Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7). Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).

Physical activity and cognitive changes in younger women after breast cancer treatment.

OBJECTIVES: Studies indicate women aged 25-49 years previously treated for cancer report cognitive alterations. Good evidence indicates physical activity can be beneficial after cancer and might additionally benefit cognitive function. This short report presents data from a substudy of the Younger Women's Wellness after Cancer Program (YWWACP), which explored cognitive alterations and investigated potential associations between physical activity and cognitive function in participants in the YWWACP. The primary aim of this substudy was to determine in younger women previously treated for breast cancer (1) whether subjectively reported cognitive function changed over time and (2) if physical activity is associated with subjectively reported cognitive function, and if time had an impact on this. METHODS: All participants had completed breast cancer treatment. Data were collected at baseline (n=41) and at 12 weeks. Measures assessed demographics, self-reported physical activity, cognitive function, sleep quality, stress, anxiety and depression using validated and reliable, subjectively reported instruments. RESULTS: Cognitive function and physical activity scores increased across the time points, with cognitive function revealing a statistically significant increase over time (p=0.004). Statistical testing revealed that physical activity was not correlated with cognitive function and that change in physical activity was not correlated with change in cognitive function. CONCLUSION: These data provide early evidence that cognitive function and physical activity improved over time in this sample. However, interpretations of a correlation between physical activity and cognitive function should be made with caution, and future research would benefit from larger samples.