Kashani–Sabet, Mohammed

9568 Background: Stage IIB/C cutaneous melanoma is associated with high recurrence risk, however stratification of risk in relation to time after surgery has not been comprehensively evaluated. We evaluated recurrence-free survival (RFS) at key time points, stratified by clinicopathologic factors, to identify patients (pts) at higher recurrence risk and personalize postoperative surveillance strategies. Methods: In this multi-institutional, international retrospective cohort study from the Sentinel Lymph Node Working Group database, we included pts with pathologic T3b/T4a/T4b and N0 disease who underwent surgical resection and sentinel node biopsy from 1994-2025. The type of first recurrence (local, regional, distant) was characterized based on time category (0-12, 12-24, 24-60, and 60+ months after surgery). Restricted mean survival time (RMST) analysis was used to measure the average survival time up to a specified time point (6-, 12-, 24-, and 60-months after surgery), and associations of clinicopathologic variables (age, sex, Breslow thickness, ulceration and lymphovascular invasion [LVI]) with RFS. Results: We included 2514 stage IIB/C pts from 19 sites in 4 countries, with a median follow-up of 53 (stage IIB) and 49 (stage IIC) months. 675 (27%) pts experienced a recurrence (92 [14%] local, 238 [35%] regional and 345 [51%] distant), and 400 (59%) recurrences occurred within 24 months. The proportion of distant recurrences as the first recurrence increased significantly with time, comprising 39%, 50%, 62%, and 59% of recurrences in the 0-12, 12-24, 24-60, and 60+ month time categories respectively (χ 2 p<0.001). No significant differences were observed for the included clinicopathologic variables for 6-month RMST estimates. At 12 months, RMST estimates for thickness ≥4 mm (11.2 vs 11.6 months for thickness 2-3.99 mm, p<0.001) and presence of LVI (10.7 vs 11.4 months, p=0.009) were significantly different. 24-month RMST estimates differed for male sex (20.7 vs 21.5 months vs females, p=0.002), thickness ≥4 mm (20.5 vs 21.9 months, p<0.001), and presence of LVI (19.0 vs 21.1 months, p<0.001). Lastly, 60-month RMST estimates differed for male sex (42.0 vs 45.2 months, p=0.001), thickness ≥4 mm (41.5 vs 46.2 months, p<0.001), LVI (36.0 vs 43.7 months, p<0.001), and age >65 years (41.5 vs 46.4 for age <42, p=0.022). Conclusions: In this real-world, multi-center analysis of pathologic stage IIB/C melanoma pts, recurrence patterns varied based on time after surgery. Breslow thickness, LVI, male sex, and age were significantly associated with earlier recurrence at different time intervals on RMST analysis. Additionally, given that >50% of first recurrences 12+ months after surgery were distant, active surveillance for distant relapses may be warranted.

Abstract Background Recently, a model to predict 5-year recurrence-free survival (RFS) and melanoma-specific survival (MSS) after sentinel lymph node biopsy (SLNB) was published. The aim of this study was to validate that model in a large independent international cohort. Methods The database of the Sentinel Lymph Node Working Group (SLNWG) was analysed for patients with malignant melanoma who underwent SLNB. Patients with clinical stage III melanoma, a history of other malignancies, or receiving concomitant systemic therapies during follow-up were excluded. The model’s predictive performance was evaluated using discrimination and calibration metrics in the eligible cohort. Decision curve analysis was performed to assess the clinical value of the model. Results The external validation cohort consisted of 6174 patients of the SLNWG from the USA, Europe, and Israel. A positive sentinel node was found in 788 patients (12.8%). The area under the time-dependent receiver operating characteristic (ROC) curve of the external validation was 0.76 (95% c.i. 0.74 to 0.77) for RFS and 0.79 (95% c.i. 0.76 to 0.81) for MSS. The model was well calibrated, as the observed 5-year survival rates aligned closely with the predicted survival rates (calibration slope of 0.98 for RFS and calibration slope of 0.99 for MSS). The model provided a net benefit versus the ‘treat all’ and ‘treat none’ strategies at the predetermined probability threshold for recurrence of 45%. Conclusion The model demonstrated good performance in a large heterogeneous independent cohort, emphasizing its robustness. Decision curve analysis revealed a clear net benefit of the model over a treat all strategy, highlighting its potential for clinical use.

BackgroundThe significance of tumor‐infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs.MethodsThe Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma‐specific survival (MSS).ResultsOverall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow‐up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64‐0.95; P = .0154).ConclusionsTILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.

AbstractBackgroundCompletion lymph node dissection (CLND) for sentinel lymph node (SLN) disease in melanoma patients is debated. We evaluated the impact of CLND on survival and assessed for predictors of nonsentinel node metastasis (positive CLND).MethodsPositive SLN melanoma patients were retrospectively identified in the Sentinel Lymph Node Working Group database. Clinicopathological factors were correlated with CLND status, overall survival (OS), and melanoma‐specific survival (MSS).ResultsThere were 953 positive SLN patients of whom 831 (87%) had CLND. Positive CLND was seen in 141 (17%) cases and was associated with worse OS and MSS (both P < 0.001). CLND was not performed (No‐CLND) in 122 of 953 positive SLN cases (13%), of whom 100 had follow‐up and 18 (18%) developed a nodal recurrence (NR). No significant differences in OS and MSS were seen comparing CLND with No‐CLND (P = 0.084, P = 0.161, respectively) and comparing positive CLND with No‐CLND NR patients (P = 0.565, P = 0.998, respectively). Gender, primary site, ulceration, and number of positive SLNs were correlated with nonsentinel node metastasis.ConclusionsPerformance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

Purpose Indications for sentinel lymph node biopsy (SLNB) for thin melanoma are continually evolving. We present a large multi-institutional study to determine factors predictive of sentinel lymph node (SLN) metastasis in thin melanoma. Patients and Methods Retrospective review of the Sentinel Lymph Node Working Group database from 1994 to 2012 identified 1,250 patients who had an SLNB and thin melanomas (≤ 1 mm). Clinicopathologic characteristics were correlated with SLN status and outcome. Results SLN metastases were detected in 65 (5.2%) of 1,250 patients. On univariable analysis, rates of Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, ulceration, and absence of regression differed significantly between positive and negative SLN groups (all P < .05). These four variables and mitotic rate were used in multivariable analysis, which demonstrated that Breslow thickness ≥ 0.75 mm (P = .03), Clark level ≥ IV (P = .05), and ulceration (P = .01) significantly predicted SLN metastasis with 6.3%, 7.0%, and 11.6% of the patients with these respective characteristics having SLN disease. Melanomas < 0.75 mm had positive SLN rates of < 5% regardless of Clark level and ulceration status. Median follow-up was 2.6 years. Melanoma-specific survival was significantly worse for patients with positive versus negative SLNs (P = .001). Conclusion Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration significantly predict SLN disease in thin melanoma. Most SLN metastases (86.2%) occur in melanomas ≥ 0.75 mm, with 6.3% of these patients having SLN disease, whereas in melanomas < 0.75 mm, SLN metastasis rates are < 5%. By using a 5% metastasis risk threshold, SLNB is indicated for melanomas ≥ 0.75 mm, but further study is needed to define indications for SLNB in melanomas < 0.75 mm.