bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of cetuximab (Cmab) plus irinotecan (CPT-11) for chemorefractory Japanese patients with advanced and/or metastatic colorectal cancer (mCRC), to evaluate the efficacy and safety based on KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status (T-CORE0801).
Authors: Shimodaira Hideki , Soeda Hiroshi , Ohori Hisatsugu , Akiyama Shoko , Kambe Mariko , Murakawa Yasuko , Suzuki Takao , Kato Satoshi , Itoh Jugoh , Watanabe Mika , Yamaguchi Takuhiro , Kato Shunsuke , Ishioka Chikashi ,   Tohoku Clinical Oncology Research and Education Society
Published: March 2020

e14597 Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) antibody (mAb) therapy among patients with mCRC based on Caucasian studies. To date, few studies have examined the relationship between KRAS status and response to Cmab therapy in Asian populations. Therefore, this prospective study investigated the relationship between the mutation status of KRAS and other EGFR-related genes along with clinical outcomes in response to Cmab + CPT-11 therapy in Japanese patients with mCRC. Methods: Samples that had been collected from 43 chemo-refractory patients with mCRC, who had undergone Cmab + CPT-11 therapy at 11 medical centers in Japan, were subjected to direct DNA sequencing to determine their KRAS, BRAF, PIK3CA, NRAS, and AKT1 status. The response rate (RR) was the primary endpoint along with safety, median progression free survival (mPFS), and median overall survival (mOS) as secondary endpoints. Results: The clinical outcomes in response to Cmab + CPT-11 therapy was observed to be better in the wild-type (WT) KRAS subgroup than in the mutant (MT) KRAS subgroup (RR: 17.9% vs. 0%; mPFS: 3.7 vs. 1.6 months (M) ; mOS: 10.3 vs. 7.5 M). The differences in clinical outcomes were more remarkable between patients with both WT KRAS and BRAFand those with MT of either of these genes (RR: 19.2% vs. 0%; mPFS: 5.2 vs. 1.6 M; mOS: 11.8 vs. 7.4 M), as well as between patients with all 5 WT genes and those with MT of either of these genes (RR: 26.3% vs. 0%; mPFS: 5.2 vs. 1.8 M; mOS: 11.8 vs. 7.4 M). Conclusions: Despite identification of a lower than expected RR to treatment among the WT KRAS subgroup, KRAS mutation status appeared to be a useful predictive marker of response to Cmab + CPT-11 therapy in Japanese patients with mCRC . Combined analysis of KRAS and BRAF improved both the sensitivity and specificity of the predictive biomarker. However, the combined analysis of all 5 genes did not result in any considerable improvement compared with that achieved with the KRAS and BRAF analysis alone. Clinical trial information: UMIN000001668.
Hsa-mir-31-3p effects on gene expression in colorectal cancer cell lines and patients.
Authors: Thiébaut Raphaële , Vincent Marc , Vazart Celine , Decaulne Virginie , Le Corre Delphine , Fontaine Karine , Genin Berengere , Carayol Jerome , Rousseau Francis , Liebaert Francois , Laurent-Puig Pierre 
Published: March 2020

e14600 Background: Recently, hsa-miR-31-3p was found to be up-regulated in some tumors of metastatic colorectal cancer (mCRC) patients and was proposed as a prognostic marker for anti-EGFR therapy in KRAS wild-type (WT) patients. The aim of this study was to identify the target genes of hsa-miR-31-3p in a CRC context. Methods: Three different KRAS WT CRC cell lines, Caco-2, Colo205 and Colo320HSR were transfected with hsa-miR-31-3p mimic or control mimic. After 24h, cells were harvested and total RNA was extracted for an expression array analysis. Linear models for micro-arrays analysis from R package was used to analyze the results. A miRNA predictive target database including 6 available databases (microRNA.org, MicroCosm, TargetScan, PicTar, PITA, miRDB) was created. Validation of the identified target genes was performed on tumors sample of 39 patients treated with panitumumab and irinotecan as third line. Results: After transfection of the 3 cell lines with hsa-miR-31-3p mimic, an expression profile analysis was done. Results obtained in each cell lines were first compared in a pair wise analysis and secondly tested with eBayes procedure without matching. Fifty –four genes were down-regulated (fold change: fc≤0.77, p<0.05). Using the predictive target database, hsa-miR-31-3p was the second most common miRNA as it targeted putatively 25 out the 54 genes, among which STAT3. To identify indirect target genes, we then studied the genes up-regulated by hsa-miR-31-3p over-expression in the 3 different cell lines and identified 27 genes. As expected all but one were not predicted to be direct target genes of hsa-miR-31-3p using the predictive target database. Interestingly, the proto-oncogene MET was up regulated by the over expression of hsa-miR-31-3p. Validation of the 25 putative targets and of the 27 genes up-regulated genes was done with RT qPCR on tumor samples of patients treated with anti-EGFR and some of the direct and undirected target genes were confirmed. Conclusions: This study shows that hsa-miR-31-3p, which expression level was shown to be correlated with prognosis of mCRC patients treated with anti-EGFR, plays an important role in CRC by regulating genes involved in cancer like STAT 3 and MET.
Use of biologics in addition to chemotherapy in the treatment of elderly Medicare patients with stage IV metastatic colon cancer.
Authors: Mullins C. Daniel , Wang Fenghao , Bikov Kaloyan A. , Seal Brian S. , Hanna Nader 
Published: March 2020

e14602 Background: On February 12 and 26, 2004, the FDA approved bevacizumab and cetuximab, respectively, two biologic drugs for the first–line treatment of metastatic colorectal cancer (mCC), followed by panitumumab, another biologic approved on September 27, 2006. NCCN guidelines suggest that biologics may be added to fluorouracil and leucovorin (5-FU/LV), irinotecan (IRI), or oxaliplatin (OX), yet a number of recent articles raise questions regarding the added benefit of biologics on top of a backbone chemotherapy regimen, which might affect the utilization pattern of biologics. To examine the adoption of biologics, we document the rate of treatment with biologics in addition to backbone chemotherapy as first-line treatment (Tx1) of mCC. Methods: This study uses the Surveillance, Epidemiology and End Results (SEER)-Medicare data and examines mCC patients diagnosed in 2003-2007 who received chemotherapy with or without biologics as Tx1. Due to the small sample size of cases involving the combined use of irinotecan and oxaliplatin (IROX) as Tx1, IROX patients were excluded from this study. The remaining 2995 observations are broken down by regimen and by year of Tx1 initiation (Table). Results: The use of biologics (90% of which was bevacizumab) in addition to chemotherapy as part of Tx1 exploded from 9% in 2004 to 55% in 2005. Utilization was highest (62%) in 2006 and fell slightly in 2007 to 57%. Of all cases utilizing biologics, 67% were oxaliplatin-based regimens, 19% were fluorouracil-based regimens and 15% were irinotecan-based regimens. Conclusions: In the first few years following FDA approval, the use of biologics in addition to backbone chemotherapy increased rapidly as first-line treatment of elderly Medicare metastatic colon cancer patients, leveling out at around half of all patients receiving chemotherapy. Biologics use has been most common among patients treated with oxaliplatin. [Table: see text]
Understanding why some people with stage III colon cancer do not receive adjuvant chemotherapy.
Authors: Heong Valerie , Wong Hui-Li , Tie Jeanne , Jefford Michael , Field Kathryn Maree , Kosmider Suzanne , Desai Jayesh , Croxford Matthew , Jones Ian , Gibbs Peter 
Published: March 2020

e14608 Background: Adjuvant chemotherapy is a standard of care for patients (pts) with stage III colon cancer. While many retrospective series have concluded that treatment is underutilised in routine clinical practice, particularly in older pts, reasons for this remain unexplored. Methods: Data was collected on all pts with stage III colon cancer attending four community hospitals in Australia between January 2003 and July 2012. Every patient was referred to a medical oncologist. For each case where adjuvant therapy was not delivered, reason(s) were prospectively documented by clinicians in a consensus database. Results: Data was collected on 875 pts. Median age 67 years (range 15 - 92). Overall, 147 (25.9%) did not receive adjuvant therapy. Comorbidity was the main reason for non-treatment in all age groups. Age alone was the reason for not recommending treatment in a small number of elderly pts (n=20, 20.4%). Risk of recurrence (N1 vs N2 disease) did not impact recommendations of clinicians (75% vs 76%) or pt acceptance (92% vs 93%). Pts with a lower socioeconomic status were less likely to be offered treatment; however this reflected greater comorbidity in these pts. Treatment acceptance was similar across all socioeconomic groups (data not shown). Conclusions: In routine clinical practice adjuvant chemotherapy should be recommended to, and can be safely delivered to a very high proportion of younger patients. Clinicians are comfortable recommending adjuvant chemotherapy to older pts, with co-morbidity the dominant reason that treatment was not recommended for pts >65 years. The rate of pts declining treatment increased with age, and further study of the factors involved in treatment refusal should be pursued [Table: see text]
Prognostic factors in KRAS wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts) treated with biweekly cetuximab (C) plus irinotecan, fluorouracil, and leucovorin (FOLFIRI): A phase II study.
Authors: Personeni Nicola , Rimassa Lorenza , Verusio Claudio , Barni Sandro , Destro Annarita , Raschioni Carlotta , Armenia Silvia , Floriani Irene , Gerardi Chiara , Monteforte Marta , Villa Eugenio , Bozzarelli Silvia , Roncalli Massimo , Torri Valter , Labianca Roberto , Santoro Armando 
Published: March 2020

e14611 Background: Retrospective studies showed that efficacy of C increases in molecularly-defined subsets of KRAS wt mCRC pts. In pretreated pts, biweekly C seems as effective as a weekly schedule. Aim of this field-practice study was to evaluate the efficacy of FOLFIRI plus biweekly C (C-FOLFIRI) as first-line treatment for mCRC and prospectively validate PTEN expression as a prognostic marker. Methods: Pts with previously untreated metastatic KRAS wt mCRC not suitable for curative-intent resection were eligible. Initially, pts were randomized to receive FOLFIRI alone or in combination with C (500 mg/m2 every two weeks). After a protocol amendment, pts were assigned to receive only C-FOLFIRI, while the FOLFIRI alone arm was discontinued. Clinical outcome was assessed according to expression of PTEN and MET by immunohistochemistry (IHC), as well as to BRAF mutations. Results: From April, 2009 to June, 2012, a total of 89 pts were enrolled. 35 pts were randomly assigned to receive FOLFIRI alone, while 54 pts received C-FOLFIRI: 33 were treated in the random phase and 21 after protocol amendment. Median overall survival (OS) was 17.7 months for FOLFIRI and 23.3 months for C-FOLFIRI. Corresponding median progression-free survival was 8.2 and 6.8 months, respectively. Objective response rate was 52.0% for FOLFIRI and 52.3% for C-FOLFIRI. The toxicity profile of C-FOLFIRI was consistent with that expected from a weekly C schedule. 23/38 pts (61.0%) assessed for PTEN were positive for IHC expression, 8/39 pts (21.0%) had a MET high status, 6/45 pts (13.3%) had BRAF mutations. In pts treated with C-FOLFIRI, only BRAF mutations negatively affected OS (Hazard ratio mutations vs. wt: 4.77; 95%CI 1.41-16.13; p = 0.01). Conclusions: Safety, effectiveness and generalizability of C-FOLFIRI validate in field practice results gained with FOLFIRI plus a weekly C schedule. Despite the small sample size, analysis of BRAF mutations reaffirms the strong prognostic impact of this biomarker. The extended analysis of BRAF mutations, PTEN and MET expression on all pts is ongoing. Data will be presented. Clinical trial information: NCT01068132.
HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.
Authors: Sclafani Francesco , Roy Amitesh Chandra , Chau Ian , Wotherspoon Andrew , Peckitt Clare , Dewdney Alice , Oates Jacqueline Rose , Cunningham David 
Published: March 2020

e14616 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.
Phase II study of weekly scheduled irinotecan and capecitabine treatment in advanced colorectal cancer patients.
Authors: Li Wenhua , Li Jin , Xu Jianming , Shen Lin , Liu Tianshu , Guo Wei jian , Zhang Wen 
Published: March 2020

e14644 Background: The clinical application of combination therapy of irinotecan and capecitabine is at a standstill due to the consideration on severe diarrhea. The aim of the current phase II study was to explore the optimal administration mode of these two drugs, and evaluate the safety and efficacy of weekly-scheduled XELIRI regimen (wXELIRI) in mCRC pts. Methods: Pts with unresectable, histologically confirmed mCRC were enrolled to receive wXELIRI: irinotecan 90mg/m(2) on Day 1 and capecitabine 1200 mg/m(2) bid on Days 1-5 weekly. Both the first-line pts and second-line treatment pts who failed with FOLFOX or XELOX were eligible. The primary endpoint was rate of Grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and other safeties. Results: From January 2011 to May 2012, totally 43 pts with measurable mCRC were enrolled, 18 of them were male and 25 were female. The median age was 60 yrs (range 32-70). No Grade 4 diarrhea was observed and the rate of grade 3 diarrhea was 4.7%. The most common Grade 3/4 toxicities included leucocyte(11.6%), neutrophile (18.6%), vomiting (4.7%), fatigue (2.3%), hand-foot-syndrome (2.3%) . With a median follow-up of 19.0 months, 23 PFS events were observed. The mPFS for all the 43 pts was 6.1 mons and the mOS was 15.5 mons. For the 31 first-line treatment pts, the mPFS was 7.5 mons and the mOS has not reached. In the second-line treatment group (12 pts), the mPFS was 5.4 mons and mOS was 13.8 mons. Conclusions: The weekly-scheduled irinotecan and capecitabine combination has a low rate of severe diarrhea and acceptable toxicity profile. It could be an alternative regimen for mCRC pts, especially in the second-line setting. Clinical trial information: NCT01322152.
Prognostic significance of presence of any mucinous component in curatively resected stage II and III colorectal cancer patients who received adjuvant treatments: Data from a single tertiary center.
Authors: Dane Faysal , Ozturk Mehmet Akif , Yumuk Perran Fulden , Kocar Muharrem , Besiroglu Mehmet , Atasoy Beste Melek , Telli Ferhat , Kanitez Metin , Aktas Bilge , Turhal Nazim S. 
Published: March 2020

e14660 Background: Mucinous adenocarcinoma colorectal cancer (CRC) is defined as presence of more than 50% mucinous component and its prognostic significance is debatable. We analyzed the prognostic importance of positivity of any mucinous component in early stage adenocarcinoma patients who were operated and received adjuvant treatments in a single tertiary cancer center. Methods: Data from charts of early stage CRC patients curatively treated between January 1998-December 2009 in our clinic was retrospectively analyzed. Cases with any degree of mucine presence in final pathology reports were noted (including mucinous adenocarcinomas). Adjuvant treatments were either 5-FU or oxaliplatin based regimens. All rectal carcinoma patients received postoperative radiotherapy. Survival analyses were made by Kaplan-Meier estimator, and independent factors of survival were tested with Cox regression test. Survival data of subgroups were compared with log-rank test. Results: 532 patients (45% female) were analyzed. Median follow-up was 36 months. Median age at diagnosis was 62 years (24-84). Fifty-four percent of patients had rectal primary (n=292). Presence of any mucinous component was found in 94 patients (17.7%). There was a close relation between mucine presence and T stage (p=0.0001) or tumor grade (p=0.0001). There was no statistical relation between presence of mucine and lymphatic invasion, vascular invasion, or perineural invasion. Five-year disease-free survival for mucine (+) and mucine (-) tumors were, 45.7% and 61.4%, respectively (p=0.031). Five -year overall survival of mucine (+) tumors was worse than mucine (-) tumors (65% vs. 74%, p=0.004). Conclusions: Presence of any mucinous component in early stage CRC appears to be an important bad prognostic feature in our patient group, which was not previously reported in the literature to our knowledge. This “context specific prognostic property” of presence of any mucinous component might serve as a stratification factor for further adjuvant CRC studies.
Effect of microRNA-202-3p on cell proliferation and targeting of ADP-ribosylation factor-like 5A in human colorectal carcinoma.
Authors: WANG Qifeng , Du Xiang 
Published: March 2020

e14667 Background: MicroRNAs (miRNAs) are small, non-coding RNAs that are strongly implicated in cancer and reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. Methods: Quantitative RT-PCR was used to evaluate miR-202-3p expression in 94 pairs of human primary CRC and adjacent noncancerous tissues (NCT) to determine the clinicopathologic significance of miR-202-3p. Cell proliferation analysis and Xenograft analysis was used to investigate miR-202-3p function in vitro and in vivo.It’s direct target ARL5A was confirmed by Luciferase assay and Western blot. Immunochemistry was performed to reveal endogenous protein level of ARL5A and analysis clinical significance. Results: In this study, miR-202-3p was verified significantly down regulated in 46.7% (44/94) of the CRC tissues when compared to the corresponding noncancerous tissues(NCT). Subsequently, DNA copy number deletion of Pre-miR-202 in 63.2%(24/38) CRC tissue was proved(compared with NCT), which was considered as a main cause of the low expression of miR-202-3p. Cell proliferation analysis and colony formation assay showed that overexpression of miR-202-3p inhibit CRC cell growth in vitro. Xenograft analysis revealed that ectopic expression of miR-202-3p decreased the tumorigenicity of CRC cells in vivo. Consistent with these results, silencing of miR-202-3p resulted in a increased growth ratio of the colon cancer cells. In addition, ADP-ribosylation factor-like 5A(ARL5A) was predicted as potential target of miR-202-3p which was confirmed by Luciferase assay and Western blot. Overexpression of miR-202-3p could reduced the endogenous protein level of ARL5A, whereas silencing of miR-202-3p obviously up regulated ARL5A expression. In human CRC tissues, miR-202-3p expression levels correlated inversely with ARL5A protein levels which was identified as an prognostic factor in this study. Furthermore, knockdown of ARL5A phenocopied the proliferation-inhibiting effect of miR-202-3p. Conclusions: These results indicated that miR-202-3p, acting as a new tumor suppressor in CRC, could decrease cell proliferation via directly targeting ARL5A, a first reported gene related to CRC prognosis.
Neoadjuvant chemoradiotherapy (NACRT) in patients with locally advanced rectal cancer (RC): Results of a phase I/II trial in Japan.
Authors: Koyama Takafumi , Gomi Daisuke , Yukinori Ozaki , Nakamura Yoshiaki , Nagano Masafumi , Mike Makio , Kano Nobuyuki , Oyama Yu 
Published: March 2020

e14670 Background: NACRT for patients with RC has been shown to increase the chance of sphincter preservation and local control, and has become the standard of care in stage T3/T4 rectal carcinoma in western countries. NACRT decreases the need for abdominoperineal resection (APR) that results in permanent colostomy and sexual/urinary dysfunction. In Japan, NACRT has not been utilized in RC and its value is unconfirmed. Thus, we performed a phase I/∥study to assess the toxicity and efficacy of NACRT. Methods: Eligibility criteria included histopathologically confirmed locally advanced adenocarcinoma with reasonable PS. Radiotherapy (RT) consisted of 5040 cGy in 28 fractions, and was delivered six times a week to the pelvis with individually shaped portals. Chemotherapy consisted of oral capecitabine (1650 mg/m2/day) or fluorouracil as a continuous infusion (225 mg/m2/day) on each RT day. Surgery was performed within 6-8 weeks after chemoradiation (CRT). Tumor response to CRT was measured using a radiologic scale, called the RECIST, and by pathologic examination of resected specimen. CTCAE v3.0 was used for evaluation of toxicity. Results: Fifty-two patients were enrolled in the study. Forty-nine (92%) patients completed CRT without treatment interruptions: 1 patient had temporary treatment interruption due to toxicity or noncompliance and 3 patienst had definitive treatment interruption. The incidence of Grade 3 lower gastrointestinal toxicity was only 9%. After NACRT, computed tomography showed that 14 patients had PR and 38 had SD. Resection was performed in 48 patients (low anterior resection in 34 and abdominoperineal resection in 14). Surgical resection resulted in R0 and R1 in 44 and 4 patients, respectively. At a median follow-up of 21.5 months (range: 4-69 months), local recurrence or tumor progression occurred in 2 patients and distant metastasis in 7. The median overall survival was 47 months. Conclusions: Our data confirm the safety and efficacy of NACRT using capecitabine/5FU in Japanese patients with locally ARC. We suggest that NACRT is the preferred treatment approach since it can provide increased resectabilility and possibly a superior rate of local control.