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Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

FLAURA ClinicalTrials.gov number, NCT02296125 BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P

Based on preclinical data demonstrating cytotoxic synergy between sorafenib and entinostat, a phase I study of this combination was conducted in patients with advanced solid tumors. Enrollment followed the traditional "3 + 3" dose escalation scheme. Entinostat was given orally once every 2 weeks, starting at a dose of 4 mg and escalating to 6 and 10 mg every 2 weeks. Sorafenib was administered as a continuous oral dose, escalating from 200 to 400 mg twice daily. A treatment cycle was 28 days. A total of 31 patients with advanced solid tumors were enrolled on the study. The three dose-limiting toxicities (DLTs) observed were grade 3 hand-foot syndrome, nausea/vomiting, and fatigue. MTD was not reached. The recommended phase II dose was defined as the full dose of the respective drugs administered individually. The most common grade 3-4 toxicities were muscle weakness (13 %), skin rash (10 %), fatigue (6 %), diarrhea (6 %), and hand-foot syndrome (3 %). One NSCLC patient achieved a partial response. Two patients (adenocarcinoma of GE junction and Hurthle cell carcinoma of the thyroid) were on the study for more than 9 months with stable disease. The combination of entinostat and sorafenib was well tolerated. Entinostat 10 mg orally once every 2 weeks in combination with sorafenib 400 mg orally twice daily, representing full single agent doses of each drug was identified as the recommended phase 2 dose (RP2D). These data support future clinical development of the combination of entinostat and sorafenib.

Introduction To assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC). Methods Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment. Planned interim analysis in first 20 patients, where 13 or more patients alive and progression-free at 12-weeks would allow continued enrollment to 40 total patients. Results All 23 evaluable patients received platinum based standard chemotherapy. Median age was 58 years (range: 48–82). 96% of patients had a performance status of 0/1. Median of two cycles given (range: 1–34). All 23 (100%) patients have ended treatment, most for disease progression (19/23). The 12-week PFS rate was 26% (6/23; 95% CI: 10–48%). From start of standard chemotherapy, median PFS was 4.7 months (95% CI: 4.5–5.1) and median OS was 11.2 months (95% CI: 9.9–13.8). Eight (35%) and three (13%) patients experienced at least one grade 3/4 or grade 4 AE, respectively. Commonly occurring grade 3/4 adverse events were thrombocytopenia (13%), fatigue (9%), nausea (9%), and vomiting (9%). Conclusions Saracatinib at a dose of 175 mg/day by mouth is well tolerated. However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment.

Background: In an effort to evaluate the single agent activity of temsirolimus in previously untreated non–small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study. Methods: Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity. Results: A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24-week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome. Conclusions: Temsirolimus given as a single agent in frontline therapy in patients with non–small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy.

UDP-glucuronosyltransferase1A1 (UGT1A1) polymorphisms have been related with irinotecan toxicity. The purpose of this study was to determine the associations between UGT1A1(*)28 and (*)6 polymorphisms and irinotecan toxicity in Thai patients with metastatic colorectal cancer. 44 metastatic colorectal cancer patients received irinotecan-based chemotherapy. Hematologic toxicities were determined in the first and second cycles of treatment. The genotypes of UGT1A1(*)28 and (*)6 were analyzed by pyrosequencing technique. The frequencies of genetic testing for UGT1A1(*)28 and (*)6 polymorphisms were 22.8% (TA6/TA7; 20.5%, TA7/TA7; 2.3%) and 15.9% (GA), respectively. No patients had the homozygous UGT1A1(*)6 (AA). Neither UGT1A1(*)28 nor UGT1A1(*)6 polymorphisms were significantly associated with severe hematologic toxicities. However, analysis of UGT1A1(*)28 and (*)6 in combination revealed an association with severe neutropenia in the first and second cycles (P = 0.044, P = 0.017, respectively). Both UGT1A1(*)28 and (*)6 polymorphisms may have an increased risk of irinotecan-induced neutropenia in Thai colorectal cancer patients.

Background Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G. Methods A 100 μL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G. Results In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G. Conclusion This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.

The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance.

Objective: The objective of this study is to determine the extent of (DPYD) Dihydropyrimidine Dehydrogenase Gene] polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: The study was conducted a pharmacogenetic analysis to determine the polymorphisms of DPYD gene in 116. Thai cancer patients. 76 patients developed severe (grade 3-4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared. Results: We detected 13 SNPs of which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in intron but only IVS14+1G>A is the intron splice site. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistically significant difference in actual ANC change and percentage of neutrophil change in homozygous GG [P = .011 and .009] were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP has cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A might be the cause of (DPD) Dihydro Pyrimidine Dehydrogenase deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study.

Non-small-cell lung cancer (NSCLC) has recently been associated with interesting molecular characteristics that have important implications in carcinogenesis and response to targeted therapies. The unsatisfactory treatment outcomes in advanced NSCLC with respect to long-term survival rates may be improved through a better understanding of the molecular etiology of this disease. For instance, several molecular alterations have been defined as "driver mutations," such as mutations in epidermal growth factor receptor (EGFR), Kirsten-rous avian sarcoma (KRAS), and a chromosome 2p inversion producing an EML4-ALK fusion gene (echinoderm microtubule-associated protein-like 4 fused with the anaplastic lymphoma kinase). Other key signaling pathways such as RAS/RAF/MEK, PI3K/AKT/mTOR (mammalian target of rapamycin), mesenchymal-epithelial transition (MET) kinase, LKB1, and insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) have also been identified as novel targets for lung cancer treatment. In this review we focus on the molecular discoveries that have led to the clinical applications and trials of novel targeted agents, including the clinical trials that selectively studied patients who were predicted to achieve the greatest benefit based on the expression of correlative biomarkers.

Only one third of patients with non-small-cell lung carcinoma (NSCLC) present with early-stage disease that is amenable to potentially curative resection and adjuvant therapy. Unfortunately, even in stage I NSCLC, 5-year survival rates are in the range of 55 to 72%. For unresectable disease in stages IIIB and IV, 5-year survival rates are < 5%. Postoperative chemotherapy (adjuvant chemotherapy) using cisplatin-based regimens has become the standard of care for resected stage II to IIIA NSCLC. However, adjuvant chemotherapy may be harmful in stage IA NSCLC, and its role for stage 1B is controversial. There are no conclusive data showing superiority of neoadjuvant chemotherapy (given prior to surgery) over adjuvant chemotherapy (given after surgery) or vice versa in early-stage NSCLC. Several emerging TARGETED therapy agents [e.g., inhibitors of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), or tyrosine kinase], and combination chemotherapy regimens are currently being evaluated in NSCLC. Specific patient subpopulation characteristics (including EGFR mutations) may be prognostically important to identify potential responders (or nonresponders) to therapy. This review will focus on chemotherapeutic approaches to treat both early stage (adjuvant and neoadjuvant chemotherapy) and metastatic disease including the use of maintenance therapy and novel agents.

Toll-like Receptor 5 (TLR5) is a type 1 transmembrane receptor involved in the first line of defense against invading bacterial pathogens expressing flagellin. TLR5 is expressed on a wide variety of tumors and induction of TLR5 signaling exhibits anti-tumor activities via mobilization of innate and subsequent adaptive antitumor immune response. Entolimod, a pharmacologically optimized flagellin of Salmonella, is the first TLR5 agonist to enter clinical trials. This agent binds to TLR5 and activates NF-kB and other signaling pathways to elicit antitumor activity. The antitumor activity of entolimod has been shown to be dependent on the expression of functional TLR5 on tumors. Since TLR5 is genetically polymorphic, we hypothesized that variations in the gene would alter responses to therapy with entolimod. We therefore characterized genetic variants of TLR5. Expression constructs for nine naturally occurring human TLR5 variants namely Thr82Ile (Ile82): c.245C>T [rs764535]; Asn143Thr (Thr143): c.428A>C [rs5744167]; Arg149Cys (Cys149): c.445C>T [rs201906412]; Gln387Ter (Ter387 or 387*): c.1159C>T [rs147164861]; Arg392Ter (Ter392 or 392*): c.1174C>T [rs5744168]; Leu487Ile (487Ile): c.1459C>A [rs5744171]; Asn592Ser (Ser592): c.1775A>G [rs2072493]; Phe616Leu (Leu616): c.1846T>C [rs5744174] and Glu731Asp (Asp731): 2193A>T [rs148986834], were created from C-terminal FLAG-tagged wild type (WT) TLR5. All constructs together with a construct with no TLR5 insert (empty vector) were transfected in cos-1 cells. In vitro translation of the constructs in rabbit reticulocyte lysates (RRL) were also performed. Cos-1 cells transfected with constructs were also treated with flagellin and entolimod and with proteasome and autophagy inhibitors. Recombinant and synthesized proteins were examined by western blot analysis and NF-kB activity was measured using a Dual-Glo Luciferase Assay. The molecular weight of the recombinant proteins was approximately 100kD. There were variations in expression levels of immunoreactive proteins (10-80% of WT) and the NF-kB activity induced was lower or similar to WT. The Ile82 variant showed a significant reduction in levels of immunoreactive protein (10% of WT) which correlated with decreased NF-kB activity compared to WT, after stimulation. All proteins synthesized in RRL had similar molecular weight except Ter387 and Ter392 which expressed truncated proteins of approximately 40kD and had no NF-kB activity compared to the WT. The Ile82 protein was degraded primarily through the autophagy pathway. The mRNA and cytokine levels of the variant constructs will be reported. These results suggest that genetic variations in the TLR5 gene may be predictive of response to entolimod. This predictive biomarker will be explored in the ongoing phase I study of entolimod. Citation Format: Andrzej J. Wierzbicki, Araba A. Adjei, Nuttapong Ngamphaiboon, Thanyanan Reungwetwattana, Andrei V. Gudkov, Alex A. Adjei. Functional characterization of human toll-like receptor 5 (TLR5) genetic variants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5492. doi:10.1158/1538-7445.AM2015-5492

Background Advanced cholangiocarcinoma (CCA) patients have a poor survival rate, even when receiving standard chemotherapy. No targeted therapy has been proven to benefit patients with CCA. The molecular alterations in Western and Eastern population are different. The aim of this study was to describe the natural history and clinical behaviour of the disease, including determining prognostic factors and molecular alterations of CCA in the Thai population. Methods A computerised search of a tumour registry database and tissue archive database in Ramathibodi Hospital from November 2007, to December 2011, identified 157 CCA patients who had adequate tumour tissue for DNA/RNA extraction. Data on the natural history and clinical behaviour were collected. The association and predictive ability of patient and tumour characteristics with overall survival (OS) and progression-free survival (PFS) outcomes were examined. ALK expression and ROS1 rearrangement were analysed. Findings Four significant prognostic factors for survival outcomes identified from multivariable-analysis included staging, performance status, surgical resection, and CA19-9 pre-treatment level. Median follow-up was 6.77 months. The median OS and PFS were 6.96 and 4.5 months, respectively. Advance stage disease, poor performance status, high CA19-9 level (⩾100 U/ml), and inoperability correlated with poor survival outcomes. CA19-9 ⩾100 U/ml was the optimal cut point, predicting both OS and PFS. There was a trend for better OS in patients without metastatic lymph nodes. One out of 50 patients had ALK expression, and this patient had OS of 30 months. No ROS1 gene rearrangement was found in 50 patients. Interpretation These data provided strong evidence for staging, performance status, surgical resection, and CA19-9 pre-treatment level as prognostic factors for CCA in the Thai population. Larger studies to elucidate the oncogenic drive genes of CCA are urgently needed.

3063 Background: Entolimod is a specific, TLR5 agonist derived from salmonella flagellin, with immunotherapeutic effects in preclinical cancer models. Entolimod activates innate and adaptive immune responses and mobilizes immunocytes to organs such as liver and bladder, with functional TLR5. A phase 1 trial was undertaken to evaluate entolimod’s safety, tolerability, pharmacokinetics, immunoactivity, and preliminary antitumor activity. Methods: Pts with advanced cancers and ECOG PS of 0-1 were treated at 5 subcutaneous doses (5, 10, 15, 20, 30, 40 µg/day) over a 2-week period. PK/PD samples were obtained pre, and 2, 4, 6, 8, 24 hrs post-dose. Immune function samples were obtained pre and 24 hrs post-dose on days1, 8, 11 and 22. Results: 26 pts (38.4% colorectal cancer [CRC] and 19% NSCLC) were enrolled. Common toxicities were transient hypotension (9 grade 1/4, 7 grade 2/4), hyperglycemia (8 grade 1/4, 6 grade 2/4), and fever (10 grade 1/4, 3 grade 2/4). Three DLTs were observed at 40 µg/day. One pt devel...

11119 Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P

1565 Background: Understanding the prevalence of cancer screening in the US and the factors associated with its accessibility is important for public health promotion. Methods: The 2004 and 2010 Behavioral Risk Factor Surveillance Systems were used to ascertain cancer screening rates among populations indicated for each test by age, gender, and the American Cancer Society recommendation for cancer screenings [fecal occult blood test (FOBT) or endoscopy for colorectal cancer (CRC) screening, digital rectal examination (DRE) or prostate specific antigen (PSA) for prostate cancer screening, clinical breast examination (CBE) or mammogram for breast cancer screening, and Papanicolaou (Pap) test for cervical cancer screening]. Results: Over this period, CRC and breast cancer screening rates significantly increased (15.9%, 13.9%) while prostate and cervical cancer screening rates significantly decreased (1.2%, 5.2%). Race/ethnicity might be an influence in CRC and cervical cancer screening accessibility. Prostate cancer screening accessibility might be influenced by education and income. The older-aged populations (70-79, >79) had high prevalence of CRC, prostate and breast cancer screenings even though there is insufficient evidence for the benefits and harms of screenings in the older-aged group. Conclusions: The disparities in age, race/ethnicity, health insurance, education, employment, and income for the accession to cancer screening of the US population have decreased since 2004. The trajectory of increasing rates of CRC and breast cancer screenings should be maintained. To reverse the trend, the causes of the decreased rate of cervical cancer screening and the high rates of screenings in older-aged populations should, however, be further explored. [Table: see text]

Peripheral T-cell lymphomas (PTCL) represent about 12%–15% of non-Hodgkin lymphomas and are characterized for being a molecularly heterogenous group of diseases. The optimal treatment for PTCLs remains to be defined as they are usually refractory to existing therapies and carry a poor prognosis. Pralatrexate (PDX), a rationally designed antifolate drug, was granted FDA approval as a single agent for the treatment of relapsed/refractory PTCL in 2009. Because of its favorable toxicity profile and activity, Pralatrexate has become a major compound for patients with refractory PTCL.

14537 Background: DPD deficiency is a genetic disease caused by molecular defects in the DPD gene (DPYD). Cancer patients with DPD deficiency developed severe toxicity after receiving 5-FU based ch...