Background: Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma. MDM2/4 as well as EGFR amplifications are supposed to be associated with hyperprogression on ICI in diverse cancers. We therefore investigated the response of metastatic acral and mucosal melanoma to ICI in regard to MDM2/4 or EGFR amplifications and melanoma type. Methods: We conducted a query of our melanoma registry, looking for patients with metastatic acral or mucosal melanoma treated by ICI. Whole exome sequencing, FISH and immunohistochemistry on melanoma tissue could be performed on 45 of the total cohort of 51 patients. Data were correlated with patients' responses to ICI and survival. Results: 22 out of 51 patients had hyperprogressive disease (an increase in tumor load of >50% at the first staging). Hyperprogression occurred more often in case of MDM2/4 or EGFR amplification or <1% PD-L1 positive tumor cells. Nevertheless, this association was not significant. Interestingly, the anorectal melanoma type and the presence of liver metastases were significantly associated with worse survival. Conclusions: So far, we found no reliable predictive marker for patients who develop hyperprogression on ICI, specifically with regard to MDM2/4 or EGFR amplifications. Nevertheless, patients with anorectal melanoma, liver metastases or melanoma with amplified MYC seem to have an increased risk of not benefitting from ICI.

The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes. Melanomas of unknown primary had a similar mutation pattern and TMB to cutaneous melanoma, which hints at its cutaneous origin. Besides the typical hotspot mutation in BRAF and NRAS, we frequently observed CDKN2A deletions. Acral and mucosal melanomas were dominated by CNV alterations affecting PDGFRA, KIT, CDK4, RICTOR, CCND2 and CHEK2. Uveal melanoma often had somatic SNVs in GNA11/Q and amplification of MYC in all cases. A significantly higher incidence of BRAF V600 mutations and EGFR amplifications, PTEN and TP53 deletions was found in patients with disease progression while on ICI. Thus, NGS might help to characterize melanoma subtypes more precisely and to identify possible resistance mechanisms to ICI therapy. Nevertheless, NGS based studies, including larger cohorts, are needed to support potential genetic ICI resistance mechanisms.

Background High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies. Methods We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel. Results The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12–4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19–23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS). Conclusion BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy.

Background The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods MTB@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the molecular tumor board (MTB) and collected prospective clinical outcome data. Results Here, we present initial data from 661 adult patients with tumors of the nervous system enrolled by 31 December 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival (PFS) ratio &gt; 1.3 in 31.3% of patients. Conclusions Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies and even clinical care.

120 g/L and pre-brachytherapy Hb < 120 g/L was 9%, 15% and 22% respectively. The 3 year overall survival rate was 72%, 65% and 49% respectively. 52 patients (38.5%) had anaemia at presentation (Hb < 120 g/L). There was significant association between anaemia and younger age, more advanced stage and lymph node involvement. Anaemia was corrected by blood transfusion and/or ferric carboxymaltose. The pre-brachytherapy Hb level had the strongest impact on both local failure and survival. The post-treatment Hb level did not have an impact on the outcomes. Conclusion Anaemia in patients with cervical cancer undergoing chemoradiation was a strong prognostic factor for local control and survival. The pre-brachytherapy Hb level had the strongest impact indicating the benefit from correcting the anaemia before treatment and maintaining the Hb level above 120 g/L during the treatment.