Post-Excision Soft X-Ray Radiotherapy for Keloids: Experience in a Tertiary Referral Center.

INTRODUCTION: Keloid is an abnormal proliferation of scar tissue that grows beyond the original margins of the injury. Even after complete resection, recurrences are common and pose a poorly understood challenge in dermatology. There is lack of large prospective clinical trials; thus, treatment recommendations are based on retrospective analyses and small cohort studies. Superficial radiotherapy is recommended in recurrent keloids; however, the successful treatment rates vary greatly. The aim of this study was to evaluate the keloid recurrence rate after post-excision soft X-ray radiotherapy and the associated factors. METHODS: We reviewed retrospective data of all patients, treated with adjuvant post-excision soft X-ray radiotherapy with 12 Gy in 6 sessions at the tertiary referral center, Department of Dermatology, University Hospital Zurich, Switzerland, between 2005 and 2018. We analyzed individual keloids as separate cases. Successful treatment was defined as no sign of recurrence within 2 years. RESULTS: Of the 200 identified patients, 90 met the inclusion criteria and were included in the final analysis. In 90 patients, 104 cases of treated keloids were analyzed. Keloids were mainly located on the trunk (49%) and were mostly caused by previous surgery (52.2%). 50% of the keloids did not relapse within 2 years after therapy. A significant factor leading to recurrence was the presence of previous therapy, with prior topical therapies, such as steroid injections or 5-fluorouracil, leading to most relapses. 69.2% of keloid cases who relapsed were pretreated. Soft X-ray radiotherapy was well tolerated, with posttreatment hyperpigmentation noted in 34% of patients, particularly in patients with non-Caucasian origin (61.3%). CONCLUSION: Treatment of refractory keloids is difficult. Post-excision radiotherapy is an established adjuvant treatment option; nevertheless, recurrence rates are high, especially in pretreated keloids. Prospective studies determining the exact dosage and fraction of post-excisional radiotherapy are needed to determine the optimal radiation parameters.

The role of triple therapy and therapy sequence in treatment of BRAF-mutant metastatic melanoma. Response to overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study.

Novel therapies have achieved unprecedented benefit in survival of advanced melanoma patients. While immunotherapy (ICI) can be administered independent of mutational status, BRAF and MEK kinase inhibitors represent another effective treatment option for patients with BRAF mutant melanoma. Given the benefits these therapies demonstrate, the natural instinct was to combine. Three studies have investigated the benefit of combination of ICI using anti-PD-1 or anti-PD-L1 antibody and targeted therapy (TT) with BRAF and MEK inhibitors over TT and placebo. Among these studies, statistically significantly superior duration of response was observed, however overall and progression-free survival were only numerically superior, if at all. One triple combination was approved for BRAF mutant metastatic melanoma; however, the expected synergistic effect of triple therapy could not be universally confirmed and the observed benefits with triple seem to depend on statistical considerations rather than a biological reason. As patients with BRAF mutant melanoma have both ICI and TT as their first-line treatment options, the question whether the sequence matters was addressed. Two prospective trials compared first-line ICI, followed by TT at progression, or vice-versa, with additional "sandwich" approach (8 weeks of TT followed by ICI until progression, then TT again) in the Secombit study. The benefit of first-line ICI was demonstrated in both studies with Secombit study showing the "sandwich" approach to have similar effect. Current data advices for immunotherapy based regiments in patients with BRAF mutant melanoma or, possibly, sandwich approach. Whether triple therapy is superior to ICI monotherapy still needs to be addressed considering not only efficacy, but also safety.

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab.

BACKGROUND: The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. METHOD: To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. RESULTS: Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61-27.81) in patients without diabetes, 10.23 months (95% CI: 5.81-14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04-78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02-44.85) in patients without diabetes, 22.12 months (95% CI: 14.41-29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29-72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose (< 137 mg/dl) and 36.27 months in those with high levels (hazard ratio 0.16, 95% CI: 0.04-0.58; p = 0.005). The patients whose glucose blood level increased after 3 months of treatment with nivolumab + relatinib compared to baseline (ratio of blood level at baseline/after 3 months > 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. CONCLUSIONS: LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained.

What Is New in Cutaneous T Cell Lymphoma?

PURPOSE OF REVIEW: This review focuses on updates in prognosis, pathogenesis, and treatment of cutaneous T cell lymphoma (CTCL). RECENT FINDINGS: Cohort studies indicate imaging may be necessary in early-stage CTCL. Risk factors for progression of CTCL have been identified. Interactions between malignant cells and the tumor microenvironment (TME) and the skin microbiome advance the understanding of pathogenesis and tumor cell dissemination. Studies support a hypothesis of circulating malignant tumor cells. MicroRNA (miR) influence tumor progression and prognosis; the IL22-STAT3-CCL20 cascade may be a novel target. IL-4, IL-5, and IL-31 cytokines are relevant for pruritus and could be targets for therapeutic interventions. Systemic therapies, such as JAK inhibitors, targeted antibodies, and checkpoint inhibitors, show promise in advanced stages. Allogenic hematopoietic stem cell transplantation provides a potential curative option for patients. Further investigations of prognosis and translational research are necessary to improve stratification of patients for treatment.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

Evaluation of the minimal erythema dose for UVB and UVA in context of skin phototype and nature of photodermatosis.

BACKGROUND: Phototesting is part of the standard procedure for the evaluation of patients with photosensitivity disorders. The response of patients to targeted UVB or UVA radiation helps to find out more about the nature of photodermatosis. Nevertheless, there are no default values of the minimal erythema dose (MED). METHODS: This study evaluated data of 203 patients (131 female, 72 male, mean age 52 years) who were referred for phototesting to the University Hospital Zurich between 2012 and 2017. We retrospectively analyzed the demographic data, medical history, skin phototype, reaction to UVB and UVA radiation, and, if present, the diagnosis of photodermatosis. In patients who did not develop erythema at the highest tested UV doses, the next logical increment was taken for analysis. In case of UVA, the two periphery doses could not be evaluated due to technical issues, so the closest reliable UVA doses were used. RESULTS: The MED-UVB correlated with the skin type and increased with a higher phototype. No such correlation could be seen for MED-UVA. However, the MED-UVA was significantly reduced in patients with photodermatosis without significant differences between the subgroups of photodermatosis. More than half of the patients did not show a reduced MED despite a diagnosed photodermatosis. CONCLUSION: We showed, how different skin types with and without photodermatosis react to UV radiation. Based on the results, we suggested threshold doses that can be chosen for phototesting, presented which doses can be considered pathologic and showed the probability of a pathologic MED in correlation with a diagnosed photodermatosis.

Radiotherapy in Periocular Cutaneous Malignancies: A Retrospective Study.

BACKGROUND: Due to the importance of function and cosmetics, periocular skin malignancies represent a therapeutic challenge. OBJECTIVE: To evaluate the safety and efficacy of radiotherapy (RT) treating periocular skin tumors. METHODS: Data of patients with periocular tumors treated with grenz or soft X-rays at the University Hospital Zurich, Switzerland, between 2009 and 2014 were reviewed. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with associated in situ lesions, cutaneous melanoma, lentigo maligna (LM), cutaneous lymphoma and Kaposi's sarcoma were included in the analysis. RESULTS: We found 159 periocular lesions in 145 patients. Overall recurrence was highest for actinic keratosis and Bowen's disease (27%), melanoma (17%) and LM (15%), whereas SCC and BCC showed recurrence in 11 and 10%, respectively. 45% of all recurrences occurred within 12 months after treatment, with a median time to recurrence of 13 months (range 3-73). CONCLUSION: RT, which provides a good therapeutic response with minimal adverse events, is a therapy option for periocular cutaneous malignancies.

The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe.

PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments.

Critical aspects to achieve a high-quality melanoma clinic.

PURPOSE OF REVIEW: With incidence of melanoma growing worldwide and new therapies prolonging the survival of patients with advanced disease, complex medical care is needed. RECENT FINDINGS: Best care of complicated melanoma cases is achieved in specialized referral centers. Aims to provide optimized melanoma therapy, best patient-reported treatment outcome, and successful clinical and translational research, necessitate a dedicated interdisciplinary team. SUMMARY: We report on critical aspects of the interaction between patients, medical care givers, clinical trial and biobanking teams, and emphasize the importance of interdisciplinary tumor boards. Specialized skin cancer nurses and local patient advocacy groups should be involved in patient care and could be the binding link between the patients and the treatment team.

Successful Use of Grenz Rays for Disseminated Superficial Actinic Porokeratosis: Report of 8 Cases.

BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is a rare keratinization disorder with potential malignant transformation, for which present treatment strategies show limited success. AIM: To evaluate the response of DSAP lesions to grenz ray radiotherapy (RTx). METHODS: Data of patients treated with RTx at University Hospital Zurich, Switzerland, between 2004 and 2015, were reviewed. Patients with DSAP, who received at least 1 RTx treatment session and who had been followed up for at least 4 weeks were included in the further data analysis. RESULTS: The study cohort consisted of 8 patients with a median age of 73 years (range 54-84). All were treated with grenz rays for DSAP. Most (7/8) patients showed complete clinical clearing of the lesions. All patients experienced temporary side effects of RTx, which resolved within 4 weeks after the last irradiation. CONCLUSION: We suggest radiotherapy with grenz rays as a treatment option for DSAP.

Infliximab in steroid-refractory immune-related hepatitis does not demonstrate hepatotoxicity and may shorten time on steroids.

BACKGROUND: Immune-related hepatitis (irHepatitis) is a relatively common immune-related adverse event (irAE) of checkpoint inhibitors. Often, it responds well to steroids; however, in refractory cases, further therapy is needed. Anti-tumor necrosis factor (TNF) antibodies are used for management of multiple irAEs, but there are little data in irHepatitis. Here, we report on safety and efficacy of infliximab in 10 cases of steroid-refractory irHepatitis. METHODS: We retrospectively reviewed patients treated with infliximab for steroid-refractory grade ≥3 irHepatitis at the Department of Dermatology, University Hospital Zurich. The positive response to infliximab was defined as no further increase in alanine aminotransferase (ALT)/aspartate aminotransferase (AST) above 50% than at the time of first infliximab infusion and control of irHepatitis without therapies other than steroids and infliximab. RESULTS: 10 patients with steroid-resistant irHepatitis grade ≥3 were treated with infliximab 5 mg/kg, of whom 7 (70%) responded positively. In two cases, the liver values increased over 50% before the irHepatitis could be controlled. In another case, therapies other than infliximab and steroids were given. At the median follow-up of 487 days, 90% of the patients demonstrated resolved irHepatitis without AST/ALT elevation following infliximab infusions. CONCLUSIONS: Treatment of irHepatitis with infliximab did not result in hepatotoxicity and led to long-lasting positive response in 9 of 10 of the cases. Further research is needed to evaluate the role of anti-TNF antibodies in management of irHepatitis.

Advances in the pharmacological management of cutaneous T-cell lymphoma.

INTRODUCTION: Current treatment guidelines for cutaneous T cell lymphoma (CTCL) advocate a stage-driven approach, considering clinical presentation, symptom burden, and patient comorbidities. Therapy selection hinges on factors like disease subtype, severity, and treatment availability. The primary goal is to enhance the quality of life by mitigating symptoms, as achieving lasting complete remission is infrequent. AREAS COVERED: Over the past decade (2013-2023), the therapeutic landscape of CTCL has experienced substantial transformation with the introduction of innovative therapies. This review explores the main pivotal developments in traditional treatment schedules and recently introduced drugs, aiming to offer clinicians and researchers a thorough perspective on the decade's progress in the field. EXPERT OPINION: Despite the progress made in CTCL therapeutics, ranging from topical chemotherapeutics to immunomodulatory agents, several unmet needs persist. Firstly, there is a pressing need for the incorporation of readily available predictors for treatment response, encompassing clinical, pathological, and molecular features. Secondly, a more profound comprehension of the tumor microenvironment is imperative to optimize the landscape of targetable molecules. Lastly, the undertaking of studies on combination regimens should be encouraged as it enhances therapy efficacies by synergistically combining agents with diverse modes of action.

Patterns of radiological response to tebentafusp in patients with metastatic uveal melanoma.

Metastatic uveal melanoma (mUM) is a rare type of melanoma with poor outcomes. The first systemic treatment to significantly prolong overall survival (OS) in patients with mUM was tebentafusp, a bispecific protein that can redirect T-cells to gp-100 positive cells. However, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the clinical impact of tebentafusp. As metabolic response assessed by PET Response Criteria in Solid Tumors (PERCIST) has been reported to better correlate with clinical outcome, we here compared the patterns of radiological and morphological responses in HLA-A*02:01-positive patients with mUM treated with tebentafusp. In the 19 enrolled patients, RECIST showed an overall response rate (ORR) of 10%, median progression-free survival of 2.8 months (95% CI 2.5-8.4), and median OS (mOS) of 18.8 months. In 10 patients, where both RECIST and PERCIST evaluation was available, the ORR was 10% for both; however, the PFS was longer for PERCIST compared to RECIST, 3.1 and 2.4 months, respectively. A poor agreement between the criteria was observed at all assessments (Cohen's kappa ≤0), yet they differed significantly only at the first on-treatment imaging ( P  = 0.037). Elevated baseline LDH and age were associated with an increased risk for RECIST progression, while lymphocyte decrease after the first infusions correlated to reduced risk of RECIST progression. Detectable ctDNA at baseline did not correlate with progression. Early response to tebentafusp may be incompletely captured by conventional imaging, leading to a need to consider both tumor morphology and metabolism.

Monitoring melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance.

Resistance to targeted therapy remains a major clinical challenge in melanoma. To uncover resistance mechanisms, we perform single-cell RNA sequencing on fine-needle aspirates from resistant and responding tumors of patients undergoing BRAFi/MEKi treatment. Among the genes most prominently expressed in resistant tumors is POSTN, predicted to signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after therapy exhibit high POSTN expression levels and high numbers of TTR macrophages. POSTN polarizes human macrophages toward a TTR phenotype and promotes resistance to targeted therapy in a melanoma mouse model, which is associated with a phenotype change in intratumoral macrophages. Finally, polarized TTR macrophages directly protect human melanoma cells from MEKi-induced killing via CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages may offer a strategy to overcome resistance to targeted therapy in melanoma.

Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. METHODS: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). RESULTS: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. CONCLUSION: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

The genetic evolution of acral melanoma.

Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Immune-Related Sclerosing Cholangitis and Subsequent Pyogenic Liver Abscesses in Two Patients With Melanoma Treated by Triplet Therapy: A Case Report.

Immune checkpoint inhibitors have improved the treatment of many cancers. However, immune-related (IR) adverse events can limit their use. A rare but potentially severe IR adverse event is IR-cholangitis, which is mostly induced by anti-programmed cell death 1 (PD1) antibodies and is often corticosteroid-resistant. Consequently, immunosuppressive therapy is increased, which interferes with the antitumor response and bears the risk of infection. We report on 2 patients with BRAF V600E mutant melanoma, who presented with IR-sclerosing cholangitis under triplet therapy with atezolizumab [anti-programmed cell death ligand 1 (PD-L1) antibody], vemurafenib (BRAF inhibitor), and cobimetinib (MEK inhibitor). In both cases, the administration of corticosteroids initially resulted in a marginal improvement but was followed by a rebound of biliary enzymes and the subsequent emergence of pyogenic liver abscesses with bacteremia. Liver abscesses developed without preceding invasive procedures, which implies that a more restrictive approach to immunosuppressive therapy for IR-cholangitis should be considered. To our knowledge, we report the first 2 cases of IR-cholangitis and subsequent liver abscesses without prior invasive intervention, the first cases of IR-cholangitis induced by triplet therapy, and 2 of the few anti-PD-L1 induced cases contributing to the evidence that both anti-PD1 and anti-PD-L1 antibodies induce IR-cholangitis. Treatment strategies for IR-cholangitis need to be improved to prevent life-threatening infectious complications.

Clock-like Mutation Signature May Be Prognostic for Worse Survival Than Signatures of UV Damage in Cutaneous Melanoma.

Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort's mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.