Multi-Modality Analysis Improves Survival Prediction in Enucleated Uveal Melanoma Patients

PURPOSE. Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM. METHODS. We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk. RESULTS. Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample’s cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7–81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up. CONCLUSIONS. UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction

External validation of a prognostic model to predict survival of patients with sentinel node-negative melanoma

Background Identifying patients with sentinel node-negative melanoma at high risk of recurrence or death is important. The European Organisation for Research and Treatment of Cancer (EORTC) recently developed a prognostic model including Breslow thickness, ulceration and site of the primary tumour. The aims of the present study were to validate this prognostic model externally and to assess whether it could be improved by adding other prognostic factors. Methods Patients with sentinel node-negative cutaneous melanoma were included in this retrospective single-institution study. The beta values of the EORTC prognostic model were used to predict recurrence-free survival and melanoma-specific survival. The predictive performance was assessed by discrimination (c-index) and calibration. Seeking to improve the performance of the model, additional variables were added to a Cox proportional hazards model. Results Some 4235 patients with sentinel node-negative cutaneous melanoma were included. The median follow-up time was 50 (i.q.r. 18 center dot 5-81 center dot 5) months. Recurrences and deaths from melanoma numbered 793 (18 center dot 7 per cent) and 456 (10 center dot 8 per cent) respectively. Validation of the EORTC model showed good calibration for both outcomes, and a c-index of 0 center dot 69. The c-index was only marginally improved to 0 center dot 71 when other significant prognostic factors (sex, age, tumour type, mitotic rate) were added. Conclusion This study validated the EORTC prognostic model for recurrence-free and melanoma-specific survival of patients with negative sentinel nodes. The addition of other prognostic factors only improved the model marginally. The validated EORTC model could be used for personalizing follow-up and selecting high-risk patients for trials of adjuvant systemic therapy.Dermatology-oncolog

Watchful waiting of the neck in early stage oral cancer is unfavourable for patients with occult nodal disease

For cT1/2N0 oral squamous cell carcinoma (OSCC), treatment of the neck is a matter of debate. Two treatment strategies were evaluated in this study: selective neck dissection (SND) and watchful waiting (WW). One hundred and twenty-three SND patients and 70 WW patients with cT1/T2N0M0 OSCC of the tongue, floor of mouth, or buccal mucosa were analysed retrospectively. Extracapsular spread (ECS), 3-year overall survival (OS), and disease-specific survival (DSS) were determined. Twenty-nine percent of SND patients and 13% of WW patients had occult nodal disease. WW-N+ patients showed thicker tumours as compared to WW-N0 patients (5 mm vs. 2 mm, P = 0.02). WW-N+ patients showed significantly more ECS as compared to SND-N+ patients (56% vs. 14%, P = 0.016) and had a significantly worse 3-year DSS than SND-N+ patients (56% vs. 82%, P = 0.02). For T1 OSCCs, a watchful waiting policy is acceptable if tumour thickness proves to be <4 mm. Otherwise, an additional treatment of the neck is advised, since WW-N+ patients show more ECS, with a worse DSS than SND-N+ patients

Prognostic value of TERT promoter mutations in conjunctival melanomas in addition to clinicopathological features

Aims To evaluate the prognostic value of clinical, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM). Methods Retrospective review of clinical, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities, correlated to recurrence and metastasis in 79 patients with CM, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium. Results Out of 78 evaluable patients, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0-260 months)). Tumour thickness >2 mm, pT status, the presence of epithelioid cells, ulceration and mitoses was significantly correlated with metastasis (p value 0.046, 0.01, 0.02, 0.001 and 0.003, respectively). Furthermore, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy. Conclusion In line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM, the pathology report should include information about pT status, tumour thickness, presence of epithelioid cells, ulceration and mitoses. Furthermore, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease

Multi-Modality Analysis Improves Survival Prediction in Enucleated Uveal Melanoma Patients

PURPOSE. Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM.METHODS. We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk.RESULTS. Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample's cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7-81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up.CONCLUSIONS. UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction.MTG