In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer (mCRC), further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with mCRC, 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The maximum tolerated dose of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by RECIST 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E cfDNA trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.

Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal growth factor receptor (EGFR) gene contribute to the progression of gliomas. As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFjB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis. We examined the activation status of Akt, NFjB, and Stat3 in 259 diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated their association with glioma grade. We observed significant positive correlations between the activation status of Akt and NFjB and glioma grade. In contrast, only focal immunoreactivity for phospho-Stat3 was observed in o9% of high-grade gliomas. In addition, we observed a significant correlation between the activation of Akt and NFjB. Functional correlation between Akt activation and the activation of NFjB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFjB-binding activity. Thus, our results demonstrate that constitutive activation of Akt and NFjB, but not Stat3, contributes significantly to the progression of diffuse gliomas, and activation of Akt may lead to NFjB activation in highgrade gliomas.

Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNAs) originate from living cells, which can better reflect underlying cancer biology. Next-generation sequencing (NGS) was used to test exoNA, and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for ,, and mutations in 43 patients with progressing advanced cancers. Results were compared with clinical testing of archival tumor tissue and clinical outcomes. Forty-one patients had , or mutations in tumor tissue. These mutations were detected by NGS in 95% of plasma exoNA samples, by ddPCR in 92% of cfDNA samples, and by BEAMing in 97% cfDNA samples. NGS of exoNA did not detect any mutations not present in tumor, whereas ddPCR and BEAMing detected one and two such mutations, respectively. Compared with patients with high exoNA mutation allelic frequency (MAF), patients with low MAF had longer median survival (11.8 vs. 5.9 months; = 0.006) and time to treatment failure (7.4 vs. 2.3 months; = 0.009). A low amount of exoNA was associated with partial response and stable disease ≥6 months ( = 0.006). NGS of plasma exoNA for common , and mutations has high sensitivity compared with clinical testing of archival tumor and testing of plasma cfDNA. Low exoNA MAF is an independent prognostic factor for longer survival. .

Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study.Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age.Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64 -7.06; P ‫؍‬ 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P ‫؍‬ 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased.Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

No abstract