Methylthioadenosine Phosphorylase Genomic Loss in Advanced Gastrointestinal Cancers.

BACKGROUND: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker. MATERIALS AND METHODS: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study. RESULTS: The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, P = .017). CONCLUSION: In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations.

Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers.

PURPOSE: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. EXPERIMENTAL DESIGN: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). RESULTS: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. CONCLUSIONS: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.

Associations of Racial and Ethnic Category, Age, Comorbidities, and Socioeconomic Factors on Concordance to NCCN Guidelines for Patients With High-Risk Biliary Tract Cancers After Surgery.

Background: Biliary tract cancers (BTC) have a limited prognosis even for localized cancers, emphasizing the importance of multidisciplinary management. NCCN guidelines recommend adjuvant chemotherapy (CT) +/- radiotherapy (RT) for high-risk disease. We analyzed the association between racial and ethnic category along with other demographic factors and concordance to NCCN guidelines among patients following surgery for high-risk BTC. Methods: Subjects were identified from the National Cancer Database (NCDB) for BTC patients who underwent surgery and found to have metastatic lymph nodes (LN+) or positive surgical margins (M+) from 2004 to 2015. We defined concordance to NCCN guidelines as receiving surgery + CT +/- RT and non-concordance to the guidelines as surgery +/- RT. Descriptive studies and multivariate logistic regression analysis was performed. Results: A total of 3,792 patients were identified with approximately half being female (55.4%) and between the ages of 50-69 (52.8%). Most were White (76.3%) followed by Black (10.6%), Hispanic (8.5%), and Asian (5.3%). The BTC included extrahepatic cholangiocarcinoma (CCA) (48.6%), gallbladder cancer (43.5%), and intrahepatic CCA (7.9%). Most patients had an M- resection (71.9%) but also had LN+ disease (88.0%). There were no significant differences between racial groups in disease presentation (histological grade, tumor stage) and surgical outcomes (LN+, M+, hospital readmission, and 90 day post-surgery mortality). Hispanic patients as compared to White patients were less likely to be insured (85.7% vs 96.3%, p<0.001) and less likely to be treated at an academic facility (42.1% vs 52.1%, p=0.008). Overall, almost one-third (29.7%) of patients received non-concordant NCCN guideline care with Hispanic patients having the highest proportion of non-concordance as compared to Whites patients (36.1% vs 28.7%, p=0.029). On multivariate analysis, Hispanic ethnicity (HR=1.51, 95% CI: 1.15-1.99) remained significantly associated with non-concordance to NCCN guidelines. Conclusion: This study indicates that Hispanic patients with high-risk BTC are significantly less likely to receive NCCN-concordant treatment in comparison to White patients. More research is needed to confirm and understand the observed disparities and guide targeted interventions at the system-level.

Idiopathic chronic pancreatitis treated with ivacaftor in a CFTR carrier with methylmalonic acidemia.

CFTR mutation carriers, numbering 1 in 25 among Caucasians, have an increased risk of developing chronic pancreatitis due to the underlying dysfunction of ion channels created by the mutant allele. Carriers do not frequently manifest disease due to the remaining wild-type CFTR protein sufficiently maintaining normal pancreatic homeostasis. However, additional risk factors for pancreatitis, such as organic acidemias (as seen in our patient) that further impact function of pancreatic acinar cells can result in the precipitation of CFTR related pancreatitis. Here we report a CFTR carrier with methylmalonic acidemia who was treated with ivacaftor and subsequently experienced resolution of her chronic pancreatitis. Our report suggests that ivacaftor may rescue the function of mutant CFTR in carriers and treat pancreatitis caused by CFTR dysfunction in situations where there are additional precipitating factors.

Adoption of single agent anticancer therapy for advanced hepatocellular carcinoma and impact of facility type, insurance status, and income on survival: Analysis of the national cancer database 2004-2014.

BACKGROUND: This study analyzes the pattern of use of single agent anticancer therapy (SAACT) in the treatment and survival of advanced hepatocellular carcinoma (aHCC) before and after sorafenib was FDA approved in 2007. METHODS: Adult patients diagnosed with HCC and treated with only ACT from 2004 - 2014 were identified in NCDB database. Patients were analyzed during three time frames: 2004-2006 (pre-sorafenib (PS)), 2007-2010 (early sorafenib (ES)) and 2011-2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan-Meier method were used for analyses. RESULTS: The NCDB contained 31,107 patients with HCC diagnosed from 2004-2014 and treated with ACT alone. Patients were generally men (78.0%), >50 years of age (92.5%). A significant increase in the rate of adaption of SAACT was observed over time: 6.2% PS, 15.2% ES, and 22.2% LS (p < 0.0001). During this later period, the highest proportion of SAACT is among academic and integrated network facilities (23.3%) as compared to community facilities (17.0%, p < 0.0001). The median overall survival of patients with aHCC treated only with SAACT improved significantly over time from 8.0 months (m) (95% CI: 7.4-8.8) to 10.7 m (10.4-11.2) to 15.6 m (15.2-16.0, p < 0.001). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.28, (5% CI: 1.23-1.32), patients without insurance (HR 1.11, 1.06-1.16) and estimated household income of <$63,000 (HR 1.09, 1.05-1.13). CONCLUSION: aHCC patients treated only with ACT have experienced an overall improvement in survival, but significant differences exist between facility type, insurance status, and income.

Case Report: Durable Response to Very Low Dose Tyrosine Kinase Inhibitors in Advanced Hepatocellular Carcinoma.

The oral tyrosine kinase inhibitors (TKI) sorafenib, regorafenib, and cabozantinib are approved for advanced hepatocellular carcinoma (aHCC) and improve survival. However, patients on these medications frequently require dose reductions or discontinuation due to multiple side effects leading to poor tolerability. Here we report three different aHCC patients with clinical responses outlasting those reported in their corresponding Phase 3 clinical trials on 1/8th the target dose for sorafenib, 1/4th the target dose for regorafenib and 1/6th the target dose for cabozantinib respectively. As these doses are below the minimal recommended doses on the FDA labels, this case series provides a preliminary demonstration that low dose TKI therapy can be effective and patients on TKIs should first assess for clinical response before empirically discontinuing TKI therapy on the basis of tolerating only a low dose.

Cis-acting single nucleotide polymorphisms alter MicroRNA-mediated regulation of human brain-expressed transcripts.

Substantial variability exists in the presentation of complex neurological disorders, and the study of single nucleotide polymorphisms (SNPs) has shed light on disease mechanisms and pathophysiological variability in some cases. However, the vast majority of disease-linked SNPs have unidentified pathophysiological relevance. Here, we tested the hypothesis that SNPs within the miRNA recognition element (MRE; the region of the target transcript to which the miRNA binds) can impart changes in the expression of those genes, either by enhancing or reducing transcript and protein levels. To test this, we cross-referenced 7,153 miRNA-MRE brain interactions with the SNP database (dbSNP) to identify candidates, and functionally assessed 24 SNPs located in the 3'UTR or the coding sequence (CDS) of targets. For over half of the candidates tested, SNPs either enhanced (4 genes) or disrupted (10 genes) miRNA binding and target regulation. Additionally, SNPs causing a shift from a common to rare codon within the CDS facilitated miRNA binding downstream of the SNP, dramatically repressing target gene expression. The biological activity of the SNPs on miRNA regulation was also confirmed in induced pluripotent stem cell (iPSC) lines. These studies strongly support the notion that SNPs in the 3'UTR or the coding sequence of disease-relevant genes may be important in disease pathogenesis and should be reconsidered as candidate modifiers.