Chronic infections with the hepatitis B virus (HBV) and high-risk human papillomaviruses (HPVs) are important risk factors for hepatocellular carcinoma (HCC) and cervical cancer (CC), respectively. HBV and HPV are DNA viruses that almost invariably integrate into the host genome in invasive tumors. The viral integration sites occur throughout the genome, leading to the presumption that there are no preferred sites of integration. A number of viral integrations have been shown to occur within the vicinity of important cancer-related genes. In studies of HBV-induced HCC and HPV-induced CC, we have identified two HBV and three HPV integrations into the human telomerase reverse transcriptase (hTERT) gene. Detailed characterization of the integrations revealed that four integrations occurred within the hTERT promoter and upstream region and the fifth integration occurred in intron 3 of the hTERT gene. None of the integrations altered the hTERT coding sequence and all resulted in juxtaposition of viral enhancers near hTERT, with potential activation of hTERT expression. Our work supports the hypothesis that the sites of oncogenic viral integration are nonrandom and that genes at the sites of viral integration may play important roles in carcinogenesis.

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186 Background: The optimal sequence strategy of BRAF/MEK inhibitors, anti-PD- 1/PDL-1 and anti-CTLA-4 in metastatic BRAF-mutated melanoma patients (pts) is unknown and no treatment guidelines exist. Therefore, we report a single-institution experience of different treatment approaches using targeted therapy (TT) and immunotherapy and its impact on outcomes. Methods: BRAF-mutated metastatic melanoma pts treated with TT and immunotherapy from 2012 to2017 were analyzed. Six groups were identified based on treatment strategy. All time-to-event analyses were calculated using the Kaplan-Meier method and Wilcoxon test. Results: Forty-four pts were identified. The median age at diagnosis was 49 years (range 21-73), 54% pts were females and 43% developed brain metastases during disease course. The most common approach strategy was immunotherapy followed by TT, the median duration of treatment was 11 and 19 weeks, respectively. Time-to-next therapy (TTNT) following 1st line treatment was similar in pts treated with TT (median 23 weeks [95% CI: 15-31]) or immunotherapy (median 26 weeks [95% CI: 10-33], p = 0.94). A trend towards better overall survival (OS) was seen in pts who received immunotherapy followed by TT (p = 0.09); patients who received salvage chemotherapy (carboplatin/paclitaxel) had significantly longer OS (median 7 years [95% CI: 3.2-7.08]) ( p = 0.03). Conclusions: No differences in TTNT were seen with immunotherapy, TT or combined (triple therapy) when used as 1st or 2nd line. The significant longer OS benefit with 1st line immunotherapy was only seen in patients who received chemotherapy later in their treatment course. [Table: see text]

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