Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy.METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent.RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p &lt; 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891).CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.</p

Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models

BACKGROUND: Patients suffering from cancer are often treated with a range of chemotherapeutic agents, but the treatment efficacy varies greatly between patients. Based on recent popularisation of regularised regression models the goal of this study was to establish workflows for pharmacogenomic predictors of response to standard multidrug regimens using baseline gene expression data and origin specific cell lines. The proposed workflows are tested on diffuse large B-cell lymphoma treated with R-CHOP first-line therapy. METHODS: First, B-cell cancer cell lines were tested successively for resistance towards the chemotherapeutic components of R-CHOP: cyclophosphamide (C), doxorubicin (H), and vincristine (O). Second, baseline gene expression data were obtained for each cell line before treatment. Third, regularised multivariate regression models with cross-validated tuning parameters were used to generate classifier and predictor based resistance gene signatures (REGS) for the combination and individual chemotherapeutic drugs C, H, and O. Fourth, each developed REGS was used to assign resistance levels to individual patients in three clinical cohorts. RESULTS: Both classifier and predictor based REGS, for the combination CHO, were of prognostic value. For patients classified as resistant towards CHO the risk of progression was 2.33 (95% CI: 1.6, 3.3) times greater than for those classified as sensitive. Similarly, an increase in the predicted CHO resistance index of 10 was related to a 22% (9%, 36%) increased risk of progression. Furthermore, the REGS classifier performed significantly better than the REGS predictor. CONCLUSIONS: The regularised multivariate regression models provide a flexible workflow for drug resistance studies with promising potential. However, the gene expressions defining the REGSs should be functionally validated and correlated to known biomarkers to improve understanding of molecular mechanisms of drug resistance. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1237-6) contains supplementary material, which is available to authorized users