Melanoma-specific Survival Research Articles

Lower limb cutaneous melanoma surgery: location matters

The anatomical location of cutaneous melanoma is a relevant independent prognostic factor in melanoma. The aim of the study is to know the prognosis of lower limb cutaneous melanoma related to their location within the limb, regardless of the histological type, and if there are any other influencing variables. A real-world data observational study was developed. The lesions were divided depending on the location of the melanoma (thigh, leg and foot). Bivariate and multivariate analysis were performed, and melanoma-specific survival and disease-free survival rates were calculated. When these analysis were done, the results showed that, in melanomas of the lower limb, location on the foot presented a lower melanoma-specific survival rate compared to more proximal locations, and only the anatomical location presents statistical significance to discriminate cases with a higher mortality risk and a lower disease-free survival rate among distal melanomas (mainly on the foot). In conclusion, this study confirms that a more distal location of lower limb cutaneous melanoma is a relevant prognostic factor.Trial registration number NCT04625491 retrospectively registered.

The effect of tumor mitotic rate on melanoma-specific survival: An analysis of 54,598 cases

To the Editor: Tumor mitotic rate (TMR) has been removed from the eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging criteria 1 Gershenwald J.E. Scolyer R.A. Hess K.R. et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; 67: 472-492 Crossref PubMed Scopus (1228) Google Scholar for T1 melanomas, though it is recognized as a related risk factor for melanoma-specific survival across all stages and in some multivariate models. Herein, we analyze the relationship between TMR and melanoma-specific survival using the Surveillance, Epidemiology, and End Results database and compare the relative prognostic value of TMR and ulceration within this cohort.

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 usingKaplan-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.

Smoking is an Independent Marker of Poor Prognosis in Cutaneous Melanoma.

Previous studies have suggested that persistent tobacco smoking impairs survival in cutaneous melanoma, but the effects of smoking and other prognostic factors have not been described in detail. This study examined the association of smoking (persistent, former, or never) with melanoma-specific (MSS) and overall survival (OS) in patients with cutaneous melanoma treated in Southwest Finland during 2005 to 2019. Clinical characteristics were obtained from electronic health records for 1,980 patients. Smoking status was available for 1,359 patients. Patients were restaged according to the 8th edition of the tumour-node-metastasis (TNM) classification. Smoking remained an independent prognostic factor for inferior melanoma-specific survival regardless of age, sex, stage, and comorbidities. The hazard ratio of death from melanoma was 1.81 (1.27-2.58, p = 0.001) in persistent and 1.75 (1.28-2.40, p = 0.001) in former smokers compared with never smokers. In 351 stage IV patients, smoking was associated with increased melanoma-specific and overall mortality: median MSS 10.4 (6.5-14.3), 14.6 (9.1-20.1), and 14.9 (11.4-18.4) months, p = 0.01 and median OS 10.4 (6.5-14.3), 13.9 (8.6-19.2), and 14.9 (11.7-18.1) months, p = 0.01 in persistent, former, and never smokers, respectively. In conclusion, since smoking represents an independent modifiable poor prognostic factor in patients with cutaneous melanoma, smoking habits should be proactively asked about by healthcare professionals, in order to support smoking cessation.

A role for pelvic sentinel lymph nodes in lower extremity melanoma?

Consensus on management of pelvic sentinel lymph nodes (PSLNs) has not been reached and thus the extent of sentinel lymph node biopsy (SLNB) of the groin in melanoma patients varies among centers and surgeons. Lymphatic drainage to PSLNs is often identified in, but the diagnostic and clinical relevance of PSLNs has been debated. Our aim was to determine if the presence of PSLNs affected recurrence or survival rates in patients with melanoma in the lower extremities. This retrospective study consisted of 702 patients with cutaneous melanoma operated between 2005 and 2018. Of these, 134 patients with melanoma in the lower extremities were included in the study. Images of lymphoscintigraphy and SPECT-CT studies were thoroughly observed together with surgery reports to define the status of SLNs. Overall, 85 of 134 patients went through SLNB and 28 of them had PSLN identified. Two had their PSLN removed, which led 26 patients with PSLN to be compared to the 57 who did not have PSLN identified. We did not find statistically significant differences in overall recurrence (26.9% versus 28.0%, p = 1.00), regional nodal recurrence (11.5% versus 15.8%, p = 0.67), local or in-transit recurrence (19.2% versus 8.8%, p = 0.17), or distant recurrence rates (15.4% versus 19.3%, p = 0.66). Disease-free survival did not differ between the groups (median 23.0 (IQR 15.0-39.0) versus 19.0 (IQR 10.3-61.8) months, p = 0.82). Likewise, there was no statistically significant difference in melanoma-specific 5-year survival (78.6% versus 87.2%, p = 0.42). We did not find more frequent recurrence, shorter disease-free survival, or poorer melanoma-specific survival in patients with drainage to PSLN. Our findings strengthen the evidence that PSLNs should not be routinely biopsied if they are not the first-tier nodes.

Effects of the Introduction of Modern Immunotherapy on the Outcome of Isolated Limb Perfusion for Melanoma In-Transit Metastases.

Isolated limb perfusion (ILP) is an effective locoregional treatment for melanoma in-transit metastasis, but the advent of modern effective immunotherapy, such as ICI (immune checkpoint inhibitors), has changed the treatment landscape. The primary aims of this study were to compare the characteristics of the patient population receiving ILP before and after the introduction of modern systemic treatments and to assess if outcomes after ILP were influenced by previous immunotherapy treatment. A single-centre analysis of patients that underwent ILP for melanoma in-transit metastasis between 2010 and 2021 was conducted, with patients grouped and compared by treatment time period: pre-ICI era (2010-2014) and ICI era (2017-2021). 218 patients were included. Patients undergoing ILP in the ICI era were slightly older (median age 73 vs. 68 years) compared to the pre-ICI era, with no other difference found. The overall response rate (ORR) was 83% vs. 84% and the complete response (CR) rate was 52% vs. 47% for the pre-ICI era and the ICI era, respectively. For patients that had received and failed immunotherapy prior to ILP (n = 20), the ORR was 75% and the CR rate was 50%. Melanoma-specific survival has improved, with a 3-year survival rate of 54% in the pre-ICI era vs. 86% in the ICI era. The patient population undergoing ILP for in-transit melanoma is largely unchanged in the current era of effective systemic treatments. Response rates have not decreased, and prior ICI treatment did not affect response rates, making ILP still a valid treatment option for this patient group.

Identification of high-risk patients with a seven-biomarker prognostic signature for adjuvant treatment trial recruitment in American Joint Committee on Cancer v8 stage I–IIA cutaneous melanoma

PurposeMany patients with resected American Joint Committee on Cancer (AJCC) early-stage cutaneous melanoma nonetheless die of melanoma; additional risk stratification approaches are needed. Patients and methodsUsing prospectively-collected whole-tissue sections, we assessed in consecutive stage I–IIA patients (N = 439), a previously-validated, immunohistochemistry-based, 7-biomarker signature to prognosticate disease-free survival (DFS), melanoma-specific survival (MSS; primary end-point) and overall survival (OS), independent of AJCC classification. ResultsSeven-marker signature testing designated 25.1% of patients (110/439) as high-risk (stage IA, 13.3% [43/323], IB, 53.2% [42/79], and IIA, 67.6% [25/37]). A Kaplan–Meier analysis demonstrated high-risk patients to have significantly worse DFS, MSS and OS versus low-risk counterparts (P < 0.001). In multivariable Cox regression modelling also including key clinicopathological/demographic factors, 7-marker signature data independently prognosticated the studied end-points. Models with the 7-marker signature risk category plus clinicopathological/demographic covariates substantially outperformed models with clinicopathological/demographic variables alone in predicting all studied outcomes (areas under the receiver operator characteristic curve 74.1% versus 68.4% for DFS, 81.5% versus 71.2% for MSS, 80.9% versus 73.0% for OS; absolute differences 5.7%, 10.3% and 7.9%, respectively, favouring 7-marker signature risk category-containing models). ConclusionIn patients with AJCC early-stage disease, the 7-marker signature reliably prognosticates melanoma-related outcomes, independent of AJCC classification, and provides a valuable complement to clinicopathological/demographic factors.

Neoadjuvant ipilimumab plus nivolumab in locally advanced melanoma: A real-world single-centre retrospective study

BackgroundNeoadjuvant immune-checkpoint inhibition (neoICI) with ipilimumab and nivolumab has shown high pathologic response rates as well as a long-lasting relapse-free survival in stage III melanoma patients. However, safety and efficacy data from real-world patients is very limited. MethodsStage IIIB-IV (M1a) melanoma patients with macroscopic nodal metastases with or without synchronous non-nodal lesions received combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg. Radiological and pathological response as well as relapse-free survival (RFS), event-free survival (EFS), overall survival (OS), melanoma-specific survival (MSS), adverse events (AE) related to neoICI and subsequent therapies were analysed. ResultsBetween November 2018 and October 2021, 23 patients received a combined neoICI. A pathologic response was achieved in 65% (15/23) of the patients, with 43% (10/23) achieving a pathological complete response. At a median follow-up of 22.8 months, median RFS, EFS, OS and MSS have not been reached. At a 3-year landmark, the RFS, EFS, OS and MSS rates were 77.6% (95% CI 60.1–100), 61.8% (95% CI 43.8–87.1), 62.0% (95% CI 42.2–91.0) and 76.7% (95% CI 55.7–100), respectively. Regarding AE, 70% (16/23) had immune-related AE (irAEs) of any grade which were classified as severe (≥ grade 3) irAEs in 13% (3/23) of patients. ConclusionThe combined neoICI with ipilimumab 1 mg/kg and nivolumab 3 mg/kg showed high response rates as well as long lasting relapse-free survival. Besides a promising efficacy, neoICI was well tolerated in our real-world patient cohort with only few high-grade irAEs indicating feasibility of neoICI in a non-trial setting.

Differences in sentinel lymph node biopsy utilization in eligible melanoma patients treated with Mohs micrographic surgery or wide local excision: A population-based logistic regression model and survival analysis

Primary melanoma management relies on tumor extirpation and staging sentinel lymph node biopsy (SLNB) in eligible patients. This study compares SLNB utilization in patients undergoing wide local excision (WLE) or Mohs micrographic surgery (MMS). American Joint Committee on Cancer seventh edition≥patients with T1b melanoma undergoing WLE or MMS in the Surveillance, Epidemiology, and End Results program were included. Propensity score matching was performed to compare patients who underwent MMS or WLE. Kaplan-Meier analysis and Fine-Gray cumulative incidence functions were used for overall and melanoma-specific survival. Eight hundred twenty-five MMS cases and 38,760 WLE cases were identified. SLNB was performed in 32.61% of MMS patients and 61.77% of WLE patients with positive rates of 12.5% and 14.82%, respectively. Multiple logistic regression of factors associated with SLNB utilization revealed that WLE, male gender, younger age, extremity location, and nodular and rare melanoma subtypes were significantly associated with increased odds of receiving SLNB whereas head and neck location and lentigo maligna melanoma subtype were significantly less likely to receive SLNB. Potential selection bias from a retrospective data set. Patients receiving WLE for≥T1b melanoma are more likely to receive a SLNB than patients undergoing MMS.

Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma

Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor necrosis factor on checkpoint-inhibitor efficacy. To determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy. This population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months. The PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS. Of 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone. In this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also other tumor types.

Gynecologic Melanoma: A 25-Year Institutional Experience

<h3>Purpose/Objective(s)</h3> Melanoma of the gynecologic tract is a rare malignancy with poor outcomes. We sought to describe clinicopathological features, patterns of care, and outcomes in a large cohort of patients (pts) with this diagnosis treated at our institution. <h3>Materials/Methods</h3> Using an institutional pathology database we identified 141 pts with gynecologic melanoma treated 1995-2021. Clinicopathologic variables were described and time to outcome was calculated by the Kaplan-Meier method. <h3>Results</h3> Median age was 62 years (IQR 54-70). Primary tumors were located at the vulva (n=97, 69%), vagina (n=34, 24%) or cervix (n=10, 7%). Of the 123 pts with known primary tumor pathology, median tumor thickness was 5.0 mm (IQR 1.8-7.1 mm), 72% had ulceration (n=88), 21% had PNI (n=26), 28% had LVI (n=35), 6% had microsatellitosis (n=7) and 42% had a component of melanoma-in-situ (MIS, n=52) with 15% (n=21) having multifocal disease at presentation. Most pts had locally confined disease at diagnosis (n=110, 78%). Nine percent (n=13) had clinically involved nodes without distant metastasis (DM) and 13% had DM (n=18). At presentation 29 pts (21%) had unresectable disease, 2 of whom had surgery after response to neoadjuvant systemic therapy. Of the 112 pts with resectable disease, 77% (n=86) had nodal sampling with 40% of those (n=34) having pathologically positive nodes. Of the 105 pts with known margins: 47% R0 (n=49), 29% MIS+ (n=30), 21% R1 (n=22) and 4% R2 (n=4). Twenty-seven pts (23% resected) received neoadjuvant systemic therapy (11 pts at diagnosis and 16 pts at recurrence). Immune checkpoint inhibitors (ICI) were the most common class (67%, n=18). Ten pts (37%) had imaging or pathologic evidence of response to neoadjuvant therapy (6 ICI, 2 chemotherapy and 2 targeted therapy). Forty-three pts (37% resected) received adjuvant systemic therapy at the time of initial resection. Thirty-nine pts (28%) received pelvic RT during their treatment course. The primary tumor bed was the target for all except 2 pts who received RT to unilateral inguinal nodes and 1 pt who received RT to a pelvic sidewall mass. The timing of RT was: 1 neoadjuvant (3%), 15 adjuvant (38%), 14 to gross disease without DM (36%) and 9 to gross disease with DM (23%). The most common adjuvant regimens were 30 Gy in 5 fractions (n=6) or 48 Gy in 20 fractions (n=3). Of 141 pts, 79 (56%) were diagnosed after 2014, the era during which ICI were used. Median follow-up of those diagnosed pre-2014 was 98 months (mo, IQR 54-111 mo) and post-2014 was 39 mo (IQR 26-50 mo). Pre- vs. post-2014 3-year actuarial event rates were not significantly different with 59% vs. 49% local control (p=0.52); 56% vs. 60% nodal control (p=0.78); 45% vs. 34% DM-free survival (p=0.11); 25% vs. 20% disease-free survival; and 55% vs. 56% melanoma-specific survival (p=0.55). <h3>Conclusion</h3> Gynecologic tract melanoma outcomes continue to be poor with a significant need for improved treatment options, both in terms of pelvic and distant disease control.

Association of metformin use and survival in patients with cutaneous melanoma and diabetes.

Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive. To investigate the association between metformin use and survival among patients with CM and diabetes. All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses. Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS. Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.

Prognostic role of microsatellites in melanoma and implications in the American Joint Committee on Cancer classification system: A cohort study

There is limited information on microsatellite survival outcomes in patients with melanoma. To evaluate survival outcomes in patients with microsatellites, assess their role within stage III stratification of the American Joint Committee on Cancer classification, and assess the results of sentinel lymph node biopsies in patients with microsatellites. A retrospective bicenter cohort study from 1998 to 2019 included patients with a diagnosis of invasive cutaneous melanoma. Of a total of 5216 patients, 108 (2.1%) had microsatellites at initial staging. Survival analysis showed that microsatellites were an independent risk factor with decreased overall survival (OS), melanoma-specific survival (MSS), and disease-free survival, with hazard ratios of 1.57, 1.76, and 1.76, respectively. Stratified analysis in patients with stage III melanoma showed a 5-year OS of 35% (95% CI, 17.3%-73.4%) and a MSS of 45% (95% CI, 23.1-87.5) for patients with stage IIIB melanoma with microsatellites. Retrospective design of the study. Microsatellites were associated with other adverse melanoma prognostic factors. A multivariate Cox regression analysis showed that they are an independent risk factor for worse OS, MSS, and disease-free survival. Patients with stage IIIB melanoma with microsatellites had worse OS and MSS, whereas patients with stage IIIC melanoma had worse OS but not MSS.

Gynecologic tract melanoma in the contemporary therapeutic era: High rates of local and distant disease progression

BackgroundGynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era. MethodsPatterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up. ResultsOf the 124 patients included, anatomic subsites were vulvar (n = 82, 66%), vaginal (n = 34, 27%), or cervical (n = 8, 6%). Primary tumor was resected for 85% (n = 106) with surgical nodal evaluation for 60% (n = 75). Systemic therapy, most commonly immune checkpoint inhibitors (ICI, 58% systemic therapy), was used to treat all except one unresectable patient (17/18) and 33% (35/106) of resectable patients. Seven patients received neoadjuvant ICI. Fourteen patients received adjuvant radiation therapy to the pelvis (RT, 13% of those undergoing resection). With a median follow-up of 45 months, 100 patients (81%) recurred. Four-year actuarial outcomes were: 46% local control, 53% nodal control, 36% distant metastasis-free survival, 17% disease-free survival, 49% melanoma-specific survival and 48% overall survival. Mitotic rate > 10/mm2, nodal involvement and non-vulvar anatomic subsite were associated with poor outcomes. Patients treated after 2016 did not have significantly better outcomes than those treated earlier. ConclusionsPatients with GTM continue to have poor outcomes in the contemporary therapeutic era with particularly notable poor local disease control relative to other mucosal melanoma subtypes. More effective oncologic therapy is needed.

Sentinel Lymph Node Gene Expression Signature Predicts Recurrence-Free Survival in Cutaneous Melanoma.

Simple SummaryDespite a negative SLN status, patients with Stage IIB/IIC melanoma demonstrate poor melanoma-specific survival when compared to Stage IIIA patients. In this study, we hypothesized that a molecular profile at the level of the SLN would provide potential insights into risk of disease recurrence and serve as a prognostic biomarker of patient outcomes regardless of the presence of SLN melanoma metastases. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. Our study suggests a novel 12-gene SLN signature risk score which may predict disease recurrence in cutaneous melanoma patients managed with wide excision of the primary tumor and SLN biopsy.We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.

Is a History of Optimal Staging by Sentinel Lymph Node Biopsy in the Era Prior to Adjuvant Therapy Associated with Improved Outcome Once Melanoma Patients have Progressed to Advanced Disease?

Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy? Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS. In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19-29) vs. 18 months (95% CI 15-20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma. Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB.

Melanoma-specific survival before and after inclusion in a familialmelanoma dermatologic surveillance program in CDKN2A mutation carriers and non-carriers.

Inherited mutations in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Further, previous studies have reported inferior melanoma-specific survival in CDKN2A mutation carriers. Here, the melanoma-specific survival was studied, depending on CDKN2A carrier status and if the melanomas had been diagnosed before or after families were included in a surveillance program. Melanoma-prone families participating in this study were identified through a nationwide preventive program starting in 1987. Information on melanoma tumours and deaths was obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan-Meier and Cox proportional hazards regression models were used to assess melanoma-specific survival in four defined cohorts, CDKN2A mutation (MUT) carriers with first invasive melanoma before or after inclusion [MUT-pre (n=53) and MUT-post (n=43)] and likewise in CDKN2A wild type (WT) cases [WT-pre (n=255) and WT-post (n=122)]. The MUT-pre and MUT-post cases were diagnosed with their first invasive melanoma at a significantly younger ages (38 and 42 years, respectively) than the WT-pre and WT-post cases (48 and 57 years, respectively). The melanomas in the MUT-pre had significantly higher T stage compared with MUT-post (p=0.006), whereas no such difference was seen comparing WT-pre with WT-post (p=0.849). MUT-pre had compared with WT-pre, significantly worse melanoma-specific survival, unadjusted (HR 2.33, 95% CI 1.33-4.08, p=0.003) adjusted (HR 2.70, 95% CI 1.46-5.00, p=0.001). However, the MUT-post cases had compared with the WT-post cases, no significant survival differences. This study is the first to address the impact on survival from introducing a dermatologic surveillance program to familial melanoma cases with or without CDKN2A mutations. The CDKN2A-mut carriers appeared to have a clear benefit with less advanced melanomas diagnosed and better melanoma-specific survival after inclusion. Among the CDKN2A-wt cases, the effect of the inclusion on the studied outcomes was less evident.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis

Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. The objective of the study was to determine the prognostic impact of Breslow thickness in AM. This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P=.004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio=0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2mm. The limitations were retrospective design and some missing variables. There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2mm.

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting

BackgroundThe role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood.ObjectiveTo perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.MethodsWe conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts.ResultsTwo loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90).ConclusionWe found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

852P Does sex affect the efficacy of immune checkpoint inhibitors? A national Danish melanoma study

Immune checkpoint inhibitors (ICI) are current standard in treating metastatic melanoma. In melanoma, males are known to have a poorer prognosis compared to females. However, metanalysis have shown conflicting results regarding differences in ICI efficacy between females and males. In this study, we evaluate the efficacy of ICI in a real-world Danish metastatic melanoma population according to sex. The primary endpoint was progression-free survival (PFS). Secondary endpoint was overall survival (OS) and melanoma specific survival (MSS). All patients treated with ICI (anti-PD-1 and/or anti-CTLA4) for metastatic melanoma in Denmark between 2011-2021 were identified in the Danish metastatic melanoma database. Only patients receiving ICI as first-line treatment were included. Baseline characteristics were evaluated according to ICI treatment for; age, ECOG performance status, lactate dehydrogenase (LDH), M-stage, BRAF status, the origin of melanoma (cutaneous or unknown primary melanoma), and granulocytes. Parameters for multivariate analysis were selected backwards, with a cutoff at 0.10. 1461 patients; 573 females and 888 males were identified. Baseline characteristics were significantly unbalanced between sex. A higher frequency of BRAF mutation and a lower age was found for females, however, also elevated LDH and advanced M stage. The median follow-up time for PFS was 51 months (95% CI 48-55). Multivariate analysis showed sex as a significant factor of efficacy with improved PFS for females (HR 1.16 (1.02-1.33), p=0.03). Females showed significantly better OS with a five-year survival of 46% (41%-51%) for females and 38% (34%-42%) for males. Multivariate analysis reinforced this significance with HR 1.29 (1.09-1.52). Five-year MSS rates were 49% (95% CI 44%-54%) for female and 45% (40%-49%) for male. Multivariate analysis showed significantly better MSS for females (1.20 (1.01-1.43), p=0.04). This study represents a complete, national dataset of ICI-treated metastatic melanoma patients. Baseline characteristics were unbalanced between sexes. Despite adjustments for clinical, validated prognostic factors, sex remains an independent prognostic factor for PFS, OS, and MSS in this real-world cohort.