Kasi, Pashtoon Murtaza

Background. Individuals after solid organ transplant may develop secondary malignancies. In our clinical practice, we noted an increasing number of individuals who developed colorectal cancers after solid organ transplantation. The primary aim of this study was to describe the characteristics and outcomes of the patients who developed colorectal cancer after solid organ transplant. Materials and Methods. Data was gathered and merged from several registries at Mayo Clinic to identify all patients who received a diagnosis of colon or rectal cancer and solid organ transplant. Continuous variables were summarized as mean (standard deviation) and median (range), while categorical variables were reported as frequency (percentage). Time to colorectal cancer after transplant and overall survival after cancer diagnosis were estimated using Kaplan-Meier method. Results. Initially, 115 colorectal cancer patients who also had a transplant were identified. The diagnosis of colorectal cancer was noted after solid organ transplant in 63 patients. The mean age at transplant was 57 years. Majority had received a kidney transplant (44.4%) followed by liver (36.5%). The median time to develop colorectal cancer was 59.3 months (range: 4.4-251.4 months). 15 (24.6%) were stage 4 at diagnosis and 13 (21.3%) had stage 3 colorectal cancer. Median overall survival was 30.8 months; 5-, 10- and 15-year survival were noted to be 42.5%, 17.9%, and 7.5%, respectively. None of the stage 4 patients were alive at 5 years; 5-year survival rate for stage 1, 2, and 3 patients was 77%, 50%, and 42%, respectively. Conclusions. Our study reports on one of the largest cohorts of patients of colorectal cancer that developed the cancer after solid organ transplant. Survival is extremely poor for advanced cases. However, long-term survivors are noted who developed the cancer at a relatively early stage. Colorectal screening recommendations may need to be revised for patients after solid organ transplant.

703 Background: In metastatic colorectal cancer (CRC), pharmacogenomics (PGx) testing presents a unique opportunity to improve outcomes since the genes DPYD & UGT1A1 encoding the enzymes metabolizing the chemotherapy drugs, 5-fluorouracil and irinotecan, are already well known. In the TRIBE clinical trial, proportion of patients with serious adverse events (SAEs) was higher in those with DPYD/UGT1A1 aberrations and were dose dependent. Critical barrier has been integration into clinical practice. We aimed to report on the feasibility and results of incorporating PGx testing into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed comprehensive test through funding from our center of individualized medicine, which reports on 28 genes and over 350 medications of interest. Pharmacists provided dosage recommendations based on test results real-time. Results: 126 patients have had the PGx testing since November 2017. Results have been available within 3-5 days. The table outlines the analyzed results thus far of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Of these, 59% had a DPYD/UGT1A1 aberration and 100% had at least one actionable aberration related to supportive care medications from all possible medications listed on their PGx report. Conclusions: Preemptive comprehensive PGx testing can be integrated into clinical practice in real-time for cancer patients. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients. [Table: see text]

660 Background: Adverse toxicities to chemotherapy remain a limiting factor for patients receiving treatment for malignancies. In gastrointestinal cancers, particularly metastatic colorectal cancer, the majority of front line treatment remains chemotherapy containing 5-fluorouracil and/or irinotecan. One particular cause that can predispose a patient to increased toxicity from 5-fluorouracil is genetic variation in the DPYD gene, as well as TYMS gene. Similarly, genetic variation in the UGT1A1 gene can increase the risk of irinotecan toxicity. These gene variations may have major implications when deciding on treatment regimens for these types of patients; however, they are not routinely checked. Methods: In Mayo Clinic Florida, patients with metastatic colorectal cancer receiving 5-fluorouracil and/or irinotecan chemotherapy during the period of July 2017-July 2018 were tested for genetic variants in DPYD/TYMS and UGT1A1. This testing was done during routine clinic visit either by buccal swab or blood test. The DPYD/TYMS and UGT1A1 variant results were evaluated together with a pharmacist for recommendations regarding dose reductions on 5-fluorouracil and irinotecan respectively. Results: A total of 292 patients were tested. Total number of patients who had a variation in the DPYD/ TYMS and/or UGT1A1 gene was 169 (57.9%). The UGT1A1 variation was the most prevalent with 154 (52.7%) patients having a variant (115 heterozygous variant, 34 homozygous variant and 5 double heterozygous variant). Specifically there were 3 patients with both UGT1A1 and DPYD variants and 3 patients with both UGT1A1 and TYMS variants. One patient had both DPYD and TYMS variations. Conclusions: Routine pharmacogenomic testing for UGT1A1 and DPYD/TYMS genetic variants should be done in all patients receiving irinotecan and 5-fluorouracil chemotherapy respectively. Avoiding or preemptively dose reducing these agents in patients with gene variations may help prevent toxic adverse events and make treatment more tolerable.

619 Background: Regorafenib (at a starting dose of 160 mg/day, rego 160), regorafenib (with a weekly dose escalation, rego 80+) and TAS-102, are suggested treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these 3 strategies. Methods: We searched PubMed, Embase, and Cochrane CENTRAL, for randomized controlled trials evaluating TAS 102 or regorafenib in refractory mCRC patients who progressed on/intolerant of previous oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Results: Six trials (3 of regorafenib and 3 of TAS-102) at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to BSC in terms of PFS (Rego 160: HR = 0.4, CI 0.26 to 0.63; TAS-102: HR = 0.46, CI 0.40 to 0.52) and OS (Rego 160: HR = 0.67, CI 0.48 to 0.93; TAS-102: HR = 0.67, CI 0.57 to 0.80). Network analysis showed that there was no difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR = 0.44, CI 0.23 to 0.84) and PFS (HR = 0.37, CI 0.21 to 0.66). There was a numerical advantage for Rego 80+ compared to TAS-102 and Rego 160 (see table). Conclusions: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. [Table: see text]

525 Background: The hallmark of circulating tumor DNA (ctDNA) is its rapid turnaround and non-invasive nature. According to American Society of Clinical Oncology (ASCO) and College of American Pathologists joint ctDNA review published in March 2018, there is no sufficient evidence to support the use of ctDNA in practice for GI cancers. However, there were numerous studies presented at ASCO Annual Meeting supporting its value. We aimed to summarizing on its role in the management of gastrointestinal cancers based on the studies presented recently. Methods: We limited our search to keywords ‘ctDNA’, ‘circulating tumor DNA’, ‘cell-free DNA (cfDNA)’ and/or ‘liquid biopsy’, at the 2018 ASCO Annual Meeting library abstracts and presentations. Results: There were 35 studies that revolved around ctDNA as a diagnostic tool, prognostic marker and a measure of tumor heterogeneity in gastrointestinal cancers. Depending on the assay used, the results of several studies showed that ctDNA was able to identify relevant mutations including RAS, HER2/Neu, BRAF, MET, BRCA2, APC, TP53, ROS1, PTEN and NF1. The prognosis in terms of tumor mutation burden, objective response rate, metastasis and survival was also estimated based on ctDNA. The findings showed that higher baseline ctDNA levels and/or increased number of mutations detected in ctDNA were associated with poor survival and multi-site metastasis. Right-sided colon cancer was associated with higher number of mutations in ctDNA than left-sided colon and rectal cancers. Similarly, tubular adenocarcinoma subtype of gastric cancer was more likely to have higher ctDNA levels than signet-ring cell subtype. The response to therapy and the residual metastatic disease which was otherwise not detected on imaging could be detected by ctDNA as well. Conclusions: The research at ASCO 2018 report an increasingly promising role of ctDNA in many forms in patients with gastrointestinal malignancies. Experts at the meeting argued that this may well indeed be ready for prime time for certain GI malignancies including colorectal cancers. Prospective studies and studies showing its feasibility into practice can potentially help revise the current guidelines.

291 Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.

288 Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = < 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.

814 Background: The importance of pharmacogenomics in optimizing drug doses and avoiding adverse events is increasingly being recognized. The FDA has listed pharmacogenomic biomarkers as part of drug labeling in many medications including chemotherapies such as 5-fluorouracil and irinotecan. Pharmacogenomics may enable selection of the most tolerable treatment without compromising treatment success. Variation in the dihydropyrimidine dehydrogenase ( DPYD) and UGT1A1 gene mutations can increase the risk of 5-FU and irinotecan based chemotherapy respectively. Also, the feasibility of testing in real-time and incorporating results into management has not been demonstrated. The focus of our study was to demonstrate this in the real world scenario as a quality improvement project. Methods: In July-August 2017, 89 patients who were on irinotecan and/or 5-FU chemotherapy were tested for DPYD and UGT1A1 genetic variations at Mayo Clinic Florida. Testing was done through blood sample which was collected at routine clinic visit prior to starting therapy or in patients already receiving chemotherapy. Pharmacy electronic consultation was obtained for recommendations regarding current and/or future chemotherapy regimens, based on pharmacogenomics results. A medication therapy management (MTM) consultation from the pharmacist was incorporated and included into the patient’s chart. Results: Total number of patients who has some variation in the UGT1A1 and/or DPYD gene was 60 (67%). Specifically, there were 12 patients who were homozygous for the UGT1A1 gene and 3 homozygous for DPYD gene. Both genes were affected in 3 patients. One patient was triple heterozygous for DPYD and homozygous for UGT1A1. Pharmacogenomic results were obtained for these patients within 5 business days. Conclusions: A higher prevalence of UGT1A1 and DPYD variants were reported in our patient cohort tested than what is reported in the literature. Additionally, we were able to obtain results for these patients in a timely fashion. This was then further incorporated into medication therapy management consultation from the pharmacist, which added further value.