bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of S-1 versus S-1 plus irinotecan (IRIS) in patients with gemcitabine-refractory pancreatic cancer.
Authors: Mizuno Nobumasa , Yamao Kenji , Komatsu Yoshito , Munakata Masaki , Ishiguro Atsushi , Yamaguchi Taketo , Ohkawa Shinichi , Kida Mitsuhiro , Ioka Tatsuya , Takeda Koji , Kudo Toshihiro , Kitano Masayuki , Iguchi Haruo , Tsuji Akihito , Ito Tetsuhide , Tanaka Masao , Furuse Junji , Hamada Chikuma , Sakata Yuh 
Published: February 2017

263 Background: Gemcitabine (Gem) monotherapy or Gem-based combination therapy is a standard first-line therapy for advanced pancreatic cancer (PC). There is no consensus on second-line therapy in patients (pts) with disease progression (PD) after Gem-based therapy. S-1, an oral fluoropyrimidine derivative, is commonly used for the second-line treatment of PC in Japan. Shitara et al previously reported that IRIS regimen showed that 44% of response rate (RR), 4.9 mo of median progression free survival (PFS), and 11.3 mo of median overall survival (OS), respectively. Therefore a randomized phase II trial was conducted to evaluate the efficacy and safety of IRIS compared with S-1 alone in the second-line setting. Methods: The inclusion criteria were as follows: (1) histologically or cytologically proven pancreatic adenocarcinoma or adenosquamous carcinoma; (2) confirmed PD after Gem treatment; (3) ECOG PS, 0-1; (4) measurable metastatic lesion based on RECIST criteria; (5) age ≥ 20 years; (6) total bilirubin < 2.0 mg/dL. Patients were randomized to receive either IRIS (CPT-11 100 mg/m2, iv, d1,15 plus S-1 80/100/120 mg/day based on BSA, po, d1-14, q4w; Arm A) or S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w; Arm B). The primary endpoint was to compare PFS in Arm A and Arm B. Results: Of a total of 137 pts enrolled between Nov 2008 and Mar 2011, 127 were eligible (60 randomized to Arm A and 67 to B). Median PFS in Arm A and B was 107 and 58 days, respectively (HR= 0.767; 95% CI, 0.527-1.114; p=0.1750). Median OS in Arm A and B was 208 and 176 days, respectively (HR=0.749; 95% CI, 0.512-1.093; p=0.1338). RR was 18.3% in Arm A (11/60; 95% CI, 9.5-30.4) and 6.0% in Arm B (4/67; 95% CI, 1.7-14.6)(p=0.0311). The incidences of grade 3/4 toxicities were as follows: neutropenia (15.6% and 4.3%), anorexia (23.4% and 17.3%), nausea (6.3% and 2.9%), and diarrhea (3.1% and 2.9%) in Arm A and B, respectively. Both regimens were tolerable. Conclusions: Although IRIS showed no significant improvement in PFS or OS compared with S-1 alone in this study, it showed significant advantage in RR, and favorable HR in both of PFS and OS. IRIS might have potential power to treat second-line PC patients. Further study is warranted. Clinical trial information: JapicCTI-080657.
HER2 status in gastroesophageal cancer: An Irish multicenter experience.
Authors: O'Reilly Aine , Quinlan Catherine , Kelly Ciara Marie , Ryan Ciara , O'Keeffe Margaret , O'Reilly Seamus , Bennett Michael William , Power Derek G. 
Published: February 2017

28 Background: Gastroesophageal cancer is a major cause of cancer-related mortality. The ToGA study, established the benefit of trastuzumab in combination with chemotherapy in HER2 positive metastatic gastroesophageal tumors. We report a multi-centre Irish experience of examining HER2 status by IHC and FISH amongst gastroesophageal adenocarcinomas. Methods: HER2 testing was performed on biopsy or resection specimens of patients with early stage and metastatic gastroesophageal tumors between 2010 and 2012. We defined HER2 positive(+) as IHC3+ or FISH(+) {HER2:17ch ≥2}. All specimens which were IHC2+ or IHC3+, where treatment with trastuzumab was under consideration, went on to have FISH testing. Results: Between 2010 and 2012 HER2 status was established in all patients presenting with biopsy proven gastroesophageal cancers, this amounted to 88 patients (53 gastric, 35 esophageal). Within the population examined 64% of patients had metastatic disease. The majority (51%) had intestinal type adenocarcinomas, the remainder having diffuse type (16%), mixed type (3%) or undetermined (18%). Nineteen patients (21%) were defined as being HER2+ (14 male, 5 female). Four were FISH (+) IHC3+, five were FISH (+) IHC2+ and in ten patients HER2 status was defined by IHC3+ alone as FISH testing was indeterminate (1 patient) or not tested (9 patients). In the subset of HER2+ patients (19 patients), the majority had gastric cancer (63%). Intestinal type adenocarcinoma occurred in 12 patients (63%), the remainder being diffuse type (2 patients), mixed (1 patient) or undetermined (4 patients). Seven patients (36%) had localized disease. In the metastatic cases the distribution of metastases was as follows: 9(47%) liver, 3(15%) lung, 3(15%) peritoneal, 1(5%) adrenal, 1(5%) brain and 1(5%) ovarian. Five patients are receiving trastuzumab for HER2+ disease in combination with cisplatin and fluorouracil based chemotherapy. Conclusions: In a cohort of Irish patients we found similar levels of HER2+ gastroesophageal cancers (21%) as that demonstrated in the ToGA trial (22%). Clinicopathologic characteristics were broadly similar also. Outcome of our experience with HER2 directed therapy will be reported.
Randomized phase II study of best available fluoropyrimidine compared with continuation of gemcitabine (Gem) monotherapy in patients with Gem-refractory pancreatic cancer.
Authors: Ioka Tatsuya , Katayama Kazuhiro , Ishida Nobuko , Takada Ryoji , Yamai Takuo , Fukutake Nobuyasu , Ashida Reiko , Uehara Hiroyuki , Ohigashi Hiroaki , Takahashi Hidenori , Ishikawa Osamu 
Published: February 2017

287 Background: Gem is a standard chemotherapy for unresectable pancreatic cancer (PC) patients (pts); however there is no standard regimen for Gem-refractory PC pts. We often continue to administer Gem for Gem-refractory PC pts because Gem is less toxic. The aim of this study is to elucidate the efficacy of second line treatment in PC. Methods: The pts who were treated with standard dose of Gem and diagnosed disease progression with radiographic findings were randomly allocated to arm A (to treat with best available fluoropyrimidine) or arm B (to continue to treat with standard dose of Gem). Each doctor could choose one of the available fluoropyrimidine (5FU, UFT and S-1) in arm A. Results: We collected 80 patients from Jan, 2004 to Sep, 2008 into this trial. 27 pts (67.5%) were treated with S-1, 8 pts (20%) with UFT and 5 pts (12.5%) with 5FU in arm A. Response Rate were 10% in arm A and 0% in arm B, respectively. Disease Control Rate were 50% and 17.5%, Progression Free Survival Time were 113 days and 50 days (p<0.1050) and Overall Survival Time were 226 days and 161 days (p<0.0384), respectively. Conclusions: Fluoropyrimidine statistically improve survival time in Gem-refractory PC pts, compared to continue Gem. Clinical trial information: UMIN000002154.
Proton reirradiation of locally recurrent pancreatic and ampullary adenocarcinomas.
Authors: Plastaras John Peter , Berman Abigail , Apisarnthanarax Smith , Both Stefan , Varillo Kristi , Larson Gary L. , Ben-Josef Edgar , Metz James M. 
Published: February 2017

317 Background: Local recurrences of pancreatic and ampullary cancer can be painful and cause significant morbidity. Their treatment after resection and chemoradiation is particularly challenging. A second course of radiotherapy (RT) in a previously radiated field carries the risk of RT-induced tissue injury. Proton therapy (PRT) may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of normal tissues. Methods: Between 2/2011 and 8/2012, 10 adult patients (pts) with locally recurrent pancreatic or ampullary malignancies in or near prior treatment fields began reirradiation. Toxicity was graded according to the CTC v4.0. Acute toxicity was defined within 90 days from start of PRT. Results: Median follow-up was 8.2 months (1.1-19.1) from the start of retreatment and 15 months (2.4-27.8) from the development of local recurrence. Mean age was 67 (54-75). Nine of the pts had pancreatic adenocarcinoma and 1 had ampullary adenocarcinoma. Median clinical target volume size was 86.4 cc (15-236). Nine received concurrent 5-fluorouracil or capecitabine-based chemotherapy. The median total dose was 59.4 Gy(RBE)(45-59.4); all pts were treated with PRT exclusively, except for one pt who was treated with 36% photon volumetric arc therapy. The median prior dose was 50.4 Gy (30-59.4). The median interval between RT courses was 34 months (17-461). Nine pts had Grade 2 and 1 had only Grade 1 non-hematologic acute toxicity. No Grade 2 or higher non-hematologic RT-related toxicities were observed after 90 days from the start of RT. Five pts developed metastatic disease at a median of 7.4 months (4.8-13.2) after starting RT, 1 of whom died at 5.3 months. One pt developed progressive regional (paraaortic) disease inferior to the fields while on treatment and was stopped early at 45 Gy. One pt developed a regional metastasis (porta hepatis) outside of the retreated volume. The other 8 pts were controlled locally within the retreated fields. Conclusions: Reirradiation of pancreatic/ampullary cancers with PRT and concurrent chemotherapy has minimal acute toxicity and encouraging short-term local control. Further follow-up on these pts is needed to assess the long-term morbidity and utility of PRT reirradiation. Clinical trial information: NCT01126476.
Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).
Authors: Simon Iris , Roepman Paul , Schlicker Andreas , Tabernero Josep , Majewski Ian , Moreno Aguado Victor , Chresta Christine M , Rosenberg Robert , Nitsche Ulrich , Macarulla Teresa , Capella Gabriel , Salazar Ramon , Orphanides George , Wessels Lodewyk F A , Bernards Rene 
Published: February 2017

333 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans. For colorectal cancer (CRC), however, a molecular classification is still missing. Methods: Using gene expression data of 188 stage I-IV colorectal cancer (CRC) patients, a molecular subtype classification was developed. The classifier was validated in 543 stage II and III patients and the subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular marker status and chemotherapy response. Results: CRC is a heterogeneous disease that consists of at least three major intrinsic subtypes (A-, B-, C-type). The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A-type and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Conclusions: We have developed a diagnostic single sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and consequently require different treatment strategies. [Table: see text]
Prevention of 5-FU-induced toxicities using pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.
Authors: Boisdron-Celle Michele , Capitain Olivier , Faroux Roger , Borg Christophe , Metges Jean-Philippe , Galais Marie-Pierre , Kaassis Mehdi , Bennouna Jaafar , Bouhier Leporrier Karine , Francois Eric , Baumgaertner Isabelle , Guerin-Meyer Veronique , Cojocarasu Oana , Roemer-Becuwe Celia , Stampfli Claire , Rosenfeld Ludovic , Lecomte Thierry , Berger Virginie , Morel Alain , Gamelin Erick 
Published: February 2017

351 Background: 5-FU is the backbone of most chemotherapy regimens in GI oncology. Patients with DPD deficiency can experience early onset severe (5%) even fatal (0.3%) toxic side-effects. We decided to confirm the medical and economic interest of pre-therapeutic screening of DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (Eudract n°2008-000026-39). Methods: Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD activity evaluation; Group B: no evaluation. Enrollment in either group was based on 5-FU administration guidelines at each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) as well as other patient characteristics (1,2,3). The 2 groups were compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed if 5-FU-induced toxic death occurred. Results: 1,130 patients were included from to 16/06/2008 to 07/31/2012. Group A: no severe toxicity despite 1 patient with complete deficiency (5-FU replaced by another TS inhibitor), 17 patients with partial deficiency safely received PK-monitored 5-FU (ODPM Protocol). Group B: 1 death: 65 y.o. patient, adjuvant FOLFOX 4, 5-FU-induced SAE at day 6: grade 4 febrile neutropenia, septicemia, diarrhoea, mucositis and secondary dehydration, renal failure, then death. 5-FU imputable Grade 5 SAE declared by investigator. Complete DPD deficiency retrospectively confirmed. The enrollment was prematurely closed after unanimous experts’ decision for ethical reasons. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A patient had safe treatment whereas Group B patient died due to 5-FU grade 5 toxicity. DPD deficiency screening by a multiparametric approach (ODPM Tox) should be performed before 5-FU treatments. Clinical trial information: 2008-000026-39. [Table: see text]
Antitumor activities of bevacizumab for KRAS, BRAF, and PIK3CA mutated human colorectal cancer xenograft models.
Authors: Harada Suguru , Yanagisawa Mieko , Iwai Toshiki , Aida Satoshi , Kurasawa Mitsue , Yorozu Keigo , Yamamoto Kaname , Harada Naoki 
Published: February 2017

362 Background: In colorectal cancer, it has been reported that mutations (mts) in KRAS, BRAF, or PIK3CA can have a negative impact on molecular target therapies. Especially, a KRAS mt represents a predictive biomarker for resistance to anti-EGFR antibodies. Bevacizumab (BV), an anti-VEGF-A antibody, has been demonstrated to have clinical benefits in colorectal cancers; however, the impact of mts in especially BRAF or PIK3CA on the efficacy of BV remains unknown. In this study, we examined the antitumor activity of BV in human colorectal cancer xenograft models harboring these mts. Methods: BALB-nu/nu mice were subcutaneously inoculated with 15 colorectal cancer cell lines. BV was intraperitoneally administered every week for 3 weeks at a dose of 5 mg/kg. Antitumor activity was evaluated by determining tumor volume and tumor growth inhibition (TGI) on day 22. The colorectal cancer cell lines used were screened for KRAS, BRAF, and PIK3CA mts by direct sequencing of hot spots. Statistical analysis was performed using Wilcoxon test for tumor volume and TGI and Fisher's exact test for the correlation of genotype and antitumor effect. Results: Genotypes of KRAS, BRAF, and PIK3CA were all wild-type (wt) in COLO320DM, KM-12 and SW48 and in other cell lines were, respectively, as follows: COLO205, HT-29, WiDr and LS411N: wt, mt, and wt; SW620 and LoVo: mt, wt, and wt; HCT-8, HCT116, DLD-1, T84 and LS174T: mt, wt, and mt; RKO: wt, mt and mt. BV as a non-responder (NR) showed no significant antitumor activity in 3 cell lines (WiDr, LoVo and DLD-1), whereas as a responder (R) significant activity was observed in the other 12 cell lines. There was no significant difference in the antitumor effect of BV between cell lines depending on KRAS, BRAF or PIK3CAmutational status in terms of TGI and R/NR ratio (Table). Conclusions: BV shows antitumor effect regardless of mutational status of KRAS, BRAF, or PIK3CA in colorectal cancers. [Table: see text]
Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib.
Authors: Jeffers Michael , Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Grothey Axel 
Published: February 2017

381 Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.
Relationship of EGFR-independent activation of PI3K in KRAS wild-type colorectal cancers and cetuximab resistance.
Authors: Corcoran Ryan Bruce , Ebi Hiromichi , Ryan David P. , Meyerhardt Jeffrey A. , Engelman Jeffrey A. 
Published: February 2017

385 Background: Therapies targeting receptor tyrosine kinases (RTKs) are typically effective only when they lead to simultaneous inhibition of PI3K-AKT and MEK-ERK signaling. Cetuximab is a monoclonal antibody against EGFR that has been approved for treatment of metastatic colorectal cancer (CRC). Studies have suggested that its benefit is restricted to patients with KRAS wildtype (WT) CRC. However, even in KRAS WT CRC, the response rate to single-agent cetuximab is low, and the mechanistic basis for this is not well-understood. Methods: The ability of cetuximab to inhibit PI3K-AKT and MEK-ERK signaling in a panel of KRAS WT CRC cell lines was assessed by immunoblotting. Paired biopsies from CRC patients obtained pre-treatment and after 3 weeks of cetuximab were evaluated by immunohistochemistry and proteomic techniques to assess inhibition of PI3K activity. We preformed immunoprecipitations (IPs) of the regulatory subunit of PI3K from cell lines and primary CRCs to identify RTKs involved in PI3K activation. Cetuximab-based therapeutic combinations were evaluated in KRAS WT CRC cell lines and xenograft models. Results: Cetuximab led to effective inhibition of MEK-ERK signaling (>75% reduction in phospho-ERK), but led to incomplete inhibition of PI3K-AKT signaling (0-50% reduction in phospho-AKT) in all KRAS WT CRC cell lines tested. Analysis of paired biopsies from patients with KRAS WT CRC obtained pre-treatment and after 3 weeks of cetuximab demonstrated that the PI3K pathway remained active in many patients, despite cetuximab therapy. PI3K regulatory subunit IPs from cell lines and primary CRCs revealed multiple RTK inputs to PI3K, most notably from IGFIR. Combined treatment with cetuximab and an IGFIR inhibitor or a PI3K inhibitor led to improved efficacy in vitro and to tumor regressions in KRAS WT CRC xenograft models. Conclusions: Cetuximab fails to inhibit PI3K signaling in some KRAS WT CRCs. Additional RTKs other than EGFR play a role in PI3K activation in these cancers, which may contribute to cetuximab resistance. Combining cetuximab with targeted therapies directed against the PI3K pathway may lead to improved efficacy in KRAS WT CRC, and should be evaluated in future clinical trials.