Gender Differences in Melanoma Progression and Survival

__Abstract__ Cutaneous melanoma is developing into a major public health problem worldwide. Incidence differs greatly across the world with high incidence rates in the Unites states, Europe and especially in Australia and New Zealand, but relatively low incidence rates in Central and South America, Asia and Africa. In Europe, melanoma incidence is rising, especially in the Northern and Western European countries. This is also true for the United States, where melanoma is one of the few cancer types which showed continuously increasing incidence rates from 1975 onward. Also in the Netherlands, incidence of melanoma keeps increasing (figure 2). Although incidence in Australia and New Zealand remains the highest in the world1, incidence has been observed to stabilize in younger individuals in both Australia5, as well as in Canada. Differences across gender in melanoma incidence have been noted for a long time

Sunny holidays before and after melanoma diagnosis are respectively associated with lower breslow thickness and lower relapse rates in Italy

Background: Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods: A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results: Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results

Donor-derived cell-free DNA detects kidney transplant rejection during nivolumab treatment

Background: In solid organ transplant (SOT) recipients, transplant rejection during immune checkpoint inhibitor (ICI) treatment for cancer is a clinical problem. Donor-derived cell-free DNA (dd-cfDNA) can be detected in blood and is a sensitive biomarker for diagnosis of acute rejection in SOT recipients. To our best knowledge, this is the first case report of a kidney transplant recipient with advanced cancer treated with ICI who was monitored with dd-cfDNA. Case presentation: A 72-year old female with a long-standing renal transplant was diagnosed with advanced melanoma in 2018 and was treated with the anti-PD1 antibody nivolumab. Within 12 days after the first administration of nivolumab, dd-cfDNA ratio increased to 23%, suggesting allograft rejection. Her kidney transplant function deteriorated and acute rejection was confirmed by renal transplant biopsy. As the rejection could not be controlled despite immunosuppressive treatment, a transplant nephrectomy was necessary and haemodialysis was started. Immunological analysis of the renal explant showed infiltration of alloreactive, nivolumab-saturated, PD1+ cytotoxic T cells. After transplant nephrectomy, she experienced nivolumab-related toxicity and rapid disease progression. Conclusion: Clinicians prescribing ICIs should be aware that SOT recipients are a

Suitability of tumor-associated antibodies as predictive biomarker for response to immune checkpoint inhibitors in patients with melanoma: a short report

In 2019, Fässler et al showed in this journal that the presence of tumor-associated antibodies correlated with response to immune checkpoint inhibitor treatment in patients with metastatic melanoma. The results of this study suggested that tumor-associated antibodies directed against melanocyte-differentiation antigens and the cancer-germline antigen NY-ESO-1 should be further investigated as candidate biomarkers for response to immune checkpoint inhibitors. The aim of the current study was to validate and extend these previous findings. Therefore, we examined the correlation between serum levels of tumor-associated antibodies and tumor response after treatment with immune checkpoint inhibitors in patients with metastatic melanoma.All patients included in this prospective study were diagnosed with advanced stage melanoma and treated with nivolumab or pembrolizumab monotherapy. Blood samples were collected before and during treatment. Serum levels of tumor-associated antibodies against the melanocyte differentiation antigen Melan-A and the cancer germline antigens NY-ESO-1, MAGE-C2, MAGE-A6 and ROPN1B were measured at baseline and during treatment. Differences between responders and non-responders were assessed using the Mann-Whitney U-test, and differences between different overall survival categories with the Kruskal-Wallis test. P values ≤0.05 were considered significant.Serum samples of 58 patients with advanced melanoma with long-term follow-up (>3 years) were collected. In contrast to the findings of Fässler et al, for all antibodies tested, we found no significant differences between serum levels of responders and non-responders before or during treatment with immune checkpoint inhibitors. In addition, no significant differences were found in serum levels of tumor-associated antibodies for different overall survival groups.Although our study included a larger and more mature cohort of patients with longer follow-up, we could not externally validate the findings of Fässler et al In addition, we were not able to identify other cancer germline antigens as predictive biomarkers of response to immune checkpoint inhibitors in patients advanced melanoma. Based on the results of the present study, clinical applicability of tumor-associated antibodies directed against tumor antigens as predictive biomarkers for immune checkpoint inhibitors in patients with advanced melanoma is not feasible

Oncological healthcare providers’ perspectives on appropriate melanoma survivorship care: a qualitative focus group study

Abstract Background The increasing group of melanoma survivors reports multiple unmet needs regarding survivorship care (SSC). To optimise melanoma SSC, it is crucial to take into account the perspectives of oncological healthcare providers (HCPs) in addition to those of patients. The aim of this study is to gain an in-depth understanding of HCPs’ perspectives on appropriate melanoma SSC. Methods Four online focus groups were conducted with mixed samples of oncological HCPs (dermatologists, surgeons, oncologists, oncological nurse practitioners, support counsellors and general practitioners) (total n = 23). A topic guide was used to structure the discussions, focusing on perspectives on both SSC and survivorship care plans (SCPs). All focus groups were recorded, transcribed verbatim, and subjected to an elaborate thematic content analysis. Results Regarding SSC, HCPs considered the current offer minimal and stressed the need for broader personalised SSC from diagnosis onwards. Although hardly anyone was familiar with SCPs, they perceived various potential benefits of SCPs, such as an increase in the patients’ self-management and providing HCPs with an up-to-date overview of the patient’s situation. Perceived preconditions for successful implementation included adequate personalisation, integration in the electronic health record and ensuring adequate funding to activate and provide timely updates. Conclusions According to HCPs there is considerable room for improvement in terms of melanoma SSC. SCPs can assist in offering personalised and broader i.e., including psychosocial SSC. Aside from personalisation, efforts should be focused on SCPs' integration in clinical practice, and their long-term maintenance

Associations between patient and disease characteristics and severe adverse events during immune checkpoint inhibitor treatment: An observational study

Aim: With increasing use of immune checkpoint inhibitors (ICIs) more patients will develop severe and potentially life-threatening immune-related adverse events (irAEs). So far, predictive models for the occurrence of grade ≥3 irAEs are lacking. Therefore, we analysed associations between patient and disease characteristics, and the occurrence of grade ≥3 irAEs. Methods: Patients with cancer who were treated with anti-PD-1 (+/−anti-CTLA-4) between July 2015 and February 2020, and who were prospectively included in the MULTOMAB-trial, were eligible for this cohort study. Time to and occurrence of grade ≥3 irAEs according to CTCAE v5.0 were retrospectively registered. The associations between patient and disease characteristics and irAE occurrence were analysed using the competing risk cox-regression model of Fine and Gray. Analyses were performed separately in patients treated with monotherapy (anti-PD-1) and combination therapy (anti-PD-1 + anti-CTLA-4). Subgroup analyses were performed in tumour types with the highest number of patients; melanoma and NSCLC. Results: Out of 641 patients, 106 patients (17%) experienced grade ≥3 irAEs. None of the analysed factors were associated with grade ≥3 irAE occurrence in the monotherapy (n = 550) or the combination therapy (n = 91) groups, nor in the subgroup analyses. Of interest, none of the patients with NSCLC with a WHO performance status of 0 (n = 34) experienced grade ≥3 irAEs. Most common NSCLC histology types were adenocarcinoma (n = 99/55%) and squamous cell carcinoma (n = 39/22%). Concluding statement: This study shows that patient and disease characteristics are not able to predict the occurrence of serious AEs in patients treated with ICIs

The course of C-peptide levels in patients developing diabetes during anti-PD-1 therapy

Introduction: Immune checkpoint inhibitor (ICI) associated diabetes is a harmful adverse event (AE) in patients with cancer following anti-programmed (cell) death protein-1 (PD-1) treatment. There are no available biomarkers able to predict this AE. The primary aim of this study was to investigate C-peptide levels as potential predictor for the occurrence of ICI-related diabetes. The secondary aim was to describe the presence of islet autoantibodies and course of pancreatic enzymes in patients with and without ICI-related diabetes. Methods: From a total of 1318 patients with cancer who started anti-PD-1 treatment 8 cases and 16 controls were studied in this nested case-control study. C-peptide levels, islet autoantibodies, and pancreatic enzymes were measured in prospectively collected blood serum. Results: In cases versus controls, median C-peptide levels were comparable at baseline and before toxicity or at the corresponding time point in controls. No patient had C-peptide levels below reference range before toxicity onset. Two out of eight patients in the ICI-related diabetes group had positive islet autoantibodies, whereas one out of 16 patients in the control group had positive islet autoantibodies. Pancreatic enzymes were elevated before diabetes onset in one patient (13%) and in one control (6%) at the corresponding time point. Conclusions: In patients developing ICI-related diabetes, changes in C-peptide levels, islet autoantibody positivity, and pancreatic enzymes before ICI-related diabetes onset seem comparable to patients without ICI-related diabetes