr. Barry Whites:
Thank you.

Dr. Robert Cook:
Can you hear me well?

Dr. Barry Whites:
Yes, Sir.

Dr. Robert Cook:
So, I'd first like to begin just by thanking the Noridian group for this opportunity to present our comments about LCD DL39589 and DL39584. My name is Bob Cook, I am the Senior Vice President of Research and Development with Castle Biosciences. Also mentioned that I'm a stockholder with Castle Biosciences.

As you've heard from Dr. Farber in Dr. Goldberg, DecisionDX-SCC is a prognostic Gene Expression Profile Test, or GEP that can provide independent information about the likelihood of cutaneous squamous cell carcinoma tumor to metastasize either regionally or distantly.

And the intent to treat population includes patients who have been diagnosed with cutaneous squamous cell carcinoma tumor, that's characterized by a high-risk feature associated with disease progression as defined by NCCN criteria.

I have two primary points that I was hoping to cover during this presentation. The first is to provide insights about the test's validation and statistical approaches, in order to clarify what we perceived to be inaccuracies in the LCD, regarding the performance of DecisionDX-SCC.

These statements suggest that the alignment of test results with clinical features negates the prognostic information, provided my DecisionDX-SCC and in fact it would be concerning I believe, that if validation studies demonstrated a dramatic difference from previously identified and validated risk factors.

So, we will submit these responses as written comments, but I think in the interest of time, I'm going to skip this section and move to slide seven for the review of requests for additional validation for the LCD that support clinical actionability and validation criteria.

So, if we can move to slide seven with the table, yes, no, back one please.

Perfect.

Which slide seven I'd like to address the first analysis that was requested within the LCD, which was to demonstrate the DecisionDX-SCC value in the context of available high risk clinical factors using a multivariable model.

More specifically, the request was to modify published multivariable models to include tumor diameter, pairing neural invasion of greater than 0.1mm, and tumor location.

And the results of that analysis are shown in the table on the right side of the slide. Columns labeled without GEP indicate that tumor thickness, diameter, differentiation, location on the head and neck, and immunosuppression are all factors associated with a higher risk of metastasis, as indicated by the significant p-value of less than 0.05.

In the columns labeled with GEP, we've done the same analysis, but we've included DecisionDX-SCC results, as a variable.

While the same clinical factors continue to provide prognostic value, both the Class 2A and Class 2B results are significant contributors to multivariable model.

And in more importantly, the Class 2B result is associated with the highest risk of metastasis of all the factors evaluated over six-fold higher than the risk for Class 1 patients.

So, I think one of the important concepts here is, it should be noted that the risks associated with each of these factors are multiplicative when a tumor is marked by more than one high risk feature.

So, a patient who's tested due to the presence of one of the clinical factors listed would have their risk multiplied by a factor of 2.41 if they received a class 2A result, and by a factor of 6.22, if they receive a class 2B result.

So, for example, the risk of metastasis for a tumor that was tested due to the presence of or differentiation, and therefore it has a hazard ratio of 2.57 who subsequently receives the class 2B result.

We'd have a metastasis risk 16, times greater than a tumor with no concerning features.

I think this is an important concept for consideration and shows the added value of the DecisionDX melanoma test in the context of clinical features that are currently being considered, when determining the management direction for a patient.

We could go to the next slide, please.

I want to build upon that concept of the independent information that's provided by the DecisionDX-SCC test, and I'd like to next demonstrate the enhanced risk stratification that's observed when the test is used in conjunction with Brigham and Women's Hospital or BWH staging system.

In general, BWH T1 tumors are thought to have a low-risk of metastasis because there's no evidence of the four clinical factors that contribute to this staging system.

And those are diameter greater than or equal to 2mm, poor differentiation, invasion below the subcutaneous fat and perineural invasion less than 0.1mm, or greater than 0.1mm.

In the population that we see here on the screen of 200 patients that were reported in Ebrahim at el, all of these 200 patients had T1 tumors, and 19 patients had a recurrence or metastasis reflecting an NPV of 91% by staging an event rate of 9.5%.

Now, layering the results from the DecisionDX-SCC testing on top of BWH staging allows clinicians to identify a low-risk Class 1 group with a metastasis rate of only 3.3%, compared to a Class 2A and 2B rate of 18.2%, and 44.4%.

These are significant adjustments for a cohort that would be deemed low-risk according to the staging system and also point out the improved NPV of 96% when including GEP results.

Moving onto the next slide, a similar evaluation of the BWH T2A and T2B also reflect important risk stratification following GEP testing.

So here, the T2A tumors are highlighted, and they have an elevated risk within the context of the BWH staging system because they're characterized by one of the risk factors that I listed earlier.

Within this cohort, the overall event rate you can see is 15.2%.

Adding DecisionDX- SCC test results provides risk stratification to identify class one patient group with an event rate of 9.3%, compared to Class 2A and Class 2B patients with significantly different event rates of 22% and 42.9%.

So, a Class 1 result identifies patients with the metastases profile similar to that of the BWH Stage T1 patient and a Class 2B result identifies patients with a metastasis profile that's higher than that of the BWH stage T2B tumor.

And on the next slide, we take a look at those T2B tumors.

And we see the same risk stratification, is observed when adding DecisionDX-SCC results to a BWH stage T2B clinical results.

In this case, metastasis profiles for patients with an overall event rate of 32.6% can be further refined to identify three populations with significantly different metastasis rates.

Again, the Class 1 patient has a low risk profile compared to Class 2A and 2B patients, who really warrant intensified management protocols to monitor for or even treat metastatic disease.

We move to the next slide, in conclusion, I've shown results from an expanded multivariable analysis that was performed as requested in the LCD and those results demonstrate independent risk prediction by the test.

I've also shown that the test results provide meaningful information that identifies levels of risk, consistent with higher and lower BWH stages, which is clinically actionable and informs the demonstrated clinical utility of the test.

So based on these and other published data, DecisionDX-SCC, we believe meets the standards established for medical reasonableness and necessity and also supports cover it supports coverage of the DecisionDX-SCC test and incorporation to the LCD prior to finalization.

I will also include in my written comments, our responses to the perceived erroneous statements regarding the alignment of DecisionDX-SCC test results with the information provided by clinical factors that are used to determine risks for patients with cutaneous SCC.

Our request here is that the medical directors from Noridian worked with medical directors from Palmetto and MolDX to correct those errors within the policy that was put forward from the MolDX program.

Thank you very much for your attention.

Dr. Barry Whites:
Thank you, sir. Another very nice presentation, as you said and I keep reminding everybody that it is really is very important to get your point across, that you write your concerns and place what you think needs to be corrected and with that placement that you do go ahead and provide the article that would support that.

Apologize in advance is it Dr. Prieto or is it Dr. Prieto or maybe neither one of the two?

Dr. Peter Prieto:
Preito, can you hear me?

Dr. Barry Whites:
Yes, sir. OK, very good. Thank you, sir.

Associate Professor Surgical Oncology at the University of Rochester Medical Center. Please go right ahead, Sir.

Dr. Peter Prieto:
Thank you, Sir. Thank you for the opportunity from the medical directors at Noridian to hear my comments this afternoon on this draft LCD. My name is Peter Prieto, as mentioned, I am an Associate Professor Surgical Oncology Associate Program Director of Research and lead the bio repository at Rochester. I am like, Dr. Farber, I operate in a consultant fashion and participated in scientific advisory boards and independent research with Castle Biosciences.

Next slide.

So as a surgical oncologist, for which I'm board certified in general surgery, surgical oncology, and medical quality. I take care of patients with high-risk squamous cell carcinoma and many of these patients have locally advanced disease on a regular basis and in my practice I use available tools for risk stratification, and we try to include careful evaluation of clinical and pathologic risk factors. More recently, I've integrated genomic testing with DecisionDX-SCC.

Based on our clinical experience and independent review, I'm speaking here, at this open meeting today, because I, quite frankly, disagree with their proposal LCD DL39583. The published analytic validity, clinical validity, and clinical utility data supporting the 40-GEP meets the Medicare standard for what is medically reasonable and necessary and I will spend my time discussing my perspective, reviewing my clinical workflow at Rochester for risk stratification and review, a case from my clinical practice.

By way of just a little further background I will tell you that although I focus on cutaneous neoplasms during my training and in practice I also work extensively on other epithelial tumors.

These include breast cancer and endocrine cancers, and in this way, I compare evidentiary thresholds in cutaneous oncology to a range of other cancers.

When comparing across disease states in this way, it's clear that when we evaluate clinical risk stratification tools, such as a staging system or a prognostic test, such as DecisionDX-SCC.

Demonstrating specific management changes with improved outcomes is not required for staging system or test to be proven clinically useful. So, this paradigm and this precedent is seen in other disease states and it's clearly stated in other MolDX LCDs for similar prognostic tests such as prostate and breast cancer. So that requiring a different level of evidence for cutaneous squamous cell carcinoma that is applied to prostate and breast cancer really establishes a disparity and an inequity between disease states.

Next slide.

So focusing back on SCC, I believe the standard for clinical utility and risk stratification is set by clinical and pathologic based risk stratification systems, such as the NCCN, AJCC Version 8 and Brigham and Women's that are clearly, again, clinically useful, but are based on retrospective data sets lack demonstrated improvement in patient outcomes, and are not specified by guidelines to inform specific management decisions.

Rather, these approaches identify broad categories of risk to inform a broad range of management options that will, I will review today.

As a result, my current management decisions for patients with cutaneous SCC are informed by the presence or absence of specific risk factors and is guided by staging risk assessment with treatment decisions made on a, really modality by modality and more importantly, patient by patient basis.

So, if we look at the proposed LCD, which elevates current risk stratification approaches in cutaneous, squamous cell carcinoma and supposes that they have a higher level of validation evidence and they actually have proven.

While NCCN and AJCC Version 8 and Brigham and Women's do certainly provide risk stratification. There's clearly room for improvement, inaccuracy in risk stratification, and a well validated test to help us navigate this complex disease really forms risk aligned management decisions and is inherently clinically useful. DecisionDX has been well validated for clinical use, in really the largest cutaneous SCC patient sets available in the U.S.

Then has now demonstrated, really in over close to a thousand patients. This slide highlights the analytic validity demonstrated for DecisionDX-SCC that meets CAP and CLIA New York State Laboratory standards, as well as robust clinical validity in multiple cohorts.

Next slide.

So, this slide, importantly recognizes that the published clinical validity data from Ibrahim, et al. demonstrates that the 40-GEP class to a or intermediate class assignment and Class 2B highest risk assignment are independent of all other risk prediction systems using clear current clinical practice.

The 40-GEP DecisionDX-SCC not only meet or actually exceeds accuracy of other staging systems, but as an independent predictor of metastasis, this is important.

Because it means we can combine GEP with clinical pathologic base staging, and that's the whole idea here and the precedent set and other epithelial cancers.

Combining genomic testing or 40-GEP with staging provides really the utmost of accuracy of risk prediction over other risk assessment approaches.

This is the true utility of the 40-GEP, which is misrepresented in the draft LCD which seem to evaluate the clinical validity in a comparison against staging.

Again, not the point. Next slide.

The LCD assumes that there are clearly defined, specific management pathways for patients with cutaneous, squamous cell carcinoma, when in fact, management decisions exist on a spectrum informed by risk factors on a patient. By patient basis patient centered decision making is a key component of a high quality cancer center that is acknowledged by NCCN guidelines and is missing from the draft LCD.

The next several slides include examples of the types of decisions that doctors taking care of patients are tasked to set in motion after definitive surgery of a patient's squamous cell carcinoma and that are influenced by the combination of both clinical pathologic and gene expression profiling results to inform really shared decision making.

Next slide.

So, let's, let's look at a few examples.

First for follow up frequency, all patients eligible for the 40-GEP DecisionDX-SCC test, by definition, are eligible for this range a follow up, but this is a broad suggestion offered based on individual risk.

We have a decision to make here.

A follow up schedule that is too intense can be expensive to the patient and the system, and really a burden to all involved in the care of that patient.

Follow up too infrequently would miss early disease progression and where it can be treated most effectively, again, doing the patient a great disservice.

We need to better focus the limited resources we have on these patients.

Next slide.

Now, let's look at nodal evaluation or surveillance.

Again, all patients eligible for the assay are technically eligible for this range of nodal surveillance and evaluation, but broad suggestions offered based on individual risk per NCCN guidelines.

So, it's clear from other cancer types that, when surveillance imaging is targeted to the patients with the highest risk of disease progression that you can identify smaller tumors sooner, that have favorable treatment responses and this is across multiple treatment modalities including targeted therapy, immunotherapy, chemotherapy, radiation therapy.

We want to find disease before it becomes symptomatic. We want to find disease early, but we're only going to know to do that if we have suspicion of a patient's true risk.

Next slide.

As a last example, adjuvant radiation therapy. For NCCN, all patients eligible for the 40-GEP fall into either the consider or recommend adjuvant radiotherapy category. However, once again, here we see there was only broad direction from the NCCN guidelines on who to treat.

We're not able to treat all patients who can be considered for adjuvant radiotherapy with this modality or are we? Are patients' high risk, or are they very high risk? Can we better distinguish and clarify that vague description?

Guidelines rely heavily on a physician's understanding of the patient's risk of regional distant metastasis to direct treatment and here is where, again we can refine and identify what a patient's true risk is because are we over or under treating these patients?

Next slide.

So, we've put this together at Rochester and here's my current workflow for high-risk cutaneous squamous cell carcinoma that we see in the clinic, and we use for our patients.

And this nicely marries staging with gene expression profiling and shows how these actually are complementary.

Across the top of the table are specific management decisions and the rows contain the combination of Brigham and Woman's T stage and 40-GEP test result class assignment.

This establishes either a low, moderate, or high relative risk level.

This additional level of risk stratification allows for identification of patients for escalation or de-escalation of their care and really helps us again identify who perhaps we would under or over treat if we only relied on Brigham and Women's.

This workflow is importantly consistent with the clinical utility studies from Farberg et al. 2020 and Singh et al. 2023, which contain clinical management algorithms that are not included in the data analysis section of the draft LCD.

Next slide.

I want to briefly review a case where my clinical practice where I was able to de-escalate my management intensity with a low-risk Class 1 assignment based on the clinical validity and clinical utility of the assay. So, in this patient example, I utilize the workflow I just reviewed and evaluated the patient specific clinical and pathologic risk factors in the context of his 40-GEP result. He was 68, was a large fungating central chest mass as you see in the picture below. It was about 4 by 4 centimeters, biopsied as a poorly differentiated, squamous cell carcinoma extending to every margin. By traditional staging, he was a Brigham and Women's T2B. His risk of metastasis was 32.6%.

However, we know that not all T2B tumors carry the same risk of disease progression and given the low positive predictive value of Brigham and Women's Staging we may be over treating a significant number of these patients, again, costing both the patient and the system. Prior to GEP, my initial plan was kind of a full court press, multi-disciplinary tumor board, pre-op axial imaging: CT, PET scan. I would offer this patient a central node added time cost risk.

This patient would be referred to Radiation Oncologist for adjuvant radiotherapy, and we would clinically follow this patient about up to four times per year, but his class was 1, lowest risk.

So now, we have a Class T2B. We have a stage T2B patient with a Class 1 result.

This new risk of metastasis is 18.8%, that's nearly a 50% reduction and it's actually more similar to the cohort risk of a Brigham and Women's T2A patient, where I would not typically recommend adjuvant radiotherapy. So, we begin to see the utility.

Now I'm updating his treatment plan accordingly, and we decided to personalize care plan, which in 2023 makes perfect sense.

In this case, he underwent wide excision wound vac with negative margins, skin graft, and active surveillance about 1 to 2 times per year, so, it again was seen half as frequently.

Since this patient is still elevated risk though again, the test tells us he's lowest risk, but not zero risk we're still following up with them regularly and doing full exam, but we were able to avoid pre-operative imaging, sentinel biopsy, adjuvant radiotherapy that are all consistent with recommendations for a T2B patient.

So how do I know, this is the right treatment for this patient? He remains disease free now, 22 months, at the time of last clinic visit.

The 40-GEP DecisionDX-SCC test help to de-escalate his care by accurately, identifying a T2A, like-risk and a patient with the Brigham and Women's T2B tumor and we were able to safely avoid unnecessary adjuvant radiotherapy.

Next slide.

Further, the reason that we know we made the right decision is that the 40-GEP result from my patient is, is that we combine the GEP result with staging information to give the most accurate assessment of the patient's metastatic risk.

I'm able to treat this patient as a patient with the Brigham and Women's T2A like risk and I'm confident that because of superior accuracy metrics at Brigham and Women's plus GEP, as opposed to just Brigham and Women's staging criteria alone.

Next slide.

The 40-GEP result combined with staging gives the most accurate assessment of metastatic risk and over treating patients [inaudible] high-risk by stage with low positive predictive values, is one of the current clinical problems for clinicians who manage high risk squamous.

Not all patients with T2B tumors benefit from high intensity management as implied in the LCD, though it is covered and routinely performed in these patients.

Shared decision making with patients, for patients with T2B tumors with a Class 1 result is an evidence-based approach informed by published data and the same approach to risk stratification clearly applies to Brigham and Women's T1 and T2A tumors.

So, finally last slide, in conclusion, I hope that my comments support reconsideration of the 40-GEP test and support positive coverage inclusion in the final LCD for the patients who really need and deserve this actionable data.

Patient management strategies, related to follow up, imaging nodal assessment, adjuvant radiotherapy are established and are known to impact on outcomes, but unclear who to treat due to low positive predictive value of risk assessment systems.

These management strategies are informed by individual risk and balance with cost benefit in a shared decision-making model.

Clinicians are trained to manage high-risk patients and interpret the GEP results in the context of the known risk factors or staging systems. Again, demonstrating how we use the assay, and this further demonstrated in clinical utility studies. De-escalation, as in my patient, with at Brigham and Women's T2B tumors is important given the low [inaudible] and potential for overtreatment and the same approach, the risk stratification can be applied to lower stage Brigham Women cutaneous squamous cell tumors.

Lastly, the use of a 40-GEP with clinical pathologic factors identifies which patients are most likely to benefit from specific management strategies already established for high-risk patients and has met the threshold for Medicare reasonableness and necessity. I thank you for your time.

Dr. Barry Whites:
Thank you so much. Another excellent presentation. Comments remain as before please provide your full documents and note the area that you think it applies to in the policy.

Last, but not least is presenter is Dr. Somani, Director of Dermatologic Surgery and Cutaneous Oncology in Indiana University Health System School of Medicine.

Dr. Somani.

Dr. Ally-Khan Somani:
Can you hear me?

Dr. Barry Whites:
Yes, sir. We can, go right ahead.

Dr. Ally-Khan Somani:
Thank you. Thank you for your time today and I appreciate given a chance to share my views regarding the molecular testing, the GEP test. I wanted to start by saying that I have my only conflict of interest is that my academic institution has carried out about one of the validation and prospective studies where I have been the PI. I, also, on an ad hoc basis, have been a speaker for Castle Biosciences. Furthermore, it's important it is also for me to stress that I'm not being compensated for my time here today. And I'm here, because I believe, in the clinical, in the clinical utility of this test, and I want to share my perspectives on the test with you and show you how it helps us manage our patients better.

Also, being a fellowship director at the university, it is very important that we're utilizing evidence-based medicine, and importantly, provide the best care possible to our patients.

It is, it is obvious that our current prognosticating factors also, although they're so useful by layering on the gene expression profile test results, we're able to better appreciate the biology of the tumors that we're treating, allowing us to better manage these patients.

Can I go to the next slide, please?

As a brief background, I use risk stratification system also in my practice, like all other clinicians, whether they're private or academic clinics and these are based on the clinical and pathological factors that have been already discussed earlier by the other presenters. I take stock of the risk factors that every patient has engage my patient's risk for outcomes based on the presence or absence of these factors, but there are well known limitations to the accuracy of these systems. As a result, and you can see in this table, there's a significant number 35% of the patients are being under staged by our current staging systems and 75% are being over staged, respectively, as shown on this table.

So, in the right clinical context, I can reasonably justify adjuvant radiation therapy for a patient with a lower stage tumor while questioning I need to aggressively manage every patient who presents with the higher stage tumor. Even do I use factor-based risk stratifications of AJJC and BWH staging, I still need to consider the full broad range of management decisions for each patient individually. And I hope you will see how this test helps us with that.

So, next slide, please.

So, here are two cases of my published case series. These cases clearly demonstrate the limitations of our current staging system and the types of management decisions we offered to patients with high-risk SCC. As you can see, both from this table and the photos, both of these patients had poorly differentiated squamous cell tumors on the left temple and both are immunosuppressed transplant recipients. Our staging considers these patients have a low-risk tumor.

The simple fact illustrates the limitation of our current staging systems. Because in my professional estimation, I did not think that these tumors are both low risks, and I was more concerned clinically, with the gentleman on the left side of the screen.

In fact, the patient was presented at multi-disciplinary tumor board and was formerly offered radiation therapy by our treatment team which the patient declined himself. Interestingly, the patient on the right side of the skin under when it technically straightforward Mohs surgery and my post Mohs treatment did not include adequate radiation therapy on what the multi-disciplinary tumor board. So, in practice, these two Medicare patients look near the identical on paper. I could have considered ART in both patients. In fact, the only offered ART to the patient on the left. Most surgeons like myself are looking for independent risk stratification to inform specific decisions in patients just like these ones.

Next slide.

So, I won't belabor the statistics on this next several slides but suffice it to say that the 40-GEP test has been clinically validated in large cohorts of patients with high-risk SCC and is statistically independent of the approaches that we use to stratify, or stage our patients.

So, whether use NCCN risk groups, or BWH or AJJC staging, the 40-GEP test results as independent prognostic value to what we currently use.

Next slide.

So as a Mohs surgeon, I'm particularly interested in the outcomes of patients treated with this effective surgical approach, and the independence of the 40-GEP result from staging system continues even in this subset of patients who were all treated with Mohs surgery.

The statistical independent scene in this court highlights, they use it for the GEP to improve the care of our patients, who we treat with Mohs surgery, by enhancing the accuracy and precision of our prognostic assessments.

Next slide, please.

So, it's critical to understand how clinicians like myself integrated results from GEP tests with the staging risk assessment information that we already have for our patients.

This slide shows that our current approache to risk stratify patients, whether it be BWH, AJJC staging or NCCN, using either my setting, an academic setting, or in the community provides important risk stratification, seen with the positive hazard ratio in each column as shown by the gray bars.

But when I layer the accuracy of the 40-GEP in the context of the known risk factors or staging of the tumor, it provides, you know, which provides a more comprehensive individualized risk assessment by integrating the clinical pathologic and the gene expression profile results. I can improve the accuracy of my risk assessment seen in the blue and red bars in each column, depending on the result of the gene test.

Again, showing that the biology of the tumor helps us here predict which patients are going to be high risk, even if they are clinically, pathologically rated as low risk, and vice versa. So, we can actually manage these patients more appropriately.

Next slide, please.

This look, this slide here looks at the data from another perspective and using likelihood ratios confirms, that including 40 gene expression profile tests in metastatic risk prediction significantly improves the prognostic accuracy of the AJJC8 and BWH staging system.

This data is important because my colleagues and I never used a gene test result in isolation, but rather in the context of the risk factor, factors are clinical stage of the patient's tumor. So, when we stratification from clinical and pathologic factors is used together, with the gene expression provide test result, this significantly refines the metastatic risk prediction that we can offer our patient and better informs our management decisions.

Next slide, please.

So, let's go back to my patients, who gain, are both considered low stage by AJJC and BWH. However, if you look on this table and you can see that the GP test results and clinical outcomes were risk align. The staging results for divergent for these patients and the patient on the left returned a Class 1 result, which is the lowest risk, and patient on the left returned a Class 2B result shown on the table, which is the highest risk, and he went on to have a recurrence in metastasis. In my practice, in addition of the independent risk information from specific management changes, and I would have considered recommending ART to the patient on the right and would not have recommended radiation to the patient on the left.

So, this test has allowed me to appropriately for my patients, for not only ART, but also for nodal imaging and multi-disciplinary care.

Next slide, please.

So, like, my cases with my colleagues, I've seen similar patients and I think that this article was mentioned earlier by Hooper and colleagues.

So, in this, in this table, and in the graphs, you can see that the third real-world case from this study highlighted on the slide.

It's like my own case and this Class 2B results will lead to an overall increase in management intensity as shown in the first graph on the bottom left, and specifically, an increased ART consideration and recommendation as shown on the second graph. This corroborates the approach to risk stratification that I just discussed an outpatient and again, as I mentioned, can be found in the published clinical utility study by Hooper and colleagues.

Next slide, please.

So, I want to conclude with one last clinical challenge that most surgeons face in another area with the validity and utility of the 40 gene expression profile that stands out in my practice.

Most surgeons like myself worried that we're missing patients with a low stage disease who actually have a significant risk of metastasis anywhere from like 30 to 50% of the eventual metastatic events will come from patients who we initially stage with our current clinical pathological staging as low risk.

So, I've been involved in research, and what we have found is that the 40-GEP was able to significantly risk stratify patients with low stage tumors, and importantly identify subsets within this cohort, that carry a significant risk of metastasis, similar to the cases that I presented.

Next slide, please.

The pie charts here drive this point home, because, again, 100% of these patients are classified as having low risk tumors by the AJJC or BWH.

And yet there are significant number of metastatic events.

The Class 2 results identify 67 to 70% of the metastatic events in this cohort. This is where the clinical validity data leads to clinical utility in my practice. I hope you can appreciate where the GEP test results help us identify patients who have low risk by staging but have significantly higher risk of metastasis after integrating their GEP test results, with our current prognosticating staging systems.

Let's go on to the last slide, please.

So, in summary, I think that the known limitation of staging in the two cases I presented underscore the need to improve the accuracy of our current risk stratification for patients with high-risk SCC.

And I think limiting access to this test by failing to be covered in the LCD will have a substantial negative impact on the care of Medicare beneficiaries and I strongly urge you to consider the reversal of this draft policy and think that it will also benefit patients because we will undertreat those patients who are high risk based on the biology of their tumors and this will be better for the patients as well as for our health care system. But at the same time, we will help us identify cases that are low risk by staging, who actually to benefit from what we can provide them and better manage their care.

So, the 40-GEP's test is the only test that helps to actually identify cases that are deemed risk by staging and has been as shown earlier, has been validated across multiple cohorts including of course Mohs surgery.

The tests can inform risk align decisions, such ART as in the two cases I just discussed and showed today.

So, the treating clinician conditions ordering this test are skin cancer experts, and we can integrate in a meaningful way, the GEP test results into our existing risk assessment to help them make better informed decisions for our patients as well as take care of them in the most appropriate way based on the biology of their tumors.

So, thank you for your time, and I appreciate your attention today.

Dr. Barry Whites:
Thank you for your presentation. Like all of our presenters a very informative common thread in all of them and I do appreciate. Again, if you want them considered, you gotta mail them in, gotta get them to us.

I will turn it over at this point in time. Thanks everybody for all your help, the Noridian staff as well as our presenters.

Kari Dupreez:
OK, thank you so much.

In closing, we would like to communicate the next steps in the policy development process.

The comment period for the proposed LCD will remain open until July 22, 2023. All comments to be considered by our medical directors for the proposed LCD must be submitted in writing. Written comments can be e-mailed to policydraft@noridian.com or mailed to the address on your screen. Comments information for our proposed LCD is located on our website at NoridianMedicare.com.

Upon review of the comments, our Medical Directors will either finalize or retire the proposed LCD responses to comments will be viewable and the response to comments article.

Please monitor our website or register for listserv notifications to be informed of actions taken on our proposed LCD.

Dr. Whites, do you have anything else you would like to say before we end the meeting today?

Dr. Barry Whites:
No, just a thank you to those who help put this on as it certainly wasn't I and the presenters for going through the trouble of the slide presentation data, very much appreciated, and very professionally done. Thank you so much.

Kari DuPreez:
Alright, perfect. This does conclude our meeting. Thank you for attending the Noridian open public meeting today.