Metastatic cutaneous melanoma has poor prognosis with 2-year survival rate of 10–20%. Melanoma cells express various antigens including gp100, melanoma antigen recognized by T cells 1 (MART-1), and tyrosinase, which can induce immune-mediated anticancer response via T cell activation. Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immune check point molecule that negatively regulates T cell activation and proliferation. Accordingly, recent phase III clinical trials demonstrated significant survival benefit with ipilimumab, a human monoclonal antibody (IgG1) that blocks the interaction of CTLA-4 with its ligands. Since the efficacy of ipilimumab depends on T cell activation, it is associated with substantial risk of immune mediated adverse reactions such as colitis, hepatitis, thyroiditis, and hypophysitis. We report the first case of late onset pericarditis and cardiac tamponade associated with ipilimumab treatment in patient with metastatic cutaneous melanoma.

Anti‐cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) and anti‐programmed cell death‐1 (PD‐1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta‐analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti‐CTLA‐4 or anti‐PD‐1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression‐free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76–0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59–0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76–0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune‐related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65–9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti‐PD‐1 treatment compared to anti‐CTLA‐4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti‐PD‐1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients.

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605 Background: The risks of breast and ovarian cancer associated with BRCA1 and BRCA2 mutations are well established. Investigations of the association of BRCA mutations and the risk of colorectal cancer(CRC) have yielded conflicting results. We performed a systematic review of published and unpublished studies evaluating BRCA and CRC risk, and meta-analyses to quantify overall CRC risk and in subgroups of BRCA mutation carriers. Methods: Eligible studies were retrieved from PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios were used to derive pooled estimates of CRC risk overall (combined BRCA1/BRCA2) and in subgroups defined by mutation type, comparison group, and study design. Both fixed and random effects models were estimated with the latter having priority. We followed the guidelines summarized in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as well as the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statements. Results: A total of 18 studies were included in the systematic review: 7 cohort studies comparing to the general population, 5 case-control studies, 4 cohort studies involving pedigree analysis, and 2 kin-cohort studies. Fourteen studies included in the systematic review were used in the meta-analysis. The overall BRCA1/BRCA2 meta-analysis revealed an increased CRC risk in a fixed-effects (OR = 1.22, 95%CI = 1.01-1.48, p = 0.041, I2= 19.5%) but not in a random-effects model (OR = 1.20, 95%CI = 0.96-1.50, p = 0.111). In subgroup random-effects meta-analyses, BRCA1 was associated with increased CRC risk (OR = 1.48, 95%CI = 1.13-1.94, p = 0.005, I2= 3.7%) but BRCA2 was not. Analyses stratified by study design and comparator found no association between BRCA mutation and CRC risk (all 95%CIs crossing 1, all p > 0.05). Conclusions: Although studies differed in their findings about the association between BRCA mutations and CRC risk, meta-analyses revealed a potential 1.22-fold greater risk of CRC in BRCA mutation carriers. This elevated CRC risk was attributable largely to a 1.48-fold greater risk in BRCA1 mutation but not in BRCA2 carriers, regardless of age.

Key Points Agents that inhibit both complexes containing the mammalian target of rapamycin are particularly toxic to acute lymphocytic leukemia cells. This killing reflects engagement of a 4EBP1/c-MYC/PUMA axis downstream of mTORC1 and an NF-κB/EGR1/BIM axis downstream of mTORC2.