The Dermatology Digest • Innovations in Personalized Medicine November/December 2024 Supplement • Journal Review

Development and Validation Study Data Demonstrate Accuracy of i31-GEP SLN Status Prediction, Point to Benefits for its More Precise, Personalized Risk Prediction

The integrated 31-gene expression profile (i31- GEP) test combining the continuous 31-GEP score with clinicopathologic features optimizes prediction of sentinel lymph node (SLN) positivity in patients with any stage primary cutaneous melanoma, according to research published in JCO Precision Oncology.

Using the i31-GEP to provide precise personalized information could therefore reduce the number of unnecessary SLN biopsies (SLNB) and improve the identification of patients likely to have a positive result who may benefit most, said investigators who developed and validated the tool.

The i31-GEP artificial intelligence algorithm for SLN risk prediction was developed using data from a training cohort of 1,398 patients with primary cutaneous melanoma tumors (T1-T4) having known Breslow thickness and a continuous 31-GEP test result. Models were generated using the continuous 31-GEP test result, Breslow thickness, and multiple other clinicopathologic features. The continuous 31-GEP score was found to be the most important variable and best predictor of SLN positivity among all covariates.

Performance validation of the i31-GEP for predicting SLN positivity was conducted using retrospective data from an independent cohort of 1,674 patients with T1-T4 disease seen across 30 centers. Linear regression analysis showed high concordance between the observed SLN positivity rates and those predicted by the i31- GEP (slope = 0.999).

The validation study also assessed accuracy of the i31-GEP by considering a predicted likelihood of a positive SLN <5% as a negative test and a ≥5% likelihood of SLN positivity as a positive test. Using these criteria and data from the entire patient population, the i31-GEP demonstrated sensitivity of 95.1% for predicting SLN positivity and a negative predictive value of 98.1% (false negative rate of 1.9%). Further analysis considering the subgroup of patients for which additional guidance on the decision to perform SLNB is needed (i.e., patients with T2 disease or considered to have “high-risk” T1a disease based on their clinicopathologic features) showed the sensitivity and negative predictive value of the i31-GEP remained high (89.8% and 97.4%, respectively).

The i31-GEP demonstrated sensitivity of 95.1% for predicting SLN positivity and a negative predictive value of 98.1% (false negative rate of 1.9%).

Comparing the i31-GEP risk predictions to those risk classifications based on T stage alone as per National Comprehensive Cancer Network (NCCN) guidelines, showed that use of the i31-GEP test would result in significant risk reclassification. The percentage of patients in the overall cohort predicted to have <5% SLN positivity risk was increased threefold using the i31-GEP test versus the NCCN guidelines (from 8.5% to 27.7%). Applying the i31-GEP to the subgroup of patients with T1 tumors predicted to have 5%-10% risk of SLN positivity by the NCCN guidelines resulted in restratification (risk prediction downgrading to <5% or upgrading to >10%) in 63% of cases.

Data on recurrence-free, distant metastasis-free, and overall survival calculated in a subset of 312 patients with long-term follow-up corresponded with the i31-GEP SLN positivity predictions. These analyses showed that patients with an i31-GEP predicted <5% risk of SLN positivity had significantly better outcomes for all three endpoints relative to both their node-positive and node-negative counterparts with a ≥5% predicted SLN positivity likelihood.

The authors observed that the significant additional prognostic information on survival provided by integrating tumor molecular characteristics using the 31-GEP test may allow clinicians to make more precise risk assessment and more personalized clinical management decisions for patients with cutaneous melanoma, which may improve patient outcomes.

TO READ MORE: Whitman ED, Koshenkov VP, Gastman BR, et al. Integrating 31-gene expression profiling with clinicopathologic features to optimize cutaneous melanoma sentinel lymph node metastasis prediction. JCO Precis Oncol. 2021;5.21.00162. doi:10.1200/PO.21.00162.

Real-world Study Data Demonstrate 31-GEP Test Performance for Predicting Survival Outcomes of Cutaneous Melanoma Patients

A population-based study analyzing real-world data confirms the ability of the 31-gene expression profile (31-GEP) test to stratify patients with stage I-III cutaneous melanoma by risk of dying from their skin cancer. The research also showed that the test was an independent predictor of 3-year survival outcomes and that patients who had the test had significantly higher 3-year survival rates compared to a propensity score-matched cohort of non-tested patients.

Commenting on the relevance of the findings, which were published in JCO Precision Oncology, the authors observed that the significant additional prognostic information on survival provided by integrating tumor molecular characteristics using the 31-GEP test may allow clinicians to make more precise risk assessment and more personalized clinical management decisions for patients with cutaneous melanoma, which may improve patient outcomes.

The study was conducted as a collaboration between the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program and Castle Biosciences. It linked 4,687 patients with stage I-III cutaneous melanoma who had a 31-GEP test between 2016 and 2018 to SEER registry data.

Using Kaplan-Meier analysis, 3-year melanoma-specific survival (MSS) and overall survival (OS) rates were determined with patients stratified by their 31-GEP risk category: low (class 1A), intermediate (class 1B/2A), and high (class 2B). The results showed that both the MSS and OS rates decreased across worsening risk category. The differences in survival rates between risk category groups were analyzed using the log-rank test and showed that patients in the low risk 31-GEP group had significantly higher survival rates than those with an intermediate or high risk 31-GEP result (MSS: 99.7% vs 97.1% vs 89.6%, P < .001; OS: 96.6% vs 90.2% vs 79.4%; P <.001).

The investigators also performed a multivariable Cox regression analysis to identify independent predictors of survival in the 31-GEP-tested cohort. Using the 31-GEP low risk cohort group as the reference group, the results showed that both an intermediate 31-GEP result and a high risk 31-GEP result were independent predictors of both MSS (intermediate risk: hazard ratio [HR], 4.86; 95% confidence interval [CI], 1.97 to 12.03; high risk: HR 7.00; 95% CI, 2.70 to 18.00) and OS (intermediate risk: HR, 2.22; 95% CI,1.51 to 3.25; high risk: HR, 2.39; 95% CI, 1.54 to 3.70).

MSS and OS mortality rates were also compared between the entire 31-GEP tested cohort and a propensity score-matched group of patients identified in the SEER database who did not have 31-GEP testing. Results of the Cox proportional hazards analysis showed significantly better outcomes for both endpoints among patients who had 31-GEP testing. Compared to the untested group, 31-GEP testing was associated with a 29% lower MSS mortality rate (HR, 0.71; 95% CI, 0.53 to 0.94) and a 17% lower overall mortality rate (HR, 0.83; 95% CI, 0.70 to 0.99). The robustness of the findings was confirmed when the analyses were repeated using 1,000 randomly resampled subsets of qualified, untested patients.

TO READ MORE: Bailey CN, Martin BJ, Petkov VI, et al. 31-gene expression profile testing in cutaneous melanoma and survival outcomes in a population-based analysis: a SEER collaboration. JCO Precis Oncol. 2023;7. doi:10.1200/PO.23.00044.

Independent Study Demonstrates Performance and Clinical Value of i31-GEP Test for Predicting SLN Positivity

Results from a single center study investigating the performance of the integrated 31-gene expression profile (i31-GEP) test for predicting sentinel lymph node (SLN) positivity add to evidence about the utility of this risk stratification tool for guiding decisions for performing SLN biopsy (SLNB).

The study was conducted by researchers at the ChristianaCare Helen F. Graham Cancer Center & Research Institute in Newark, DE, as an independent validation trial. It included 156 patients who underwent SLNB, of whom 45 (29%) had a T1 tumor, 46 (30%) had a T2 tumor, and 65 (41%) had a T3-T4 tumor. The i31-GEP test identified 30 (19.2%) patients as having <5% risk for SLN positivity, 32 (20.5%) as being at 5-10% risk, and 94 (60.5%) having a >10% risk. Thirty of the 94 patients identified as having a >10% risk of SLN positivity had a T1-T2 tumor, while no patient with a T3-T4 tumor was identified by the i31-GEP as having <5% risk of SLN positivity.

Looking at SLNB results, the study showed that none of the 30 patients considered low risk for SLN positivity by i31-GEP testing had a positive SLNB while the SLNB was positive in 30 (31.9%) of the 94 patients estimated to have a >10% risk of SLNB positivity. The actual SLN positivity rate was similar in patients with a T1-T2 tumor and i31-GEP predicted risk of SLN positivity >10% compared to patients with T3-T4 tumors (31.3%).

Applying the i31-GEP results to patient care decisions such that SLNB would not have been performed in the 30 low-risk individuals with an i31-GEP predicted SLN positivity risk <5% would reduce the number of unnecessary biopsies by 19.2% (P < .001) when the analysis considered the entire study population of 156 patients.

Within the subgroup of 91 patients with T1-T2 tumors, foregoing SLNB in the 30 patients with a <5% predicted risk of SLN positivity would have reduced the number of unnecessary biopsies by 33.0%.

Based on their findings, the investigators concluded that used preoperatively as an additional tool to guide shared decision-making, the i31- GEP can beneficially alter patient care, avoid unnecessary biopsies, and increase the positivity rate when SLNB is performed.

An additional analysis of data collected in DECIDE showed that had the i31-GEP test result been used to inform management decisions for SLNB for all patients, it could have reduced the number of unnecessary SLNB procedures by approximately 25%.

TO READ MORE: Kriza C, Martin B, Bailey CN, et al. Integrating the melanoma 31-gene expression profile test with clinical and pathologic features can provide personalized precision estimates for sentinel lymph node positivity: an independent performance cohort. World J Surg Oncol. 2024;22(1):228. https://pubmed.ncbi.nlm.nih.gov/39215342/

Prospective Study Validates i31-GEP Test Performance for Guiding SLNB Decisions

The integrated 31-gene expression profile test (i31-GEP) offers an accurate and precise clinical tool for identifying patients with T1-T2 cutaneous melanoma who may safely forego sentinel lymph node biopsy (SLNB), thereby reducing the number of patients who undergo this costly and invasive procedure, according to findings from DECIDE that were presented at the 2024 annual meeting of the Society of Surgical Oncology.

DECIDE is a prospective, multicenter validation study designed to investigate the impact of the i31-GEP test on SLNB decisions and clinical outcomes in patients with a recent diagnosis of T1-T2 melanoma being considered for SLNB. Its results showed that among patients with an i31-GEP predicted risk of SLN positivity <5%, no patient had a positive SLN. An additional analysis of data collected in DECIDE showed that had the i31-GEP test result been used to inform management decisions for SLNB for all patients, it could have reduced the number of unnecessary SLNB procedures by approximately 25%. As further evidence supporting use of the i31-GEP test for identifying patients who may safely forego SLNB, data from 3 years of follow- up in DECIDE showed that 100% of patients who had a Class 1A 31-GEP test result remained recurrence-free.

Participants in DECIDE were adults (aged ≥18 years) being considered for SLNB after having a primary melanoma diagnosis within the previous 2 months. The decision to proceed with SLNB was made on a shared basis between the patient and physician, taking into account results of the GEP test along with other factors, including patient preference.

Many of these individuals experience fear of cancer recurrence and suffer other emotions relating to their diagnosis and need for follow-up that have a profound negative impact on their lives and psychological well-being, according to findings from a recent study.

Among the 322 patients enrolled in DECIDE, 140 (43.5%) underwent SLNB, of which 35 (24.8%) insisted on having SLNB despite having an i31-GEP SLNB predicted risk of <5%. The latter 35 patients included 11 patients with T1a disease, 19 patients with T1b disease, 4 patients with a T2a tumor, and 1 patient with T2b disease. None of the 35 patients had a positive SLN.

Data from DECIDE were also analyzed to determine the survival rate of patients with a low risk 31-GEP test result (Class 1A) who did not undergo SLNB. This analysis included 68 patients and found that after 3 years of follow-up, they were all recurrence-free.

In addition, DECIDE provided evidence that fewer SLNBs are performed when physicians incorporate the 31-GEP test to inform management decisions. The impact of the test on SLNB performance was investigated by comparing the rate of the surgical procedure in the DECIDE population and in a similarly sized cohort of patients who did not have 31-GEP testing who were matched by age, T-stage, and mitotic rate. The results showed that SLNB was performed in 200 (62.1%) of the 322 patients who did not have the 31-GEP test compared with only 140 (43.5%) of the DECIDE participants. The 18.6% difference in SLNB rate between the two groups was highly statistically significant (P < .001). Excluding the 35 patients in DECIDE who insisted on having SLNB despite having an SLNB predicted risk of <5%, the SLNB rate would have been further reduced to just 32.6% (105/322 patients).

Patients who have undergone surgical treatment for localized cutaneous melanoma have an excellent prognosis. Nevertheless, many of these individuals experience fear of cancer recurrence and suffer other emotions relating to their diagnosis and need for follow-up that have a profound negative impact on their lives and psychological well-being, according to findings from a recent study.

Citing a gap in knowledge about the repercussions of a localized melanoma diagnosis, researchers from the University of Texas, Austin aimed to delve into the lived experiences and fear of cancer recurrence among adults who were survivors of localized cutaneous melanoma (stages 0 to IIA). Data were collected using semi-structured interviews and the Fear of Cancer Recurrence Inventory short form (FCRI-SF) survey.

A total of 51 patients participated in the study at an average of about 4 years after their most recent melanoma diagnosis. The subjects had a mean age of 49.5 years and overall were well-educated and of higher-than-average socioeconomic status. With one exception, all participants were White, two-thirds of the cohort were female, one-third had been treated for stage 0 melanoma, and the remaining individuals had at least one diagnosis of invasive melanoma (stage I-IIA).

Analyses of the participants’ interview responses revealed anxiety and/or worry about need for future biopsy, diagnosis of new or recurrent melanoma, and family members’ risk. Negative emotions also emerged in association with lifestyle changes initiated to reduce sun exposure, and the participants experienced increased thoughts about death, relating to both melanoma and other cancers.

Results of the FCRI-SF showed that 75% of the participants (38/51) had a score ≥13, which is the threshold for having a clinical fear of cancer recurrence. Mean scores on the FCRI-SF were similar for patients who had a stage 0 cancer compared to those with stage I-IIA melanoma.

The researchers concluded that the findings indicate the importance of addressing the psychological well-being of patients with early melanoma. They also suggested that the potential psychological harms identified in their study should be considered when assessing the potential risks and benefits of melanoma screening.

The age-adjusted annual melanoma mortality rate in the United States decreased significantly between 2013 and 2020, according to a recently published analysis of nationwide data. However, the research also identified variations in this trend reflecting persisting demographic- and geographic-related disparities, and the investigators suggested that the findings can help inform targeted interventions to achieve further reductions in melanoma mortality.

The research, which represents the first U.S. population-based study assessing demographic differences in melanoma mortality trends in the era of checkpoint inhibitor treatments for melanoma, extracted information from the Centers for Disease Control Wide Ranging Online Data for Epidemiologic Research (CDC WONDER) database for the years 1999 to 2020. It identified 184,416 melanoma-related deaths and calculated that the annual age-adjusted melanoma mortality rate dropped from 2.7 per 100,000 people in 1999 to 2.0 per 100,000 people in 2020, representing an annual percentage decrease of 1.3%. Trend analysis showed that the mortality rate was relatively stable until 2013, declined at an annual rate of 6.6% between 2013 and 2017, and continued to fall thereafter but at a slower annual rate of 1.6%.

Differences in mortality related to demographic and geographic factors were investigated by analyses that stratified patient data by sex, race, age (25-44, 45-64, 65+), geographic density (urban, suburban, rural), and U.S. census region. Notably, the findings showed the melanoma mortality rate was higher in men compared to women, non-Hispanic Whites compared to all other racial groups, and in individuals aged >65 years compared to their younger counterparts. Analyses for geographic differences showed the mortality rate was higher among rural dwellers compared to urban and suburban populations and generally similar across U.S. census regions, although the decrease in mortality rate was greatest in the South.

Notably, the findings showed the melanoma mortality rate was higher in men compared to women, non- Hispanic Whites compared to all other racial groups, and in individuals aged >65 years compared to their younger counterparts.

The investigators proposed that improved diagnostic and therapeutic approaches along with increased public education may explain the documented decrease in melanoma mortality. At the same time, they called for targeting vulnerable subgroups with increased screening and education to further reduce melanoma mortality and existing disparities.

TO READ MORE: Didier AJ, Nandwani SV, Watkins D, et al. Patterns and trends in melanoma mortality in the United States, 1999-2020. BMC Cancer. 2024;24(1):790. https://pubmed.ncbi.nlm.nih.gov/38956559/

Swedish Epidemiologic Study Offers Encouraging News on Melanoma Incidence and Mortality

Findings of a nationwide cohort study analyzing data from the Swedish Melanoma Registry and Swedish Cancer Registry provide hope for seeing decreases in both melanoma incidence and mortality rates in Sweden in the future.

The two national registries used for the research cover more than 99% of all primary invasive cutaneous melanomas diagnosed in Sweden. The study examined melanoma and incidence trends in individuals younger than the average age of melanoma onset using data for all patients diagnosed with a primary invasive cutaneous melanoma from 1990 to 2022.

A total of 34,800 melanoma cases in 33,324 individuals younger than 60 years of age were found, of which 56.3% were in females and 43.7% in males. With patients categorized into subgroups by decade of age, the annual melanoma incidence rate was found to increase continuously over the study period in the 50- to 59-year-old subgroup. However, the annual incidence rate for the 20- to 29-year-olds, 30- to 39-year-olds, and 40- to 59-year-olds peaked between 2013 and 2015 and remained stable or declined significantly thereafter. Melanoma mortality also declined significantly over time in the 30- to 39-year-old, 40- to 49-year-old, and 50- to 59-year-old subgroups. Melanoma incidence in the subgroup aged <20 years was low throughout the study period and showed no significant trends.

The study did not aim to identify factors that might explain the observed trends, and the investigators suggested a need for further studies to address this question. However, they proposed several possibilities, including raised public awareness about ultraviolet protection as well as changing population demographics and availability of effective therapeutics for melanoma.

TO READ MORE: Helgadottir H, Mikiver R, Schultz K, et al. Melanoma incidence and mortality trends in Sweden. JAMA Dermatol. 2024;160(11):1201-1210. doi:10.1001/jamadermatol.2024.3514.

SEER Data Analysis: COVID-19 Pandemic Led to More Advanced Melanoma Diagnoses

Missed routine doctor visits in 2020 as a consequence of the COVID-19 pandemic seem to have led to a dramatic reduction in total melanoma incidence but an increase in Breslow thickness among diagnosed tumors.

To investigate the potential impact of the COVID-19 pandemic on melanoma screening and diagnosis, researchers from the University of Buffalo and Columbia University in New York analyzed data from the November 2022 SEER data submission for cancers diagnosed during the first year of the pandemic. A lookback at historical data showed rising rates of melanoma diagnoses in the 20 years prior to onset of the COVID-19 pandemic—the annual percent change in melanoma incidence increased 3.3% from 2000 to 2005 and by 1.1% between 2005 and 2019. In 2020, however, the reported melanoma incidence dropped by 16.3% compared with the previous year.

Data on Breslow thickness at time of diagnosis were compared between a pre-pandemic period from January 1, 2017, to March 14, 2020, and the pandemic period from March 15, 2020, to March 31, 2022. The results showed a 67% increase in mean thickness between the two timeframes, from 1.80mm in the pre-pandemic period to 3.00 mm for tumors diagnosed in the first 2 years after the beginning of the pandemic.

The investigators noted that further research is needed to fully understand the impact of the pandemic on melanoma incidence, stage at presentation, and patient survival. Recognizing that melanoma can be fatal if not diagnosed and treated early, however, they concluded that their findings speak to the importance of prioritizing melanoma screening, even in times of public health emergency.

TO READ MORE: Kent JA, Schreidah CM, Gordon ER, et al. Incidence of melanoma during the COVID-19 pandemic: SEER database analysis. J Am Acad Dermatol. 2024;91(3 Suppl):ab54.

Study Characterizing Sun-protective Practices Identifies Targets for Improvement

Practicing sun-protective behaviors (SPBs) reduces the risk for developing melanoma, and older studies show higher use of SPBs among high-risk individuals. Now, new research provides information about SPBs in more contemporary U.S. populations of both individuals at high risk for developing melanoma and those with little risk.

The study extracted data from the dermatology questionnaire of the 2015 and 2020 cross-sectional National Health Interview Survey to compare sun protective practices among individuals classified by melanoma history (personal family, both, or none) and to look for temporal trends within subgroups.

The results showed that in both 2015 and 2020, individuals at high risk for melanoma based on having a personal and/or family history showed the highest rate of SPBs and used sunscreen as their preferred method. In addition, the research documented adoption of most SPBs increased between 2015 and 2020 in the general population, although the same pattern was not seen among high-risk individuals.

The investigators concluded their findings suggest that SPBs could be increased by public education on melanoma development and the role of ultraviolet exposure as a risk factor. Recognizing that inadequate sunscreen application and sunburn are common problems among sunscreen users, they recommended encouraging high-risk patients to practice more comprehensive photo-protective measures by adding sun avoidance, staying in the shade, and wearing a sun hat or long-sleeved shirt to their use of sunscreen.

TO READ MORE: Fernandez K, Schneider J, Moore D, et al. Sun protective behaviors among patients at a higher risk for melanoma. J Am Acad Dermatol. 2024;91(3 suppl):ab319.

Systematic Literature Review Offers Insights on How Dietary Components and Nutraceuticals Impact Melanoma Risk

Public interest in nutritional supplements and dietary approaches for improving health and disease prevention is high, so it is not surprising that a poll of dermatology patients found that 50% were interested in implementing complementary medicine as a strategy for melanoma prevention.

Results from a comprehensive search and systematic review of the literature conducted by researchers at the University of Nebraska offer some information that clinicians can use when queried about this topic by patients.

Searching Embase and Medline for studies on the effects of diet and supplements on melanoma risk, including randomized controlled, cohort, case-controlled, in vivo, and in vitro studies, the researchers identified 314 studies, of which 40 were selected for further analysis. Potentially protective and detrimental effects of different supplements, macronutrients, and other dietary components were explored based on reported clinical trial outcomes, including odds ratios, hazard ratios, or relative risk with 95% confidence intervals.

The 40 studies provided information about 21 different supplements or dietary components, and for many of those, the information about impact on melanoma risk was inconclusive. However, the evidence showed a significant protective effect for vitamin A, citrus fruits, vegetables, low fat diets, vitamin E, garlic, and oils/fats (higher intake of olive oil, >7 servings of butter/week). Vitamin C, vitamin B, alcohol, and starches were associated with an increased risk of melanoma. In vitro study results showed that ajoene (found in garlic), capsaicin (found in chili peppers), and curcumin (found in turmeric) had cytotoxic effects on melanoma cells, indicating a potential benefit for supplements containing these chemical compounds.

The evidence showed a significant protective effect for vitamin A, citrus fruits, vegetables, low fat diets, vitamin E, garlic, and oils/fats (higher intake of olive oil, >7 servings of butter/week).

TO READ MORE: Shabaz A, Sutton A. Nutritional supplements and dietary components for melanoma prevention: a systematic review. J Am Acad Dermatol. 2024;91(3 suppl):ab266.