Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma.

PURPOSE: Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in patients with melanoma, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. METHODS: Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. RESULTS: We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions and ulcerated lesions and was associated with shorter survival in primary and metastatic tumors. On multivariable analysis, Breslow thickness, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. CONCLUSION: Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Circulating Tumor Reactive KIR+CD8+ T cells Suppress Anti-Tumor Immunity in Patients with Melanoma.

Effective anti-tumor immunity is largely driven by cytotoxic CD8+ T cells that can specifically recognize tumor antigens. However, the factors which ultimately dictate successful tumor rejection remain poorly understood. Here we identify a subpopulation of CD8+ T cells which are tumor antigen-specific in patients with melanoma but resemble KIR+CD8+ T cells with a regulatory function (Tregs). These tumor antigen-specific KIR+CD8+ T cells are detectable in both the tumor and the blood, and higher levels of this population are associated with worse overall survival. Our findings therefore suggest that KIR+CD8+ Tregs are tumor antigen-specific but uniquely suppress anti-tumor immunity in patients with melanoma.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

Immunotherapy utilization in stage IIIA melanoma: less may be more.

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Educational Review: Clinical Application of Immune Checkpoint Blockade for the Treatment of Melanoma.

In the last decade, immunotherapy has become the cornerstone in the management of patients with melanoma, the foremost cause of skin-cancer-related death in the USA. The emergence of immune checkpoint blockade as a crucial element in current immunotherapy and combination strategies has significantly transformed the treatments of resectable and advanced (unresectable or metastatic) melanoma. This paper reviews the landmark clinical trials that formed the basis of management of melanoma in the perioperative and metastatic setting. Furthermore, we discuss the rationale for the applications of PD-1 blockade and its combination with anti-CTLA-4 and anti-LAG-3. The review also explores new experimental combinations of PD-1 blockade with other immunomodulatory agents, including targeted therapies, anti-TIGIT antibodies, TLR-9 agonists, antiangiogenic agents, and mRNA vaccines.

Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Melanocortin 1 receptor (MC1R) expression as a marker of progression in melanoma.

Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in melanoma patients, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions, ulcerated lesions, and mucosal melanomas compared to cutaneous melanomas and was associated with shorter survival in primary and metastatic tumors. On multi-variable analysis, Breslow thickness, ulceration, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. In the metastatic melanoma cohort, MC1R expression and mucosal melanomas were independent predictors of inferior overall survival. Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

Impact of COVID-19 on the gastrointestinal surgical oncology patient population.

Background: The onset of the COVID-19 pandemic led to substantial alterations in healthcare delivery and access. In this study, we aimed to evaluate the impact of COVID-19 on the presentation and surgical care of patients with gastrointestinal (GI) cancers. Methods: All patients who underwent GI cancer surgery at a large, tertiary referral center between March 15, 2019 and March 15, 2021 were included. March 15, 2020 was considered the start of the COVID-19 pandemic. Changes in patient, tumor, and treatment characteristics before the pandemic compared to during the pandemic were evaluated. Results: Of 522 patients that met study criteria, 252 (48.3%) were treated before the COVID-19 pandemic. During the first COVID-19 wave, weekly volume of GI cancer cases was one-third lower than baseline (p = 0.041); during the second wave, case volume remained at baseline levels (p = 0.519). There were no demographic or tumor characteristic differences between patients receiving GI cancer surgery before versus during COVID-19 (p > 0.05 for all), and no difference in rate of emergency surgery (p > 0.9). Patients were more likely to receive preoperative chemotherapy during the first six months of the pandemic compared to the subsequent six months (35.6% vs. 15.5%, p < 0.001). Telemedicine was rapidly adopted at the start of the pandemic, rising from 0% to 47% of GI surgical oncology visits within two months. Conclusions: The COVID-19 pandemic caused an initial disruption to the surgical care of GI cancers, but did not compromise stage at presentation. Preoperative chemotherapy and telemedicine were utilized to mitigate the impact of a high COVID-19 burden on cancer care.

Case report: Metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases.

Merkel cell carcinoma (MCC) is a rare tumor with a high risk of recurrence after definitive therapy; however, the optimal duration of surveillance is unclear. First recurrences typically occur within 3 years. National guidelines recommend that patients undergo physical examination and imaging for surveillance during this time period. However, the duration of surveillance beyond this is not defined. Here, we describe a case of a patient developing a recurrence of MCC 7 years after the primary diagnosis with interval in-transit and regional lymph node metastases 15 months following the treatment of the primary MCC. Such late recurrences are rare, largely not reported, and the risk factors contributing to late recurrences are not well described. This case highlights the possibility of late recurrences of MCC after an initial in-transit and nodal recurrence and underscores the importance of identifying predictors of recurrence that may better guide the duration of surveillance.

Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance.

Checkpoint inhibitors have revolutionized cancer treatment, but resistance remains a significant clinical challenge. Myeloid cells within the tumor microenvironment can modulate checkpoint resistance by either supporting or suppressing adaptive immune responses. Using an anti-PD-1-resistant mouse melanoma model, we show that targeting the myeloid compartment via CD40 activation and CSF1R blockade in combination with anti-PD-1 results in complete tumor regression in a majority of mice. This triple therapy combination was primarily CD40 agonist-driven in the first 24 hours after therapy and showed a similar systemic cytokine profile in human patients as was seen in mice. Functional single-cell cytokine secretion profiling of dendritic cells (DC) using a novel microwell assay identified a CCL22+CCL5+ IL12-secreting DC subset as important early-stage effectors of triple therapy. CD4+ and CD8+ T cells are both critical effectors of treatment, and systems analysis of single-cell RNA sequencing data supported a role for DC-secreted IL12 in priming T-cell activation and recruitment. Finally, we showed that treatment with a novel IL12 mRNA therapeutic alone was sufficient to overcome PD-1 resistance and cause tumor regression. Overall, we conclude that combining myeloid-based innate immune activation and enhancement of adaptive immunity is a viable strategy to overcome anti-PD-1 resistance.

The role of imaging and sentinel lymph node biopsy in patients with T3b-T4b melanoma with clinically negative disease.

Background: Previous studies demonstrate minimal utility of pre-operative imaging for low-risk melanoma; however, imaging may be more critical for patients with high-risk disease. Our study evaluates the impact of peri-operative cross-sectional imaging in patients with T3b-T4b melanoma. Methods: Patients with T3b-T4b melanoma who underwent wide local excision were identified from a single institution (1/1/2005 - 12/31/2020). Cross-sectional imaging was defined as body CT, PET and/or MRI in the perioperative period, with the following findings: in-transit or nodal disease, metastatic disease, incidental cancer, or other. Propensity scores were created for the odds of undergoing pre-operative imaging. Recurrence free survival was analyzed using the Kaplan-Meier method and log-rank test. Results: A total of 209 patients were identified with a median age of 65 (IQR 54-76), of which the majority were male (65.1%), with nodular melanoma (39.7%) and T4b disease (47.9%). Overall, 55.0% underwent pre-operative imaging. There were no differences in imaging findings between the pre- and post-operative cohorts. After propensity-score matching, there was no difference in recurrence free survival. Sentinel node biopsy was performed in 77.5% patients, with 47.5% resulting in a positive result. Conclusion: Pre-operative cross-sectional imaging does not impact the management of patients with high-risk melanoma. Careful consideration of imaging use is critical in the management of these patients and highlights the importance of sentinel node biopsy for stratification and decision making.

Malignant Melanoma in Older Adults: Different Patient or Different Disease?

Objective In this study, we aimed to compare the clinical outcomes between older and younger patients with melanoma and to evaluate for differences in tumor genetic makeup that might explain differences in clinical behavior between older and younger cohorts. Materials and methods A consecutive sample of patients diagnosed with melanoma at a single institution from 1984 to 2019 was categorized by age into younger, middle, and older cohorts. Tumor characteristics, melanoma-specific survival, and recurrence-free survival were assessed while accounting for differential follow-up and death from other causes using Kaplan-Meier analysis with log-rank testing. Results A total of 4378 patients were included in the study. Older patients presented with a higher incidence of T3 and T4 tumors, and a lower incidence of T1 tumors (p<0.001). The same group of patients had a lower nodal positivity at any given Breslow thickness (p<0.01). Melanoma-specific survival was lower for older patients with T2 tumors (p=0.046). There was no difference in recurrence-free survival among all age groups and tumor thicknesses (p>0.05). For patients with a given genetic profile, the melanoma-specific survival and recurrence-free survival were equivalent across ages. BRAF was the most common driver in the younger group, while NRAS and other mutations increased in prevalence as age rose. Conclusions Older adults have decreased melanoma-specific survival for T2 tumors and lower nodal positivity, suggesting a different pattern of metastatic progression. The mutational drivers of cutaneous melanoma change with age and may play a role in the different metastatic progression as well as the differential melanoma-specific survival across all age cohorts.

Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments antitumor activity in melanoma.

Targeting tumor-associated blood vessels to increase immune infiltration may enhance treatment effectiveness, yet limited data exist regarding anti-angiogenesis effects on the tumor microenvironment (TME). We hypothesized that dual targeting of angiogenesis with immune checkpoints would improve both intracranial and extracranial disease. We used subcutaneous and left ventricle melanoma models to evaluate anti-PD-1/anti-VEGF and anti-PD-1/lenvatinib (pan-VEGFR inhibitor) combinations. Cytokine/chemokine profiling and flow cytometry were performed to assess signaling and immune-infiltrating populations. An in vitro blood-brain barrier (BBB) model was utilized to study intracranial treatment effects on endothelial integrity and leukocyte transmigration. Anti-PD-1 with either anti-VEGF or lenvatinib improved survival and decreased tumor growth in systemic melanoma murine models; treatment increased Th1 cytokine/chemokine signaling. Lenvatinib decreased tumor-associated macrophages but increased plasmacytoid DCs early in treatment; this effect was not evident with anti-VEGF. Both lenvatinib and anti-VEGF resulted in decreased intratumoral blood vessels. Although anti-VEGF promoted endothelial stabilization in an in vitro BBB model, while lenvatinib did not, both regimens enabled leukocyte transmigration. The combined targeting of PD-1 and VEGF or its receptors promotes enhanced melanoma antitumor activity, yet their effects on the TME are quite different. These studies provide insights into dual anti-PD-1 and anti-angiogenesis combinations.

Indoor Versus Outdoor: Does Occupational Sunlight Exposure Increase Melanoma Risk? A Systematic Review.

INTRODUCTION: Melanoma is the fifth most common cancer diagnosed in the United States, representing 5.6% of all new cancer cases. There are conflicting reports correlating a relationship between primarily outdoor occupations, associated with increased exposure to direct sunlight, and the incidence of cutaneous melanoma. Our objective was to outline and critically evaluate the relevant literature related to chronic occupational exposure to sunlight and risk of developing cutaneous melanoma. METHODS: The study protocol for this systematic review was submitted to the International Prospective Register of Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. For each relevant study included, the following information was extracted: author names, publication year, study name, study design, age, exposure assessment, outcome, comparison, number of cases, case ascertainment, and descriptive and adjusted statistics. Study quality and evidence certainty was assessed using the Grading of Recommendations, Assessment, Development and Evaluations model. RESULTS: The initial database search yielded 1629 articles for review and following full-text screening, a total of 14 articles were included for final analysis. Of the studies included, seven articles were retrospective case control and seven were cohort studies. The studies did not report any differences in the likelihood of cutaneous melanoma development based upon membership in the outdoor versus indoor occupation groups included in each study. CONCLUSIONS: Overall, the articles included in this systematic review did not report an increased risk of developing cutaneous melanoma among individuals with outdoor occupations. Further investigation is required to determine if other occupational or life-style-related risk factors exist, to help support the development of individualized skin screening recommendations and improve the early detection of melanoma in all populations.

Unmeasured factors are associated with the use of completion lymph node dissection (CLND) in melanoma.

BACKGROUND: Completion lymph node dissection (CLND) was the standard treatment for patients with melanoma with positive sentinel lymph nodes (SLN) until 2017 when data from the DeCOG-SLT and MLST-2 randomized trials challenged the survival benefit of this procedure. We assessed the contribution of patient, tumor and facility factors on the use of CLND in patients with surgically resected Stage III melanoma. METHODS: Using the National Cancer Database, patients who underwent surgical excision and were found to have a positive SLN from 2012 to 2017 were included. A multivariable mixed-effects logistic regression model with a random intercept for the facility was used to determine the effect of patient, tumor, and facility variables on the risk of CLND. Reference effect measures (REMs) were used to compare the contribution of contextual effects (unknown facility variables) versus measured variables on the variation in CLND use. RESULTS: From 2012 to 2017, the overall use of CLND decreased from 59.9% to 26.5% (p < 0.0001). Overall, older patients and patients with government-based insurance were less likely to undergo CLND. Tumor factors associated with a decreased rate of CLND included primary tumor location on the lower limb, decreasing depth, and mitotic rate <1. However, the contribution of contextual effects to the variation in CLND use exceeded that of the measured facility, tumor, time, and patient variables. CONCLUSIONS: There was a decrease in CLND use during the study period. However, there is still high variability in CLND use, mainly driven by unmeasured contextual effects.