Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

BRCA2 gene mutations and coagulation-associated biomarkers.

Thromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 non-mutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.