Predictors Of Melanoma-specific Survival Research Articles

Validation of the 31-gene expression profile test to stratify melanoma-specific survival in an unselected, prospectively tested cohort of patients with stage IIB-III cutaneous melanoma.

e21538 Background: Given recent FDA extended approval of Pembrolizumab for stage IIB-IIC cutaneous melanoma (CM) patients, it is critical to risk-stratify patients to balance potential benefits versus toxicities of adjuvant therapy. The 31-gene expression profile (31-GEP) is a validated test for CM for risk of recurrence or metastasis prognosis in patients with stage I-III CM. A low-risk (Class 1A) 31-GEP result is associated with lower recurrence risk and higher melanoma-specific survival than an intermediate (Class 1B/2A) or high-risk (Class 2B) result. To validate the 31-GEP’s ability to stratify patients’ risk in an unselected, prospectively tested cohort of therapy-eligible CM patients, we collaborated with the National Cancer Institute and the Surveillance, Epidemiology, and End Results (SEER) program. Methods: A linkage was conducted between SEER registries’ CM cases diagnosed 2012-2018, and 31-GEP tested patients between 2013-2020. A de-identified dataset was used for the analysis. Kaplan-Meier analysis with log-rank test was used to analyze patient melanoma-specific survival (MSS) in the overall cohort and the subset of patients with potential adjuvant therapy access: stage IIB-III melanoma (n = 615). Results: In the overall cohort of patients (N = 5,225), those with a 31-GEP Class 1A result had higher 3-year MSS than patients with a Class 2B result (99.7% vs. 90.4%, p < 0.001). In multivariable Cox regression analysis, a Class 2B result was an independent significant predictor of MSS (HR = 5.71, p = 0.01), as were age (HR = 1.05, p < 0.001), SLN positivity (HR = 2.42, p = 0.02), and T2b (HR = 8.29, p = 0.025) and T4b (HR = 11.99, p = 0.009) tumors. In the subset of patients with stage IIB-III melanoma, those with a 31-GEP Class 1A result had higher 3-year MSS (98.8% vs. 82.4%, p = 0.02) than patients with a Class 2B result. Patients with a Class 2B result had a five and a half times higher event rate than those with a Class 1A result for MSS (5.5% [21/382] vs. 1.0% [1/105]). Conclusions: In a large, unselected, prospectively tested cohort of patients with stage I-III CM, the 31-GEP stratified patient risk of dying from melanoma, validating previous studies. While the 31-GEP identified a subgroup (Class 1A) of traditionally high-risk patients (stage IIB-III CM) who had a > 98% MSS over three years, it can also facilitate identifying patients who could warrant earlier adjuvant therapy with a higher 31-GEP class designation.

Sentinel Lymph Node Biopsy vs. Observation in Thin Melanoma: A Multicenter Propensity Score Matching Study.

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients.

The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients

IntroductionThe Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. MethodsIn 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. ResultsS-100B was elevated (>0.15 μg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. ConclusionIn newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis.

Sentinel Lymph Node Biopsy Is Prognostic in Thickest Melanoma Cases and Should Be Performed for Thick Melanomas.

Sentinel lymph node biopsy (SLNB) is recommended for intermediate thickness melanoma, but for thick melanoma, guidelines are less definitive about the use of SLNB in this population. We present a study on thick melanoma evaluating for prognostic factors. The Sentinel Lymph Node Working Group database was queried for thick (> 4mm) melanoma cases that had a SLNB from 1993 to 2018. Clinicopathologic characteristics were correlated with SLN status and melanoma-specific survival (MSS). There were 1235 patients. Median follow-up was 28months. Median thickness was 5.9mm, with 956, 175, and 104 cases presenting thickness > 4-8, > 8-12, and > 12mm, respectively. SLN metastases were seen in 439 of 1235 (35.5%) cases and in 33.9%, 40.6%, and 42.3% of melanomas > 4-8, > 8-12, and > 12mm, respectively. In each thickness group, MSS was significantly worse for SLN-positive compared with SLN-negative cases (all P < 0.005). Multivariable analysis showed that SLN metastasis, male gender, increasing thickness, lymphovascular invasion, and microsatellitosis significantly predicted worse MSS for melanomas > 4-8mm, with SLN metastasis showing the greatest risk (HR 2.17, 95% CI 1.64-2.87, P < 0.0001). For melanomas > 8mm, only SLN metastasis significantly predicted MSS (> 8-12mm: HR 3.93, 95% CI 2.00-7.73, P < 0.0001; > 12mm: HR 3.58, 95% CI 1.56-8.22, p < 0.0027). Thick melanoma patients with SLN metastasis have significantly worse MSS compared with SLN-negative patients, even in the thickest cases, and SLN status is the most powerful and/or only predictor of MSS. Given these results, SLNB shows important prognostic value in this population and is indicated for clinically localized thick melanoma.

Survival prediction in patients with cutaneous melanoma by tumour lymphangiogenesis

ABSTRACT Objectives: Melanoma induces lymphangiogenesis by secreting lymphangiogenic growth factors. The aim of this study was to examine the role of tumour lymphangiogenesis in survival of patients with cutaneous melanoma. Methods: Immunostaining of one hundred melanoma specimens was done with lymphatic-specific antibody D2-40. The quantification of tumour lymphangiogenesis – lymphatic vessel density (LVD) and lymphatic vessel area (LVA) – was calculated by computer-assisted morphometric analysis. Results: High intratumoural LVD, high peritumoural LVD, male gender, greater tumour thickness and Clark level IV/V were significantly associated with shorter disease-free survival (p= 0.001, p= 0.004, p= 0.004, p= 0.000 and p= 0.008, respectively) and melanoma-specific survival (p= 0.002, p= 0.002, p= 0.001, p= 0.000 and p= 0.017, respectively), while the trunk melanoma site was significantly associated only with shorter disease-free survival (p= 0.033). No significant association of LVA with survival was found. At multivariate analysis, peritumoural LVD [hazard ratio (HR) = 2.143, 95% confidence interval (CI) 1.097–4.189, p= 0.026)] and melanoma thickness (HR = 1.276, 95%CI 1.106–1.473, p= 0.001) were independent predictors of disease-free survival, while intratumoural LVD (HR = 3.446, 95%CI 1.465–8.109, p= 0.005), peritumoural LVD (HR = 2.742, 95%CI 1.313–5.725, p= 0.007) and gender (HR = 2.880, 95%CI 1.304–6.362, p= 0.009) were independent predictors of melanoma-specific survival. Conclusion: Тhis study shows that LVD enables better prediction of survival than melanoma thickness and other clinical-pathological parameters. Intratumoural LVD is the most significant predictor of melanoma-specific survival, while only peritumoural LVD has a significant impact on both, a disease-free survival and a melanoma-specific survival.

Clinical validation of a prognostic 11-gene assay in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma (CM).

9518 Background: AJCC comprises two markers (Breslow thickness and ulceration) to subdivide stage II CM patients into groups with relatively low, average, or high risk of death. Recent updates of clinical guidelines (NCCN, AAD) suggest that patient management be further tailored to an individual prognosis, e.g. through gene expression profiling (GEP). The aim of this single center study was to clinically validate a prognostic GEP-based risk score (MelaGenix) for stage II CMs. Methods: All obtainable, formalin-fixed paraffin-embedded (FFPE) primaries of AJCC stage II CMs from the Central Malignant Melanoma Registry of Germany archived in Tuebingen were included. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome (data exchange overseen by independent data clearing house) to determine GEP low- vs. high-score groups with a pre-specified GEP score cut-off (≤0.00 &gt; ). Melanoma specific survival (MSS) was evaluated by Kaplan-Meier (KM) analysis and prognostic performance was assessed by multivariate Cox regression. Results: Study cohort comprised 245 stage II primaries (IIA/B/C n = 118/78/49). Median follow-up was 40 months, 5y/10y MSS was 86/75%, median thickness was 3.0 mm, 142 tumors were ulcerated. GEP low-score group had 5y&amp;10y MSS of 92%; GEP high-score group had 5y/10y MSS of 82/67%. KM log-rank was significant (p = .018); GEP score contributed independent prognostic information in multivariate Cox regression (p = .024 HR = 1.45 [1.05 – 2.00]) vs. covariates pT categories (p = .002 HR = 1.59 [1.19 - 2.13]) and age (p = .001 HR 1.05 [1.02 - 1.09]). Conclusions: MelaGenix has been validated as an independent predictor of MSS in stage II patients and refines prognosis beyond AJCC. MelaGenix could serve as an important prognostic decision tool regarding patient management, especially whether adjuvant systemic treatment is appropriate – once drugs become available. It seems reasonable to include this score in future clinical trials. [Table: see text]

Sentinel Lymph Node Status is a Main Prognostic Parameter Needful for the Correct Staging of Patients with Melanoma Thicker than 4 mm: Single-Institution Experience and Literature Meta-Analysis

ABSTRACTPurpose of the study: The usefulness of sentinel lymph node biopsy in thick melanomas is debated. The aim of this study was to evaluate the possible prognostic significance of sentinel lymph node biopsy in T4 melanoma patients and to verify whether this was a homogeneous group of patients with similar poor behavior.Materials and Methods: A retrospective observational study was performed. Data were extracted from the Tuscan Regional Referral Center database. The outcome of sentinel lymph node-negative and sentinel lymph node-positive T4 melanomas were compared. A systematic review of published series on this issue and a meta-analysis were performed.Results: Among 125 T4 melanoma patients, 53 patients (42.4%) were sentinel lymph node-positive and 72 (57.6%) patients were sentinel lymph node-negative. The 5-year and the 10-year melanoma specific survival were 81.9% and 72.3% for sentinel lymph node-negative patients and 42.4% and 17.9% (P < 0.001) for sentinel lymph node-positive patients. A positive sentinel lymph node showed an HR of 3.08. The meta-analysis confirmed that there was a significantly greater risk of death for patients with thick melanoma and positive sentinel lymph node (RR 1.75).Conclusions: The results of the study point out that the sentinel lymph node biopsy is required for the correct staging of patients with melanoma thicker than 4 mm and that the status of sentinel lymph node is a significant predictor of melanoma specific survival. This knowledge allows early surgical and adjuvant treatment as well as appropriate trial enrollment and tailored follow-up.

Gastrointestinal metastases from melanoma: Does surgical resection improve survival when performed in combination with immunotherapy?

340 Background: Prior studies have shown the benefits of metastasectomy and more recently, immunotherapy, in Stage IV melanoma. We report the largest series of gastrointestinal (GI) melanoma metastases, in order to clarify the role of surgical resection in the setting of systemic treatment options. Methods: A review of our institutional melanoma database identified all patients with hollow viscus GI metastases diagnosed between 1971 and 2013. Patient age and sex; primary tumor location, thickness and ulceration; GI-metastasis free interval; and types of treatment were analyzed. The primary endpoint was melanoma-specific survival (MSS), measured from the diagnosis of GI metastases. Survival analyses compared combination therapy to immunotherapy (i.e. vaccine, interleukin-2, interferon, ipilimumab) or surgery alone. Operative patients were further stratified by surgical intent (curative or palliative). Results: The 393 study patients had a median GI-metastasis free interval of 49.5 (0 – 416.0) months from the initial diagnosis; their mean age at GI metastases was of 53.5 ± 14.1 years. Median MSS was 20.0 months with surgery plus immunotherapy (n=160), 13.0 months with surgery alone (n=111), 8.0 months with immunotherapy alone (n=64), and 5.0 months with neither treatment (n=58) (p&lt;0.001). By multivariable analysis, age at GI metastasis diagnosis (HR=1.014; p=.014), truncal melanoma site (HR=1.659; p=.017), immunotherapy (HR=0.675; p=.030), and metastasectomy (HR=0.544; p&lt;.001) were significant predictors of MSS. Surgical intent was known in 98 patients: curative surgery had a median MSS of 30.0 months (n=49) and palliative surgery had a median MSS of 12.0 months (n=49) (p=.015). Conclusions: Treatment of GI melanoma metastases should use a combination of metastasectomy and immunotherapy, instead of either modality alone. Select patients are likely to obtain an enhanced benefit from GI metastasectomy, specifically curative surgery, in the setting of newer immunotherapy options.

32. Sentinel lymph node biopsy in patients with thin melanoma

Background Most new cases of melanoma are thin (≤1 mm) tumours. A small but significant proportion of patients with thin melanoma suffer disease progression and melanoma-related death. We sought to determine clinico-pathological factors predictive poor clinical outcomes in patients with thin melanoma who underwent sentinel lymph node (SLN) biopsy. Methods Patients diagnosed with a single primary thin cutaneous melanoma who underwent SLN biopsy between 1992 and 2009 were identified from the database of the Melanoma Institute Australia. Thin melanomas were defined as having a Breslow thickness ≤1.00 mm. Clinico-pathological factors associated with SLN positivity, regional lymph node recurrence and survival were analysed. Results There were 432 patients (226 male, 206 female, median age 49.5 years). SLNs were positive in 29 (6.7%) patients. No SLN positivity was detected in 37 patients with tumour thickness ≤0.50 mm. Breslow thickness (OR = 52.0, 95%CI 1.4-1948.7) and presence of lymphovascular invasion (OR = 8.5, 95%CI 1.8-41.4) were the only independent predictors of SLN positivity. Anatomic location in head/neck region (OR = 8.5, 95%CI 1.8-40.2; compared to location in the limbs) was the only independent predictor of regional lymph node recurrence. Mitotic rate was the only independent predictor of melanoma-specific survival (HR=1.2, 95% CI 1.1-1.3). SLN positivity in Clark level III tumours (HR=8.0, 95%CI 1.8-36.0) and anatomic location in head/neck region in Clark level IV tumours (HR = 23.7, 95% CI 2.0-277, compared to limbs) were the only independent predictors of poorer disease-free survival. Conclusions Patients with thicker tumours (>0.5 mm) and other adverse prognostic factors (e.g., ulceration, elevated mitotic rate, lymphovascular invasion) have a greater risk of occult nodal metastasis and are more likely to benefit from SLN biopsy.