bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma.
Authors: Park Jeong A , Kang Hyoung Jin , Im Ho Joon , Shin Hee Young , Ahn Hyo Seop 
Published: March 2020

10051 Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.
Hypoxia, angiogenic markers, and response to neoadjuvant radiotherapy in soft-tissue sarcomas.
Authors: Lewin Jeremy , Khamly Kenneth , Mitchell Catherine , Hicks Rodney J , Toner Guy C. , Ngan Sam , Powell Gerard , Desai Jayesh , Choong Peter , Stacker Steven , Slavin John , Thomas David Morgan 
Published: March 2020

10567 Background: Hypoxia is common in soft-tissue sarcomas (STS) and may correlate with radiotherapy (RT) resistance and worse outcomes. We aimed to quantify intratumoral hypoxia with 18-fluoroazamycin arabinoside (FAZA)-PET in resectable STS and correlate this to 18-fluorodeoxyglucose (FDG)-PET, tumour response, angiogenesis biomarkers and patient (pt) outcomes. Methods: This phase II prospective study enrolled pts with resectable STS prior to neoadjuvant RT. Pts underwent FDG-PET and FAZA-PET prior to RT. Circulating and immunohistochemical (IHC) markers of hypoxia and vessel architecture were measured weekly. Response to RT was measured by surgically resected pathologic necrosis (PN), radiological response and relapse-free survival. Results: 23 pts were recruited. 47% (8/17) demonstrated hypoxia on FAZA-PET with a possible association between hypoxia and enhanced metabolic activity on FDG-PET (FDG SUVmax=15.33 with hypoxia; SUVmax=5.86 without hypoxia p=.08). FDG-PET response to RT correlated with PN (good/equivocal FDG-PET response: 59% PN; poor FDG-PET response: 19%PN p=.008). All relapses were distant (n=10) at average follow up of 5 years. Relapse was associated with higher FAZA-PET SUV (1.94 vs 1.28 p=0.02), FDG-PET SUVmax (14.4 vs 6.2 p=0.05), and poorer response to RT (PN 36% vs 66%, p=0.04). Baseline VEGF-C (531±82pg/ml, mean±SEM) were higher than VEGF-A (35±8pg/ml) and VEGF-D (131±17pg/ml), and correlated with protein expression on IHC staining. Hypoxia on FAZA-PET correlated with lower baseline VEGF-A/C (VEGF-C: (292pg/ml vs 688pg/ml p=0.16) and VEGF–A (14pg/ml vs 46pg/ml p=0.13). Low VEGF-C correlated with resistance to RT assessed by FDG-PET. In hypoxic tumors after 1 week of RT, VEGF-A and C levels were significantly increased (VEGF-A 80pg/ml vs 14pg/ml; VEGF-C 541ng/ml vs 292ng/ml). Response to RT correlated with less induction of VEGF-A/C. Relapse was associated with lower baseline VEGF and higher IHC levels of other hypoxic markers (GLUT-1, CA 9). Conclusions: In STS, hypoxia is common, measurable, predicts poorer response to RT and is associated with adverse outcomes. Circulating levels of VEGF-C, the dominant isoform, inversely correlated with hypoxia and is induced by RT.
Association between single nucleotide polymorphism (SNPs) of CYP3A4 and SLC28A3 and clinical outcome in metastatic breast cancer (MBC) patients receiving paclitaxel plus gemcitabine (PG) chemotherapy as first-line treatment.
Authors: Im Seock-Ah , Park Yeon Hee , Lee Soo-Youn , Woo Sook Young , Kim Seonwoo , Chang Won Jin , Choi Moon Ki , Hong Jung Yong , Ok Oh-Nam , Seo Jeong Ju , Ahn Jin Seok , Im Young-Hyuck 
Published: March 2020

1088 Background: Paclitaxel and gemcitabine (PG) combination chemotherapy is an effective regimen in metastatic breast cancer (MBC) patients as first-line chemotherapy. The primary purpose of our study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC patients treated with PG chemotherapy. Methods: A total of 324 MBC patients were enrolled in this prospective multicenter trial as the first-line chemotherapy. Eighty five of 324 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 15 genes (27 SNPs) from pathways that may influence cellular sensitivity to paclitaxel and gemcitabine were genotyped from PB sample. Results: Median progression free survival (PFS) and overall survival (OS) of all 324 patients was 8.7 months (95% CI: 7.5-9.6 mo.) and 26.9 months (95% CI: 23.6-30.1 mo.), respectively. Among clinical parameters, young age (p = 0.047, HR 1.03 [95% CI, 1-1.07]), positive hormonal receptor status (p = 0.0004, HR 0.26 [95% CI, 0.12-0.54]), and hepatic metastasis (p = 0.046, HR 2.30 [95% CI, 1.02-5.18]) were identified predictive factors for OS in Cox-regression analysis. SLC28A3 SNP which participates in transcription showed correlation with OS. OS of the patients with CC and CT genotypes in SLC28A3 was significantly longer than the OS of the patients with TT genotype (median OS: 31 vs. 37 vs. 21 months, p = 0.027, HR 2.6 [95% CI, 1.1-6.3]). OS of the patients with TT genotype in CYP3A4 was significantly longer than the OS of the patients with TC genotype (median OS: 37 vs. 19 months, p = 0.021, HR 5.8 [95% CI, 1.3-25.7]). After adjusting hormonal receptor status, age, and hepatic metastasis, prognostic value of SLC28A3 remained significant (HR 2.9, p = 0.047). Other SNPs were not significantly associated with PFS, OS, or toxicities. Conclusions: SLC28A3 SNP can predict with the clinical outcome of MBC patients treated with PG chemotherapy. Further studies for functional mechanism of germline polymorphisms in SLC28A are warranted.
ALDH1-positive cells in primary tumor and axillary lymph node metastases after chemotherapy as a prognostic factor in breast cancer patients.
Authors: Sakakibara Masahiro , Nagashima Takeshi , Sangai Takafumi , Fujimoto Hiroshi , Suzuki Tiberu-Hiroshi , Miyazaki Masaru 
Published: March 2020

1097 Background: The cancer stem cell theory that was established for hematopoietic neoplasms has significantly changed the concept of cancer therapy. Aldehyde dehydrogenase 1 (ALDH1)-positive cells show stem-like or progenitor ability, and have been considered as a clinically important diagnostic and therapeutic target in breast cancer patients. However, responsiveness of ALDH1-positive cells to chemotherapy in primary and metastatic lesions remains unclear, along with relationships to prognosis in patients with breast cancer. This study evaluated responsiveness to chemotherapy in the ALDH1-positive cells for primary and metastatic lesions and relationships to prognosis in patients with node-positive breast cancer. Methods: We evaluated 115 breast cancer patients with cytologically confirmed lymph node metastases who had undergone surgery after neoadjuvant chemotherapy (NAC). Using ALDH1 immunohistochemistry of core needle biopsy for the primary tumor and cytology samples for axillary lymph nodes before NAC and pathological samples of each after NAC, we evaluated the clinical significance of ALDH1-positive cell status in primary and metastatic lesions before and after NAC. Results: Presence of ALDH1-positive cancer cells, not ALDH1-negative cancer cells, in primary and metastatic lesions after NAC was associated with worse prognosis. In multivariate analysis, only ALDH1-positive cells in metastatic lesions after NAC correlated with overall survival. Responsiveness of ALDH1-positive cells to chemotherapy differed between primary and metastatic lesions, and ALDH1-positive cells in metastatic lesions after NAC might clinically precede those in the primary lesion. Conclusions: Responsiveness of the ALDH1-positive cells to chemotherapy in primary and metastatic lesions, and the prognostic significance, were clarified in breast cancer patients. ALDH1-positive status might offer a surrogate marker as a new concept in patients with node-positive breast cancer.
Cell-free DNA copy number variations as a marker for breast cancer in a large study cohort.
Authors: Beck Julia , Schütz Ekkehard , Urnovitz Howard B. , Tabchy Adel , Mitchell William M. , Mills Gordon B. , Meric-Bernstam Funda 
Published: March 2020

11013 Background: Massive parallel sequencing provides high numbers of cell-free nucleic acid serum DNA sequences (cfDNA) that can detect trace amounts of tumor derived chromosomal imbalances and copy number variations (CNVs) in patients with cancer. The aim of this study was to determine if there is a difference between the cfDNA CNVs from patients with breast cancer (BrCa) compared to healthy controls. Methods: DNA extracted from serum samples of 225 BrCa (Stage 1 to 4) and 205 gender and age-matched healthy controls (HC) was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on an Illumina HiSeq system and aligned to the human genome (Build 37). Hits were counted in sliding 1Mbp interval regions and normalized. Using a Random-Resampling procedure, a model was established to distinguish BrCa from HC using the copy number variations (CNV) and cross validated. Results: From 1,100 rounds of random resampling (50/50), a set of 31 regions was selected, based on the frequency of occurrence in the models. Using 20 random sets of a 10-fold cross validation, the selected regions were found to be highly significant discriminators between BrCa and HC (p<10-5). When using a final linear model with 16 regions the AUC of a diagnostic ROC curve was found to be 0.895 for all samples, for Stage I and II the AUC was 0.86 compared to 0.93 for the higher stages. The final model included three regions from chromosome 8 and 1 and two regions from chromosome 15, the remaining regions were found as one per chromosome. Conclusions: Using comparative massive parallel sequencing of cfDNA from cancer patients vs. controls, we were able to show that a 16-region model based on CNV, is useful to distinguish patients with breast cancer from matched controls. Genomic instabilities that are shed into the circulation from breast cancer may play a role in screening, monitoring or as companion diagnostic tests in breast cancer.
Sensitivity for detecting PIK3CA mutations in early-stage breast cancer with droplet digital PCR.
Authors: Beaver Julia A. , Balukrishna Sasidharan , Jelovac Danijela , Higgins Michaela Jane , Jeter Stacie , Stearns Vered , Wolff Antonio C. , Kessler Jill , VanDenBerg Dustin , Valda Toro Patricia , Argani Pedram , Park Ben Ho 
Published: March 2020

11019 Background: PIK3CA is mutated in up to 30% of breast cancers. Classically somatic mutations are identified by Sanger sequencing of the primary tumor specimen. However third generation droplet digital PCR technologies offer a novel platform for quantitative mutation detection with improved sensitivity. Methods: Thirty stage I-III breast cancer patients were consented on an IRB-approved prospective repository study at Johns Hopkins for collection of their primary breast tumor specimen. Formalin-fixed paraffin embedded (FFPE) samples were analyzed by standard sequencing for three PIK3CA hotspot mutations. The DNA from these samples was then analyzed using the RainDrop digital PCR platform with TaqMan probes in a triplex format to simultaneously detect and quantitate hotspot mutations and genome equivalents. Results are expressed as a percentage of mutant to wild-type PIK3CA molecules for each sample. Results: Standard sequencing of all tumors (n=30) identified seven PIK3CA Exon 20 mutations (H1047R) and three Exon 9 mutations (E545K). Samples were scored as PIK3CA mutation positive by digital PCR if the tumor DNA contained at least 5% mutant molecules. All ten mutations identified by sequencing were verified by digital PCR with quantities of mutant molecules ranging from 20.3-55.6% in a given sample. Digital PCR identified additional PIK3CA mutations that were wild type by standard sequencing including three mutant Exon 20 samples, two mutant Exon 9 samples and one sample with an Exon 20 and Exon 9 mutation. Quantities of mutant molecules in these additional samples ranged from 5-28.9%. Conclusions: RainDrop digital PCR offers improved sensitivity and quantification for detecting PIK3CA mutations in FFPE samples using nanograms of DNA. Additional mutations identified by digital PCR may reflect genetic heterogeneity or possibly tissue contamination. The clinical utility of identifying a small proportion of mutations is unknown but may impact eligibility for targeted therapies and clinical trials. Ongoing studies will also address whether the identification of solid tumor mutations in circulating cell-free plasma DNA by digital PCR can improve diagnostics and aid in therapeutic decisions.
mRNA expression profiles in circulating tumor cells (CTCs) of patients with metastatic breast cancer (MBC) treated with aromatase inhibitors (AI).
Authors: Reijm Esther Anneke , Sieuwerts Anieta M. , Bolt-de Vries Joan , Mostert Bianca , Onstenk Wendy , Peeters Dieter , Dirix Luc Yves , Seynaeve Caroline , Jager A. , de Jongh Felix E. , Hamberg Paul , van Galen Anne M. , Kraan Jaco , Jansen Maurice P. H. M. , Gratama Jan-Willem , Foekens John A. , Martens John W. M. , Berns Els M. J. J. , Sleijfer Stefan 
Published: March 2020

11045 Background: Enumeration of CTCs can be used to assess prognosis in MBC and to evaluate treatment response. Besides enumeration, molecular CTC characterization is a promising tool to develop a more personalized treatment approach. Here, we evaluated the association between mRNA expression of currently known CTC-specific genes and response to first-line AI in MBC patients with estrogen receptor (ER)+ primary tumors. Methods: CTCs were isolated and enumerated from blood of 25 MBC patients before first-line therapy with an AI. Fourteen patients received a non-steroidal AI (8 letrozole, 6 anastrozole) and 11 patients were treated with exemestane. mRNA expression levels of 96 genes were measured by quantitative RT-PCR as previously described (Sieuwerts et al. Clin Cancer Res. 17:3600-3618, 2011). Expression levels of these genes were studied for their association with time to progression (TTP) after start first-line AI. Results: Median TTP was 338 (range 14–1,239) days. Median baseline CTC count for the 25 patients was 14 (range 0–753). In this relatively small cohort, the clinically relevant cut-off level of ≥5 CTCs in association with TTP did not reach statistical significance (Hazard Ratio [HR] 4.76, 95% Confidence Interval [CI]: 0.59–38.22, P=0.14). For type of AI, when comparing steroidal with non-steroidal AI, the measures in Cox univariate regression analysis were HR 2.54 (95% CI: 0.67–9.64), P=0.17. A 10-gene CTC profile was constructed based on the Wald statistics of the contribution of the individual genes in univariate Cox regression analysis of TTP. To identify patients with good and poor outcome, the Wald corrected sum of the 10 genes was used to dichotomize the continuous 10-gene predictor (HR 12.87 [95% CI: 1.60–103.56], P=0.016). In multivariate analysis, corrected for the clinically relevant variables type of AI and CTC count, only the 10-gene CTC profile was an independent factor associated with TTP (HR 12.46 [95% CI: 1.29-120.08], P=0.029). Conclusions: A 10-gene CTC predictor was constructed which distinguishes good and poor outcome to first-line AI in MBC patients. This profile is currently being validated in an independent group of patients.
Evaluation of UGT1A1 genotyping for predicting individual toxicity of irinotecan plus platinum analog regimens: Interim safety analysis of a prospective observational study.
Authors: Takano Masashi , Yamamoto Kaichiro , Tabata Tsutomu , Minegishi Yuji , Yokoyama Takuma , Hirata Eiji , Ikeda Takeshi , Kigawa Junzo , Yamada Kouzo , Morita Satoshi , Ando Yuichi , Okutani Yukihiro , Sugihara Masahiro , Sugiyama Toru , Ohashi Yasuo , Sakata Yuh 
Published: March 2020

11049 Background: Irinotecan (IRI)+platinum (Pt) therapy works synergistically and is widely used for solid carcinomas. Although UGT1A1 genotyping has been implemented in daily practice since long, recommended doses of IRI+Pt therapy according to UGT1A1 genotyping remain undetermined. Risk factors for severe toxicities of IRI+Pt regimens remain uncertain. We conducted a prospective observational study to examine the correlation between UGT1A1 genotyping and toxicity/efficacy in IRI+Pt regimens (NCT 01040312). Methods: During October 2009 and March 2012, 321 patients were enrolled. Eligible patients had histologically confirmed SCLC, non-SCLC, cervical, ovarian, or gastric cancer; had PS 0-2; and were receiving IRI+Pt (cisplatin, carboplatin, and nedaplatin) regimen, following UGT1A1 genotyping: hetero (*1/*6, *1/*28) and homo (*6/*6, *6/*28, *28/*28). Primary endpoint was to evaluate overall toxicity profile during first 3 cycles of treatment. In this interim analysis, incidences of grade 3/4 toxicities were compared among UGT1A1 phenotypes, and logistic regression models were used to identify independent risk factors for these toxicities. Results: At the time of abstract writing, toxicity data from 137 patients were available. There were 110 (80%) hetero and 27 (20%) homo genotypes. Combination therapy of IRI (57.2 ± 12.2 mg/m2 for average initial dose) and Pt analogs (cisplatin, 63%; carboplatin, 20%; nedaplatin, 17%) was administered. Incidences of grade 3/4 toxicities during first 3 cycles of treatment in hetero and homo were as follows: leukocytopenia, 38% and 59%; neutropenia, 55% and 67%; thrombocytopenia, 7% and 22%; and diarrhea, 9% and 7%. Overall grade 3/4 hematological toxicity was 50% (55/110) in hetero and 78% (21/27) in homo; the adjusted odds ratio was 3.379 (p = 0.0185) in homo compared with hetero. Conclusions: A higher rate of grade 3/4 hematological toxicity in homo than in hetero was confirmed with IRI+Pt therapy. Thus, UGT1A1 genotyping could be a potential biomarker of toxicity with individualized chemotherapy using low-dose IRI regimens. At the presentation, analysis of >250 patients’ data will be shown. Clinical trial information: NCT01040312.
Impact of IVS14+1G>A and 2846A>T DPYD polymorphisms on toxicity outcome of patients treated with fluoropyrimidine-containing regimens.
Authors: Del Re Marzia , Loupakis Fotios , Barbara Cecilia , Latiano Tiziana , Vasile Enrico , Zafarana Elena , Cordio Stefano Sergio , Toffolatti Luisa , Ricasoli Miriam , Prestifilippo Angela , Venturini Filippo , Di Donato Samantha , Grifalchi Federico , Rinaldi Antonio , Butera Alfredo , Maiello Evaristo , Siena Salvatore , Falcone Alfredo , Cappuzzo Federico , Danesi Romano 
Published: March 2020

11058 Background: DPD deficiency is an inherited syndrome resulting from loss-of-function mutations within the DPYD gene. The IVS14+1G>A variant is associated with DPD deficiency as a result of a 165-bp deletion in the DPD mRNA. A rare mutation, 2846A>T, is characterized by a change of the acidic aspartic acid to the aliphatic valine with potential impairment of enzyme activity (Amstutz et al., 2011). In this study, we describe the spectrum of toxicities of 5-FU and capecitabine in patients carrying the IVS14+1G>A and 2846A>T variants. Methods: Data were collected from 450 patients with gastrointestinal, breast and pancreas cancers. They were evaluated for DPD genotype upon development of grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) secondary to standard fluoropyrimidine-containing regimens in combination with other cytotoxic agents and/or EGFR and VEGF antibodies. DNA was extracted from blood and IVS14+1G>A and 2846T>C DPD variants were screened on a Real-Time Life Sciences 7900 HT platform. The study was approved by the local Ethics Committee. Results: A total of 23 IVS14+1GA, four 2846AT, one IVS14+1AA and one 2846TT subjects were identified. Toxicities in all subjects were G3/4 diarrhea (100%), G3/4 mucositis (48%), febrile neutropenia (45%), G3/4 thrombocytopenia (38%), G3/4 anemia (24%), G2/3 hand-foot syndrome (14%), G3 dermatitis (7%) and G2/4 alopecia (7%). The homozygous IVS14+1AA patient survived because she was given a reduced 5-FU 250 mg/sqm test dose without folates, while the 2846TT patient deceased after the first cycle of FOLFOX4 treatment. Conclusions: Patients carrying the deleterious IVS14+1G>A and 2846T>C variant alleles display severe toxicities which is fatal in homozygous variant subjects. This finding suggests the usefulness of pre-treatment screening of DPD in patients candidates to fluoropyrimidine treatment. Acknowledgmnents. This study was supported by the Italian Association for Cancer Research (AIRC, Milano) and the Istituto Toscano Tumori (ITT, Firenze, Italy). Reference. Amstutz U, Froehlich TK, Largiadèr CR. Pharmacogenomics 2011;12:1321-36.