Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. ...Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6-10%, I
= 71%) while the lesion-specific clearance rate was 23% (95% CI 16-31%, I
= 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.
Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) ...expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.
We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.
For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53
, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53
in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.
While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
BRAF and MEK inhibitors have demonstrated significant survival benefits for patients with cutaneous melanoma. However, their use for uveal melanoma (UM) is less established. The aim of this ...systematic review was to summarise the current evidence on the efficacy and safety of MEK inhibitors in metastatic UM.
We performed a systematic literature search in MEDLINE, Embase and the Cochrane Library CENTRAL from 1946 through 17 April 2018. Abstracts of oncologic conferences, trial registers and reference lists were handsearched for relevant publications. The risk of bias was assessed with the Cochrane Risk of Bias Tool.
Of 590 records identified, six studies met the eligibility criteria and were included in the qualitative synthesis. Data were available for selumetinib ± dacarbazine (n = 3), trametinib ± AKT inhibitor (n = 2) and binimetinib plus sotrastaurin (n = 1) from three open-label phase II, two open-label phase I and one placebo-controlled phase III trial. The overall response rate was available in five studies and ranged from 0 to 14% with an average of 2.5%. The median progression-free survival ranged from 3.1 weeks to 16 weeks. Data on overall survival and 1-year survival rates were not consistently reported. Severe treatment-related adverse events were observed most commonly for the combination use of selumetinib plus dacarbazine (62%) and binimetinib plus sotrastaurin (75%).
UM is little responsive to MEK inhibition, regardless of the inhibiting agent and combination partner. Our results do not support the use of MEK inhibitors in UM. Novel treatment options are urgently needed in this patient population.
•Metastatic uveal melanoma (UM) is an orphan disease of a high unmet need.•The current use of MEK inhibitors in UM is not evidence based.•A systematic review on the use of MEK inhibitors for UM was performed.•MEK inhibitors have low radiologic response rates in UM.
Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic ...keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors’ expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.
Cutaneous squamous cell carcinoma is a common type of skin cancer that may progress to locally advanced or metastatic disease. Both disease stages are managed by a variety of treatment options, ...including immune checkpoint blockade (ICB), targeted therapy to epidermal growth factor, chemotherapy or treatment combinations. However, the comparative efficacy of such treatments is unclear.
We performed a systematic literature search of Medline, Embase and Central to identify eligible studies reporting Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS). Kaplan–Meier curves were digitised using the “‘WebPlotDigitizer” program. Individual patient data was subsequently remodelled and pooled for distinct treatment groups.
Overall, 22 independent studies were included of which n = 927 patients were evaluable for PFS and n = 1054 for OS. ICB showed the highest median PFS (mPFS 9.9 months (95% CI: 8.1–19.9)) and median OS (mOS not reached (95% CI: 31.5 months-not reached)) compared to chemotherapy (mPFS 3.0 months (95% CI: 2.2–4.8), mOS 12.6 months (95% CI: 9.6–15.8)), targeted therapy to epidermal growth factor (mPFS 4.9 months (95% CI: 4.4–5.6), mOS 12.7 months (95% CI: 11.9–14.9)) and combination therapies without ICB (mPFS 9.1 months (95% CI: 8.0–12.1), mOS 18.1 months (95% CI: 16.3–22.8)). The survival benchmark with ICB after 26 months for metastatic squamous cell carcinoma was 70.8% (95% CI: 61.5%–81.5%) versus 37.9% (95% CI: 29.5%–48.8%) for the combination group and 17.1% (95% CI: 9.5%–30.8%) for chemotherapy.
ICB is superior to other systemic treatments and sets a novel survival benchmark for advanced cutaneous squamous cell carcinoma.
•The relative efficacy of treatments for cutaneous squamous cell carcinoma is unclear.•Immune checkpoint blockade is superior to other systemic treatments.•Immune checkpoint blockade sets a new survival benchmark.
Summary
Squamous cell carcinoma of the skin (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all cutaneous tumors. An S3 guideline from the German ...Guideline Program in Oncology has been available since 2019 and was updated in 2022. The diagnosis of cSCC is based on clinical examination. Excision and histological confirmation are required for clinically suspicious lesions to allow for prognostic assessment and correct treatment. The treatment of first choice is excision with complete histological assessment of the surgical margins. Adjuvant radiation therapy may be considered if there is a high risk of recurrence. The immune checkpoint inhibitor cemiplimab is approved and recommended as the treatment of first choice for locally advanced or metastatic cSCC in Europe. If contraindications are present, chemotherapy, EGFR inhibitors, or palliative radiation therapy may be used. Surveillance should be performed in a risk‐stratified manner and includes a dermatological control supplemented by sonography examinations in high‐risk patients. Much research is still needed for solid organ transplant patients, concomitant hematologic diseases, and cSCC showing primary or acquired resistance to immunotherapies. Current developments include new drug combinations, intralesional therapies alone or in combination with immune checkpoint inhibitors, and neoadjuvant approaches.
Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large ...phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear.
The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed.
Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 - 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 - 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors.
NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.
BackgroundUveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic ...UM is currently unclear.MethodsPatients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.ResultsThe best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0–65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0–65.0). The median PFS was 3.0 months (95% CI 2.4–3.6). The median OS was estimated to 16.1 months (95% CI 12.9–19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).ConclusionsThe tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically ...sun-damaged skin. However, the therapeutic value of c-Kit inhibitors for these subtypes currently remains unclear.
The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma.
We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts.
Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval CI: 12–18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14–26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6–24%) and 22% for acral lentiginous melanoma (95% CI: 14–30%). At least one sAE was reported in 42% of patients (95% CI: 34–50%).
c-Kit inhibitors represent a valuable treatment option for patients with KIT-mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy.
•The therapeutic value of c-Kit inhibitors in rare melanoma subtypes is unclear.•Twenty-one studies with n = 649 patients were identified in a systematic literature research.•Pooled objective response rate was 15% (95% confidence interval: 11–20%) for all c-Kit inhibitors.•Combination of c-Kit inhibitors with immunotherapy should be further investigated.
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