Programmed cell death ligand 1 (PD-L1) is a cell surface molecule that plays a critical role in suppressing immune responses, mainly through binding of the PD-1 receptor on T lymphocytes. PD-L1 may ...be expressed by metastatic melanoma (MM). However, its clinical and biological significance remains unclear. Here, we investigated whether expression of PD-L1 in MM identifies a biologically more aggressive form of the disease, carrying prognostic relevance.
PD-L1 expression was analyzed by immunohistochemistry using two different antibodies in primary tumors and paired metastases from 81 melanoma patients treated at a single institution. Protein expression levels were correlated with PD-L1 mRNA, BRAF mutational status and clinical outcome. PD-L1+ and PD-L1- subsets of the A375 cell line were stabilized in vitro and compared using gene expression profiling and functional assays. Results were confirmed using xenograft models.
PD-L1 membrane positivity was detected in 30/81 (37%) of patients. By multivariate analysis, Breslow thickness and PD-L1 membrane positivity were independent risk factors for melanoma-specific death {PD-L1 5% cutoff hazard ratio (HR) 3.92, confidence interval (CI) 95% 1.61–9.55 P < 0.003, PD-L1 as continuous variable (HR 1.03, 95% CI 1.02–1.04 P < 0.002)}. PD-L1 expression defined a subset of the BRAF-mutated A375 cell line characterized by a highly invasive phenotype and by enhanced ability to grow in xenograft models.
PD-L1 is an independent prognostic marker in melanoma. If confirmed, our clinical and experimental data suggest that PD-L1+ melanomas should be considered a disease subset with distinct genetic and morpho-phenotypic features, leading to enhanced aggressiveness and invasiveness.
Summary
Background
The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM).
Objectives
To investigate whether the extent of ulceration (EoU) ...predicts relapse‐free survival (RFS) and overall survival (OS) in PCM.
Materials and methods
We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU.
Results
A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS hazard ratio (HR) (1‐mm increase) 1·26, 95% confidence interval (CI) 1·08–1·48, P = 0·0047 and OS HR (1‐mm increase) 1·25, 95% CI 1·05–1·48, P = 0·0120 was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour‐infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01–4 mm and > 4 mm BT.
Conclusions
This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports.
What is already known about this topic?
Ulceration is a well‐known prognostic factor in melanoma.
There are conflicting results on the prognostic value of the extent of ulceration.
What does this study add?
The extent of ulceration is an independent prognostic factor in primary cutaneous melanoma with Breslow thickness (BT) ≤ 2 mm.
The extent of ulceration should be incorporated into the pathology report as a required, core element.
Patients with extensive ulceration with a BT ≤ 2 mm are at high risk of recurrence and should be included in prospective adjuvant trials.
Linked Comment: Wilkinson and Gyorki. Br J Dermatol 2021; 184:192–193.
Backgroud
Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of ...care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile.
Method
We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms.
Results
We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents.
Conclusion
This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.
BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the ...expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP.
PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAFV600-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining.
Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7–43.3, P < 0.001 and the presence of TIMC (OR 6.5, 95% CI 1.7–24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression hazard ratio (HR) 4.3, 95% CI 2.1–8.7, P < 0.0001 and absence of TIMC (HR 2.5, 95% CI 1.4–4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8–14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5–6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival.
Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAFV600-mutated MMP treated with BRAFi.
Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data ...regarding VLD patient features and their echo on the therapeutic outcomes.
To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors.
A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients.
Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration.
•This multicentric retrospective study outlined the melanoma profile of 148 patients with vitiligo-like depigmentation (VLD) induced by checkpoint inhibitors.•Median VLD onset was 26 weeks and it was associated with other immune toxicities in one-third of cases.•After 3 years of VLD onset, 52% and 82% of patients, respectively, were progression free and still alive with a response rate of 73%.•Some features such as BRAF V600, female sex, and M stage were associated with better outcomes as well as a specific blood profile.
In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative ...prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT).
The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included.
Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001 and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028 was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513 and OS aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548.
ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.
The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma ...may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date.
From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors.
The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together.
Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.
•Gene panel testing doubles germline variants detection rate compared to CDKN2A-only testing.•If only two melanoma events at > 60 years of age are reported, eligibility to genetic testing requires careful consideration.•Pancreatic cancer is a strong predictor of germline status.
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