PowerPoint Presentation For patients with T1aHR-T2 cutaneous melanoma (n=582),3 we compared the i31-GEP profile the MIA nomogram in patients with T1a-HR – T2 melanomas. Precision was evaluated using 95% CIs for the MIA and the i31-GEP. MIA 95% CIs obtained directly from the online calculator. i31-GEP 95% CIs obtained using a Lowess spline. The integrated 31-gene expression profile (i31-GEP) test for cutaneous melanoma outperforms a clinicopathologic-only nomogram at identifying patients who can safely forego sentinel lymph node biopsy. Background › National Comprehensive Cancer Network (NCCN) guidelines recommend forgoing sentinel lymph node biopsy (SLNB) if the population-based point-estimate risk of positivity is <5% (T1a with no high-risk features), discuss and consider SLNB if the risk is 5-10% (T1a with high-risk feature(s), T1b), and recommend SLNB if the risk is >10% (T2-T4).1 › As it relates to guiding SLNB recommendations, clinicians know that using T-stage provides a broad bin for recommendations, but the precision of these population- based point estimates has generally not been published. › Novel tools have been developed to improve SLNB recommendations. Most recently, the integrated 31-gene expression profile (i31-GEP) which combines the 31-GEP with clinical and pathological factors was developed to identify patients who can safely forego SLNB and also provides risk of recurrence outcomes.3-10 Separately, the Melanoma Institute of Australia (MIA) developed a nomogram using only clinical and pathological features, some of which were not included in the i31- GEP.11-12 Most importantly, the MIA model does not include genomic evaluation of the melanoma (Table 1). Acknowledgments & Disclosures References › Funding provided by Castle Biosciences. › AJ and PP are on the speaker's bureau for Castle Biosciences. CB and BM are employees and stock and options holders at Castle Biosciences. Methods Presented at the 2022 Fall Clinical Dermatology Conference. Abel Jarell, MD,1 Christine Bailey, MPH,2 Brian Martin, PhD,2 Peter Prieto, MD, MPH3 1Northeast Dermatology Associates, PC, Portsmouth, NH, 2Castle Biosciences, Inc., Friendswood, TX, 3University of Rochester Medical Center, Rochester, NY › Actionability requires precision, defined here as confidence in a risk prediction of SLN+ below the threshold (≤10%) where SLNB is recommended to be ‘offered’. › All patients identified as having <5% risk by the i31-GEP had upper 95% CIs ≤10%; meaning none of these patients would have been ‘offered’ an SLNB under current guidelines. › In contrast, using the MIA nomogram, only 0.9% of the entire cohort had an SLN+ risk <5% with 95% CI ≤10%, suggesting lack of confidence in the estimate of risk and, thus, in the decision to forgo the SLNB. › Separately, in a previously published cohort (n=433), patients that had an i31-GEP predicted SLN positivity risk <5% had a 5-year distant metastasis free survival rate of >98%,7 an outcome not reported by this MIA nomogram. › In this multi-center cohort of 582 patients, the i31-GEP was superior to MIA in identifying T1aHR-T2 patients who could avoid SLNB. Furthermore, the i31-GEP identified more patients traditionally thought to have a 5-10% risk (T1aHR- T1b tumors) who had <5% risk (141 vs. 4) and could forego SLNB. Summary & Conclusions Scan or click here for more info 1. National Comprehensive Cancer Guidelines, v2, 2022. 2. Chen et al. Oncotarget. 2016. 3. Whitman et al. JCO PO 2021. 5. Vetto et al. Future Oncology. 2019. 6. Hsueh et al. JCO PO 2021. 7. Jarell et al. JAAD. 2022. 8. Arnot et al. AJS. 2021. 9. Dillon et al. CMRO.2022. 10. Ahmed et al. Cancer Med. 2022. 11. Lo et al. JCO 2020. 12. El Sharouni et al. BJD. 2021. 13. Vickers et al. BMJ. 2016. 14. Vickers et al. Diagn Progn Res. 2019. Figure 1. Comparing point-estimate and 95% CIs for i31- GEP and MIA model and i31-GEP (T1aHR-T2) › MIA identified 20.8% (121/582) of patients as having <5% positivity risk, but just 0.9% (5/582) of patients had <5% risk with upper 95% CIs ≤10%, casting doubt on the ability of the MIA nomogram to provide precise, actionable, risk assessment. › The i31-GEP identified 28.5% (166/582) of patients as having <5% positivity risk with 100% (166/166) of the upper 95% CIs being ≤10%, indicating confidence in the i31-GEPs ability to provide actionable risk estimates. Table 1: Variables included in i31-GEP test or MIA Model Potential Prediction Variables Included in i31-GEP Test Relative Importance* Included in MIA Model Relative Importance** 31-GEP continuous score √ 91.3 P<.001 Breslow thickness √ 53.5 P<.001 √ 1.75 (per mm) Mitotic Rate √ 20.7 P<.001 √ 1.89-2.47 (1-4+/mm2) Ulceration √ 19.1 P<.001 √ 1.32 (presence) Age √ 10.5 P=.001 √ 0.97 (per year) TILS LVI √ 4.31 (presence) Microsatellites Sex Histopathologic subtype √ 0.06– 2.15 (pure desmoplastic-acral) Transected bases Tumor Site Regression *Log-likelihood value (G2); reported in Whitman et al. 2021. **Odds ratio; reported in Lo et al. 2020 › Patients are included in the <5% risk category when the upper 95% CI is also ≤10%. Patients are included in the >10% risk category when the lower 95% CI is also ≥5%. Table 2. Reclassification of risk in patients with 5-10% risk (T1aHR- T1b tumors) for whom guidance is not definitive. Test NCCN risk Reclassified as <5% risk, % (n/N) Reclassified as >10% risk, % (n/N) Total reclassified, % (n/N) i31-GEP 5-10% risk (T1aHR-T1b), N=284 49.6% (141/284) 10.6% (30/284) 60.2% (171/284) MIA 1.4% (4/284) 12.3% (35/284) 13.7% (39/284) Clinical Issue and Aim To make evidence-based decisions about performing SLNB, clinicians should have confidence that patients predicted to have <5% risk by a model are truly low-risk based on the model's precision, measured by 95% CIs that do not cross clinically relevant decision thresholds. To answer this clinical question, we evaluated the i31-GEP and subsequently compared it to the Melanoma Institute of Australia (MIA) developed nomogram model. https://castlebiosciences.com/research-development/publications/