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Castle Biosciences is a skin cancer diagnostics company focused on providing physicians and patients with personalized, clinically actionable genomic information enabling more accurate treatment plan decisions. From its formation in 2008, Castle Biosciences has applied emerging artificial intelligence techniques in molecular diagnostics to improve patient care and outcomes. Our DecisionDx family of molecular diagnostic tests have the ability to meaningfully impact how cancers are diagnosed and managed (castletestinfo.com ).
DecisionDx®-Melanoma predicts risk of recurrence or metastasis that can inform decisions on the risk of sentinel lymph node positivity and the intensity of follow-up, surveillance imaging, referral and adjuvant therapy for patients with invasive cutaneous melanoma. The test uses tumor biology to provide an individual risk of melanoma recurrence beyond traditional factors such as AJCC staging criteria and sentinel lymph node status and is supported by consistent evidence in over 25 publications including two meta-analyses showing Level 1A evidence classification.
DecisionDx® DiffDx-Melanoma is a new gene expression profile test designed to reduce diagnostic uncertainty by providing a highly accurate and objective evaluation. DiffDx-Melanoma adds diagnostic clarity leading to a more confident diagnosis and a clearer treatment path for patients.
DecisionDx®-SCC predicts metastatic risk for patients with cutaneous squamous cell carcinoma who have one or more risk factors. The test complements factors commonly used for risk assessment in SCC. The incorporation of DecisionDx-SCC results with traditional risk factors provides additional risk prediction to better inform choices about treatment and follow-up care.
DecisionDx-UM predicts risk of metastasis for patients with uveal melanoma, a rare eye cancer. The test is standard of care in a majority of ocular oncology practices. Castle Biosciences has active research and development programsfor tests in other dermatologic diseases with high clinical need. The company is based in Friendswood, Texas with laboratory operations in Phoenix, Arizona (www.CastleBiosciences.com ).
Resources:
DecisionDx-Melanoma Quick Access Resource Guide »
DecisionDx-SCC Quick Access Resource Guide »
DecisionDx DiffDx-Melanoma Quick Access Resource Guide »
So my name is Matthew Goldberg on the Dermatologist on Dramatic pathologist and medical director here at Castle Biosciences Onda. Today we're gonna be talking about diagnostic and prognostic testing in melanoma and continue screaming cell carcinoma. Andi, we're joined here today, also by one of our medical science liaisons, Liz Holland, who will be on the chat as well. So there's questions you know, please chime in on. But we'll be able to answer those questions at the end with time for questions. So again, thank you for joining us today, and I look forward to the conversation as well. All right, so as a background for the presentation today, we're going to be discussing a range of tests that are offered by Castle Biosciences and fundamentally at at this time. Castle has a range of gene expression profile tests that address multiple different cutaneous malignancies, and you have the melanoma that present molecular diagnostic solutions, really for the advancement of patient care. Starting in 2000 and eight, Castle Biosciences developed the decision dx, um test for patients with Julia melanoma that has been incorporated into guidelines for the care of patients with melanoma to inform management decisions for cutaneous melanoma. We have two tests of prognostic. Test the decision DX melanoma test that is intended for patients with invasive cutaneous melanoma. Help inform important management decisions, and we're recently developed. Test the decision. The X 50 x melanoma test, which is intended as a diagnostic aid for difficult to diagnose. Milan acidic lesions that will also discuss today. And then we'll end on another test. The decision. The SCC test for patients with cutaneous squamous cell carcinoma and one or more high risk features. And taking together, we'll be discussing really the suite of gene expression profile tests. The castle's developed again for the benefit of patient care for the clinicians that taking care of our patients with these cutaneous malignancies and union melanoma. So first I want to just highlight that the platform that really under underlies thes gene expression profile tests eyes similar for each of the three products will be discussing today, but they each start with a different tissue of interest to begin with. So whether it's difficult to diagnose Milan acidic lesion and invasive cutaneous melanoma or squamous cell carcinoma with high risk creatures, uh, the analyst here or the tissue that's being tested is fundamentally formalin. Fixed paraffin embedded tissue that's macro dissected on our DNA is extracted from the tissue in, then amplified with RT. PCR Uh, at this stage, this is where the gene expression profile tests are then run on this material here that produces gene expression. Profile result. It's different for each of the products will be discussing that fundamentally helps inform diagnostic decisions as well as a prognostic information that can help guide clinicians for the management of their patients, but that all of these tests fundamentally have the same development on the way that the actual tests are run in the laboratory here in Castle Out Sciences. So the first test that we're going to be discussing today is the newest test from Castle. The decision T X DF DX melanoma test that's designed for difficult to diagnose Milan acidic lesions. And we recognize that that these lesions pose a diagnostic challenge for dramatic pathologists as well as management challenges for the dermatologist that air treating patients with these lesions and pigmented lesions are a main reason why patients present to dermatologists. We estimate that about two million biopsies were performed per year of suspicious pigmented lesions that come into the clinic Andi. This results in about 130,000 invasive melanomas per year and almost 100,000 melanoma in situ diagnoses that air made per year. And what I think missed in kind of identifying just the melanomas, Millennium Insight is, is that many of these suspicious pigmented lesions result in biopsies that can't be confidently diagnosed with just the HD tools that we have today. And we estimate that there are about 300,000 lesions where there's a significant amount of equipment, equivocation or ambiguity in the diagnosis of these mine acidic lesions. And so, just as a schematic for this, if we start on the left hand side here with these two million biopsies that performed per year, the majority of them are actually a benign in Milan, acidic Nia blossoms here I've seen on the bottom row here, where dramatic pathologist could give a confident diagnosis of a benign Nia plasm and reassure patients that no further treatment is needed and they can return to routine, follow up on the high end in here and read these air the melanomas, invasive melanomas and melanoma and site twos that are all treated with definitive surgical procedure and then depending on the specifics of the tumor, additional procedures such a sentinel lymph node biopsy eyes could be obtained and then follow up. Decisions such as image ing or increased rates to follow up can also be recommended again based on the specifics of the region. And it's at this stage is, well, the gene expression profile test could be used to help guide some of those decisions. The focus of the diff TX test is really in this orange zone here for lesions with uncertain malignant potential, where there's significant diagnostic, um, ambiguity for these cases and what happens in clinical practices that the lesions may have a broad differential diagnosis. And clinicians may opt to treat for the worst case scenario in the differential diagnosis, which can result in significant overtreatment of lesions that are fundamentally benign. It may not require definitive procedures and also could lead to under treatment. If in a melanoma is not diagnosed a time of initial biopsy, it can lead to under treatment a swell. And so the diff TX test is fundamentally positioned to address lesions here in this zone of uncertain malignant potential toe. Add the diagnostic clarity to help guide patient management decisions to better match the biology of the tumor in question. So here's the schematic for house slides. Air moving through Durham PATH labs on where the 50 X test is positioned in that process. So again dramatic pathologists are their training is really focused to identify whether Maleness that equations represent benign or malign, acidic or malignant processes. And it's readily, uh, identifiable whether additional work up is needed for these cases that are more challenging. And we have many tools in the Durham Path lab to help, UH, add more clarity, such as immune to chemical stains, deeper levels or bringing a case to local experts. Whether that's walking a case down the hall of bringing it to a daily consensus conference in the Durham Path lab, waken reach a diagnosis of a benign or malignant Pacific region for many cases that way failed to do so. On the first pass, However, there remain a significant number of cases where they're significant equivocation or ambiguity, and there are additional ancillary tests that are currently available for the MTA pathologists to help again add more clarity for these cases, a second opinion could be obtained where the case could be sent to a regional or national expert or molecular studies such as fluorescence in situ, hybridization or or a comparative genomic hybridization could be obtained as well as gene expression. Profile tests toe add more diagnostic clarity relations that are difficult to diagnose, using the routine methods of immunities to chemistry. NH Any standing. And that's really where the Dft X test is positioned for these cases with significant diagnostic ambiguity. Onda The Dft X melanoma test is fundamentally a gene expression profile test. That's an in vitro analysis of these primary cutaneous metastatic lesions, for which the malignant potential is uncertain. And as an ancillary test, it really can help to interpret leisure. Uh, characterized these lesions as benign or malignant in the context of the other clinical laboratory and hissed a pathologic information that we have about the case and when the 50 x melanoma test can do is that it's ah, 35 gene expression profile test that's again performing on this macro dissected tissue on that uses ah, proprietary algorithm to produce a score of benign with gene expression. Profile suggestive of the 90. A plasm intermediate risk, where gene expression profile cannot exclude malignancy or malignant profile that were a gene expression profile suggestive of melanoma. And the evidence that supports the Dft X melanoma test is from published development and clinical validation paper, as well as a first clinical utility study that were published at the end of 2000 and 20 in the two articles seen below from Skin, the Journal of Continuous Medicine. And I'll go through here in the next several slides describing the initial training invalidation cohort to describe the evidence that supports the use of this test. So the development efforts started with 1300 benign Levi and 1500 million melanomas that were randomly selected into a study cohort of 951 patients. These cases were subsequently divided into a training cohort and a separate independent validation cohorts seemed below. I just wanna highlight that this first, um, number here. This MGF rate here speaks to the multiple gene failure rate within the study cohort and highlights only 32 cases that were included in the study. Cohort were not able to produce a result from the DF DX essay and This speaks to a very high rate of technical success relations that were in the study cohort and submitted for testing, which we would anticipate, um, in clinical use as well. So the training cohort here was wearables will start in the second half. We'll focus on the validation co port. So for the training cohort, what we started were with archival benign samples and malignant melanoma samples with concordant diagnoses and on these samples. This is where we performed the RT PCR, with an expanded set of 76 genes at the 76 genes were subsequently reduced in the training step to a set of 30 to discriminate jeans and three control genes, using deep learning techniques and neural networks to refine a 35 gene expression profile locked algorithm. That algorithm was subsequently validated on this independent validation cohort of 503 samples, again producing these three scores of benign intermediate risk and malignant. So in the training cohort, they included a range of benign Levi and melanoma subtypes, uh, that are intended to provide evidence for how this test could be used in clinical practice to differentiate between the nine de vie and malignant melanoma. And again, this was the step where deep learning techniques and neural networks were applied to produce the 35 gene expression profile algorithm that best characterized the benign lesions as benign and malignant melanoma lesions as malignant in the clinical validation cohort, the 35 gene expression profile was subsequently validated. On this separate set of the nine Naive, I enjoyed a melanomas. Now the subtypes of nearby and melanomas are the same that for the training and validation. But the numbers are different because again, these cases were randomly included in the training and validation cohort, and they're made up of common subtypes of the 90 by, such as intradermal navy or just plastic nearby, Um, and then on the melanoma side, common subtype, such as for spreading melanoma and natural melanoma, in addition to some less common subtypes, like desmond plastic, melanoma or any void melanoma. In addition, melanoma insight to was included in both the training and validation steps. Concordance was established here for the benign lesions, with the majority of cases being three out of three concordance of three independent dramatic pathologists arriving at the same diagnosis but also a smaller subset with two out of three concordance, which I think speaks to the ability for the test to perform in concordance of three out of 32 out of three dramatic pathologist agreement. Onda performance of the test was the same in these cases with these two types of concordance here for the benign subjects, the performance by specific subtype of benign Eva's melanoma are outlined in detail and the paper here from the Estrada at all and overall, the test was able to accurately identify thes benign divide the vast majority of cases as benign, with a small rate of intermediate risk lesions and a small rate again of malignant lesions that were classified by the pressure profile test. I do wanna highlight here that of the seven Spit Steve I that were highlighted as malignant in this validation set. Six of these occurred in Children on, and as a result, the 50 X test is actually only available in the adult population, and we have additional studies ongoing to better evaluate the performance of the dft excess A and the pediatric population. So the specific performance by subtype is informing where the test is clinically available, which is currently on Lee in the adult population, and I'll speak to that when I go over the performance of the at the end of this section for the performance in melanoma. Overall, the test was able to identify the vast majority of cases of malignant melanoma as malignant with the gene expression profile with a small rate of intermediate risk and only two lesions that were classified as benign. The gene expression profile test and this performance speaks to the outstanding performance metrics here in the Validation study in the Middle column, we have the performance of the test in the all age group andan on the right, with the over 18 on gonna going to focus on the over 18 population the adult population, because this is where the test is currently clinically available, with the sensitivity and specificity of 99.1 96.2 that lead to the high positive predictive value and negative predictive value of this essay. On importantly, these accuracy metrics are calculated with only 3.8% of the cases removed. That received an intermediate risk result, which speaks to the fact that over 96% of cases that receive a result with the lefty X melanoma essay in this validation cohort would receive an actionable result of either benign or malignant, with a high rate of accuracy in this validation cohort. And so fundamentally what this test can provide for dramatic pathologists and dermatologists are slightly different. So for dramatic pathologists in cases where there significant diagnostic ambiguity, that gene expression profile can add more diagnostic clarity to reports that could lead to clear articulation of desired management plans that dermatology colleagues would follow. That's informed by a gene expression profile test of the lesion in question. For dermatologists receiving these tests receiving these results from pathology, the reports could be more clinically actionable so that in cases where there significant uncertainty, we can add clarity and confidence to the treatment plan that's initiated for these difficult, diagnosable and acidic regions. Um, informed again by the gene expression, profile and what's more seen on the bottom, there could be rapid access to Decision DX melanoma essay and where that fits in, the workflow for these difficult to diagnose cases is again for these challenging Milan acidic lesions that are currently difficult to diagnose using routine methods as an ancillary tests add additional diagnostic clarity and decision DX melanoma. You know fear can follow after the decision. Dx 50 x melanoma test. So if a lesion that's diagnostically challenging is receives a malignant result through the Dft X melanoma test and is appropriate for testing for the decision. DX Melanoma test to inform important management decisions. This test can be performed with the tissue sparing approach if the lesion is appropriate. ONDAS diagnosed formally as a melanoma by by the dramatic pathologists or treating clinician here. So the tests could go from 50 x two Decision DX melanoma when this is appropriate and can inform management decisions so again, this leads us to the second portion of the talk. The Decision DX melanoma test that's designed for invasive, continuous noma. Um, not to belabor this with this audience here, but the majority of patients who are diagnosed with invasive cutaneous melanoma are diagnosed at early stage and dermatology eyes actually that identifying early melanoma, and we have many tools that air designed to really catching on time early with DeMoss copy, total body photography and excellent skin exams in dermatology clinics, and so 92% of patients are actually stage one or stage two at the time of initial diagnosis. However, what could be missed by a staging approach on Lee is that patients who have stage one or stage to disease fundamentally patients without a positive center lymph node actually make up about 60% of the melanoma deaths. If you exclude patients who are Stage four at the time of diagnosis. And so fundamentally, what we're proposing here is that patients who are diagnosed at early stage actually experience poor outcomes, and that if we had prognostic tools that could provide more accuracy to prognosis, things could actually inform management decisions for the benefit of patients and identify patients at earlier stage may go on to experience outcomes of interest that could affect management decisions. And this could have impacts for patients because a recent study, actually just from late last year from a Canadian group, Ebrahim at all identified that patients who had um, asymptomatic imaging, who's who had imaging to detect asymptomatic recurrences had about twice twice as high likelihood of survival in patients who had symptomatic recurrences identified. And so essentially the early identification of recurrence can have impacts for patient survival, so decision DX, melanoma was developed to assess risk of recurrence that's independent of traditional clinic pathologic factors that's fundamentally based on the tumor. Biology of the Legion in question on what it is based on is a 31 gene expression profile essay using RT PCR to produce four discrete classic calls. The Class one A. The lowest risk Class one B, Class two and class to be recognizing the highest risk of the gene expression profile essay for patients with invasive cutaneous melanoma. And there's a robust range of clinical validity and clinical utility evidence that supports the use of the decision to expel in an essay to inform management decisions for our patients. And it could really address a range of important management decisions for the patients that we take care of with basic cutaneous melanoma and for the purpose of this talk will focus on two important clinical decisions that can impact treatment plans. First guiding sentinel lymph node biopsy and then assessing the risk of recurrence to inform important decisions around intensity. Ah, follow up. Whether we're dealing with the patient has a low risk for a higher risk to develop guideline appropriate management plans based on that risk of outcomes of interest. So first on the discussion of Sentinel Lymph Node biopsy Prediction. Currently, the guidelines for Sentinel Lymph node biopsy a really intended to direct sentinel node biopsy for patients who have a greater than 5% likelihood of sentinel lymph node biopsy positivity and based on pathologic stage that speaks to patients who are t one B and above Onda. Also a subset of patients with T one A. Tumors with high risk features. Such a simple vascular invasion, uncertainty of micro staging or very high. My Todd a great um, and what's important to highlight here is that the central local biopsy procedure cannot important prognostic information for patients, but that the majority of patients who received a sentence of no biopsy actually obtain a negative results. So 88% of patients we estimate who obtain a sentinel node biopsy actually have a negative sentiment, a biopsy and don't obtain additional prognostic information based on that procedure. So in a cohort and published in 2000 and 19, with 1421 patients by Doctor Gianvito and colleagues really highlighted a prospective study that could identify patients who are at low risk for having a positive sentinel lymph node. And this has been recently expanded upon with another cohort of 60 over 1600 patients, leading to over 3000 patients that we've been able to analyze with T one to t to disease, um, to really identify if we could select patients who would have a low risk of sentinel lymph node biopsy positivity, and what we found is essentially that using the the Castle class. The Decision. TX Melanoma Test. You can identify a group of patients who have a low risk of sentinel lymph node biopsy positivity when you stratify these patients by their age, so specifically in patients who are 55 years and older with a class one, a result, they had a below 5% risk of a sentinel lymph node biopsy positivity. In this study, cohort in patients over 65 had a less than 2% risk of sentinel lymph node biopsy positivity, and so based on that 5% threshold might not benefit from a sentinel lymph node. Biopsy enoughto warrant the procedure being performed on the other side of this, the class to be score even in the same age cohort had above a 5% risk and in fact, above a 10% risk of sentinel lymph node biopsy positivity and could suggest a group of patients who would significantly benefit from obtaining a sentinel lymph node biopsy to add prognostic information for the management of these patients. So moving on to decisions about their guided on the risk of recurrence for patients with invasive, continuous melanoma that could be obtained with the gene expression profile test decision. The X melanoma. So when we're counseling patients about their risk for outcomes of interest, if we turn to the A J. C C. Version eight, we obtain information about melanoma specific survival. However, melanoma specific survival is not the only outcome of interest or importance for patients and clinicians. Andi Gene expression profile testing can add information that, in addition to melanoma specific survival. But if we just look at melanoma specific survival for the purpose of this chart, this tracks nicely from Stage one Stage two, Stage three in the A. J. C. C population. However, if we layer on decision DX melanoma class score can actually articulate a significant differences from the predicted rate of the patient by stage, so even in patients with Stage one disease who have an excellent five year melanoma specific survival patients with the class one. A result had an even better or five year survival and could be additionally reassured in this cohort on def. They have a to be result. Their survival is actually, um, in the study reference below. It's more similar to that of either Stage two or Stage three, a patient here in this cohort and in the same way, patients with Stage three disease with the class when the result had a much better melanoma specific survival than did patients with the class to be results. So again, the decision DX Melanoma Test GP score could be used to essentially refined this risk, as would be predicted by the patient's stage with their melanoma specific survival. However, as I mentioned, there are other end points of interest that guide important decisions for patients with invasive melanoma that speak to the recurrence. Free survival in the distance metastases free survival, for example, and the decision DX melanoma test has had consistent results across archival retrospective, as well as multiple prospective studies that demonstrate how the decision DX melanoma score can be used to produce discreet risk groups within patients with Class one, uh in class to result from the decision to X melanoma test so we can identify Class one a Class one, Class two and class to be patients that have significant differences in their recurrence, free survival and distant metastases. Free survival and these trends are consistent across the range of these papers. I want to focus for the purpose of this talk on the largest study to date, a recent meta analysis published at the end of 2000 and 20 by Dr Greenhorn colleagues that released identified 1479 patients across four different cohorts that in the meta analysis was really looking about how the gene expression profile test can be integrated with clinical pathologic factors, too. Provide improved risk prediction for patients with basic melanoma. So overall in this meta analysis, the recurrence, free survival and distant metastases re survival is seen in these km curves. Above the class scores the Class one a class one, class two and class to be were stratified into discrete risk groups with significantly different rates of recurrence and distant metastases. So in the class one a group, the distance metastases rate was 5.5% and in the class to be group it was 38.8% Which suggests AH meaningful difference in event rate in the class one A compared to the class to be population in this in this study. So the class to be specifically had the strongest hazard ratio and multi variable analysis and importantly, is statistically significant, even when taken into consideration with other clinical pathologic factors that we know to be important for prognosis such as Breslow thickness, ulceration age and sent a lymph node biopsy status and specifically when compared with sentinel node biopsy status. ANDI Even when combined with sentinel lymph node biopsy, the gene expression profile test can add additional information that can help refine prognosis for these patients. When a highlighting that that in this meta analysis sentinel lymph node biopsy is adding important prognostic information with the sensitivity and specificity seen here of 57 74% So send them in for a biopsy performing well in this meta analysis, and even so, the gene expression profile test, when combined with the Sentinel lymph node biopsy, can produce a greater sensitivity and specificity on improved negative predictive value for recurrence, free survival and distant metastases free survival. So essentially articulating how gene expression profile testing can be integrated with the current work that we do to refine prognosis for our patients. E I wanna highlight one aspect of this data as well from this meta analysis that really focuses on the sentinel lymph node biopsy patients. So here, uh, this can curve describes 555 patients who had a who were eligible and assessed by sentinel lymph node biopsy, who had a negative sentinel lymph node. And within this group, 61% of the events in this cohort had to be results. So essentially the sensitivity here of the Castle decision DX melanoma test A 61% for recurrence events in the sentinel lymph node biopsy. Negative population in this trend holds for distant metastases as well, where 54% of the events in the sentinel lymph node biopsy negative population. Those patients had a class to be results. So I think that this evidence demonstrates how even in patients with the scent negative sentinel lymph node, biopsy the decision DX melanoma score the class to be result can add it important information toe identify group of patients who who in the study had a high rate of both occurrence events as well as distant metastases events on I think it's important for patients who have a negative sentinel lymph node in this study and then finally, on decision DX Melanoma, a recent expert panel publication from Dr Quattro and colleagues articulated how the 31 GP test the decision. DX Melanoma test can be incorporated into management for patients. Um, when you're using the patient's stage thio, refine your treatment based on the patient's risk of recurrence. So essentially, what the value of this study articulates is that you can identify patients who will basically benefit from gene expression profile testing based on both their tumor characteristics, but also some of the specific characteristics of the patient. So it breaks down how the gene expression profile test can be integrated into management for patients based on their clinical stage, but also based on their patient characteristics. So if you have a patient who is looking for additional reassurance, the gene expression profile tests can add that reassurance for a particular group of patients and in the same way, if you have a patient, is really looking for more data about endpoints of interests, such as for currents. Free survival, which is in the testes Free survival gene expression profile test, can add important prognostic information to help refine treatment that is based on the clinical stage combined with the gene expression profile result. It also I think, importantly, highlights the role of multi specialty or multi disciplinary care teams to really help make informed decisions patient care and can use the gene expression profile information conscientiously and integrate that into patient management plans. I'm at a high level. So overall the decision, TX Melanoma has a robust um underlying evidence that supports its clinical use. With over 5700 patients that have been included in both retrospective and prospective studies over 26 to date and for clinical testing, over 59,000 patients have been tested from over 6800 conditions here in the United States. Onda. The strength of the evidence has led to Medicare approval for this test. Andi Eyes is clinically available toe for the benefit of patients. Onda clinicians who are making decisions guiding their care. So for the last section of this talk, I'm going to just speak briefly on decision DX SCC, which is for patients with cutaneous squamous cell carcinoma with one or more high risk features that was just launched the end of August here. So I noticed the shifting gears from the talk here today. But cutaneous squamous cell carcinoma is an emerging problem here in the United States, and based on the high incidence of cutaneous squamous cell carcinoma, has a significant disease related mortality in the United States. And unlike melanoma or breast cancer, squamous cell carcinoma does not have other personalized at tests that can add value by using gene expression. Profile to produce a more refined sense of patient risk of poor outcomes and current staging. Relying on clinical factors or clinical staging systems have a low positive predictive value for identifying patients will go on to experience poor outcomes. On DSO, the unmet clinical need is developing gene expression profile test that can add in this prediction toe identify patients who will go on toe have thes poor outcomes. So fundamentally the decision. The ex SEC test is intended for patients with cutaneous squamous cell carcinoma with one or more high risk factors to help inform individual risk of metastases to then guide risk appropriate management decisions. Now the high risk factors in squamous cell carcinoma are, of course, different from those in melanoma and speak to things that are identified both on clinical exam as well as on review of history. Ethology so, uh, tumors with a very large size over two centimeters, Um, patients were immuno suppressed, as well as some histological findings such as Perry in Ireland, Perry Neural invasion, poor differentiation on histology or very deep invasion. All of these air considered high risk factors that could identify the clinicians, which patients might benefit from gene expression profile test information to refine their risk of metastases. So the decision to ex SEC test is a 40 gene gene expression profile essay that uses validated neural network algorithm to produce one of three class calls, Class one or a low biological risk class to A with a moderate biological risk for class to be with the high biological risk. As a result of testing the evidence that supports the decision, the SCC test has also been published. The Discovery development invalidation is published in paper by Dr Wysong at All. Um, in the chat of this past year, Onder several clinical utility papers have also been published, and I'll also be presenting some data that remains unpublished. Hear from Castle from the upcoming slides. So the decision DX SEC test is fundamentally validated to predict metastatic risk for these patients with continuous witness across them and one or more high risk factors. And as a result of testing that we identified three groups the Class one Class two A in class to be patients that had statistically significant event rates over the three year period of this validation so that the Class One patients had a 6.6% overall event rate of metastases in this cohort in the class to be had a 52.2% event rate. Speaking to the high positive predictive value of this essay, the distribution of the class calls is such that about half of the patients had a class one or low biological risk score and about half had a class to class to a or class to be class call in this Study co board. When we look at the statistical significance and the impact of this class call from the gene expression profile we're looking to compare to the current risk factors that we used to guide our patient decision. So on, you know, very analysis some of the things that we know produce high risk squamous cell carcinoma, searches, parenthood, invasion, deep invasion and for differentiation or statistically significant as as well as the Class two, a result with similar hazard ratios to any of thes independent features that we know are high risk on multi variant analysis. The Class two A also remained significant in addition to for differentiation and deep invasion, suggesting that the Class two a call could be integrated with the other known risk factors to produce a more refined sense of risk. Metastases for a patient with a class to a result. And what's more, the class to be result had a uneven, stronger hazard ratio. That's about three times the risk of any of the known risk factors here on, you know, very analysis. And this pattern holds up on Multivariate analysis, really suggesting that the class to be result and highlight patients who have a very high risk of metastases. Andi can be linked with these other risk factors to produce an even more refined sense of metastatic risk in patients with cutaneous squamous cell carcinoma. One of these high risk factors. Energy and expression. Profile of class to a or class to be eso based on staging. Currently there are different approaches that air used clinically, and if you have a factor based approach where you're essentially adding up or summing clinical risk factors, the decision T X SEC class call can be added to this assessment to producing even more refined risk of metastases. So here, with patients who had over two risk factors on the K M curve here on the right, this is a group of patients have a high risk of events in the study cohort, with a risk in the overall population here of almost 20%. However, the Class one patients had about a 9% risk in this cohort, about half of the total risk in this group of patients, whereas the class to be patients had a 50% of that rate. On the Class two A patients had about 25%. So again, classical can identify three discrete risk groups within patients who have over one or two risk factors that could be clinically meaningful when deciding how to manage these patients, using a risk based approach in thinking about the risk of metastases. If you're using formal staging guidelines as well, such as Brigham and Women's or A. J. C. C. We think that the gene expression profile test can add independent information that can further clarify the patient's risk of recurrence. So again, if you look at a group of patients who are either Brigham and Women's T to be or T three, the Castle class score of either to a or two B can add additional information to produce a more refined sense of this patient's risk of metastases, even when you account for their Brigham and Women's or a J. C C class score here on this multi variable analysis. So again, the the purpose of this test is to integrate the gene expression profile test with the clinical pathologic risk factors to develop risk appropriate management plans, and some of these plans may include for your low intensity patients, definitive surgery for all of these high risk squamous cell carcinomas, as well as a clinical nodal exam and then return to, um ah follow up interval that matches that of patients with a high risk, you genius squamous cell carcinoma. However, if in combination with the gene expression, profile result and the clinical pathologic features, it's possible to identify patients who would benefit from moderate intensity or even a high intensity follow up plan based on this risk of recurrence. That could include ah greater intensity of nodal image ing or nodal evaluation effect effectively as well as consideration for multi disciplinary clinics that could include colleagues in search of oncology or even medical oncology, depending on the tumor characteristics, uh, there gene expression, profile and their risk of recurrence. And so essentially this information may inform management plans That could be more risk appropriate for patients with high risks from us, of course. And so I know that's a lot of information for a short discussion here. But I hope that I was able to present the molecular program that we have here a Castle Biosciences that really aims to address important, clinically impactful, cutaneous malignancies and dissent, and that these tests are designed to inform difficult management decisions for clinicians for the benefit of patient care on the diagnostic side with the decision. DX 50 X Melanoma test for these difficult to diagnose swine acidic lesions. The Decision DX melanoma test for patients with invasive cutaneous melanoma and the decision DX SEC for patients with cutaneous squamous cell carcinoma with one or more high risk factors. So I thank you for your attention, and I hope that we have time for some additional questions here. So I'm going to turn to the chat here. All right, so 1st, 1st question here on the def. TX Melanoma test Looking at 18 as a as a cut off. The question here is, you know, some in clinical practice use puberty is a cut off for adults in terms of biology. Andi, in this cohort of the Spitzer TV that were classified as malignant in the validation cohort, those were all in patients under the age of eight. So we did not have patients age 14 through 18 in the validation cohort, and I do think that the question here is is it worth moving the age delineation? I think that's a fantastic question and something that we're really focused on through future research, where we're going to focus on the pediatric population and the application of the Dft X melanoma test specifically in pediatric patients looking at Spit Steve I, um, Spitzer, melanoma and pediatric melanoma to really identify where that cut point could be and 18 at this time is really focused on where the bulk of the patients are in the validation, Um, and until we can move the test range earlier, we'll keep it to 18. But that's a great question. Puberty could be a more appropriate endpoint because again, those misclassified cases in the validation were limited to the under eight population. Okay, another test question here. Just about the decision in the x 50 x melanoma. I'm a focus on first looking at the MGF rate, and the MGF rate is similar in the 50 x melanoma Validation, as it is with other products, Way have a lot of experience in the the Castle about Sciences Lab to have robust essays that have a good ability to extract RNA from the form of expression, it better tissue and the the success rates are even higher, actually for some of the other assays in clinical use. But the 3% range I think is an expected range that way can anticipate this to be effective. And I think for the 50 x melanoma test, that rate is so high of technical success. Because the cut off for testing performance is actually 10% tumor content on DSO, it can be focused on visions where there's a smaller amount of material fundamentally, and the test is has robust processing effectively to be able to produce a score even in the setting of small regions. So I think that you know the performance of the S. They should be expected to be in that range based on the experience with using those results. Mhm have a test question here. So I have a patient with a 0.5 millimeter Breslow on a shave biopsy with a class to be, uh, would it be wise to actually recommend on our pathology report to do a sentinel lymph node biopsy? Or is that mentioned somewhere in your report? That's another good question. I think that, you know, at Castle, the reports are not prescriptive about what must be done clinically as a result of the test, it's really we present the information the strength of it. We believe what helps clinicians interpreted in the context of their practice to then have that inform their management decisions were working on updates of our report, which will hopefully be forthcoming to provide some additional clarity around how the clinical pathologic factors can be integrated with Castle class score to provide, you know, clearer sense of the patient's risk of recurrence. Sorry. Excuse me. Risk of sand 11 or biopsy in our large data sets on DSM of that. You know, for example, in this example of 0.5 millimeters in a class to be, it may depend on the patient ages well to guide the strength of your recommendation. Whether that's in the 5 to 10% risk range greater than 10% risk range, which may change how you council thinks patients. So at present, the information is presented really in a descriptive way about the strength of the evidence that we have on Ben. Having physicians integrate that into practice based on their assessment of interpretation of the data on Booth patients preferences. Well, so I think they're looking to that Quattro manuscript that I was referencing could be helpful to kind of think about how to integrate this into practice, thinking about the tumor in question, combining that with the castle class. Score another question here about spindle cell squamous cell carcinoma and whether or not decision to ex SEC could be applicable to those cases. And so the sorry. There's another aspect of this year talking about using center carried in stains or other special stains to characterize these a squamous cell carcinomas. I will highlight that a definitive diagnosis of continuous squamous cell carcinoma is required to run the decision. The SCC test ah 100% of the cases that were included in testing and validation were confirmed to be continuous chemical carcinomas. That's a that's a nen tree point to have the test run spend also is considered to be an aggressive subtype of squamous cell carcinoma, potentially linked to poor outcomes, and so that is considered to be a high risk factor and would allow testing for the decision. The ex SEC, which more is that often spindle cell squamous cell carcinomas can be deeply invasive or have poorly defined borders, and so those are other factors that could motivate testing for decision. The ex SEC. But I think It's a great point that it must be confirmed to be a squamous cell carcinoma, uh, for in order to allow testing looking another question here about squamous cell carcinoma. How we validate the impact of the test results on management. It's a great question. This test was just commercially released the end of August on DSO. Looking at how this will be affect management decisions is something that we're really focused on moving forward. We have ongoing prospective studies to further, um, describe the test performance in clinical practice when addressing cutaneous squamous cell carcinoma, as well as looking at significant endpoints that are currently debated in the management of high risk for us, of course amendments. So we're thinking about studies to address radiation therapy, a specific endpoint to really help toe determine how the identification of tumors that are higher rate of metastases or higher risk from metastases might be managed differently when you combine their risk factors and the gene expression profile test. So definitely something that we're going to be focused on, I'm to ensure that we can evaluate how this will impact management decisions. I think that those air the questions that we have here. Um, if there are others, please list them here. I think we have a little bit more time. I'd be happy to address any questions they're concerned about. The the range of the three tests was predictable. Okay, so I don't see any more questions here that are that are coming up. But I do want to thank you all for your attention. I will stay on until the end of time here at the end of the time here for the session, not the end of all time, but the I really appreciate your attention today. This is one of the first times when we're presenting the full, the full range of a diagnostic and prognostic tests. I hear that Castle Biosciences now has available. So I appreciate your attention across the range of those products. And I hope that the rest of the meeting here for the for the conference goes well, thank you again. Mhm.
