bluuebunny/crossref_metadata_2025 huggingface dataset:
Early outcome of a phase I study of interrupted pulse dosed axitinib combined with FOLFOX or FOLFIRI in refractory metastatic colorectal cancer.
Authors: Roeland Eric , Shimabukuro Kelly Anne , Fanta Paul Timothy , Parker Bethany H. , Hwang Michael , Reid Tony R.
Published: February 2017

473

Background: In mCRC, bevacizumab studies have shown improved survival in 5-FU based chemotherapy. Therapeutic inhibition of angiogenesis pathways may improve response of chemotherapy refractory malignancies. We evaluated the combination of axitinib, a VEGF receptor inhibitor, used intermittently with 5-FU based chemotherapy for refractory mCRC. We hypothesized that intermittent pulse dosed axitinib may improve response by delivering chemotherapy during tumor reperfusion after release from angiogenesis inhibition. We present preliminary data of the Phase I portion evaluating the safety and efficacy of interrupted pulse dosed axitinib + FOLFIRI.

Methods: Initially, Pfizer A4061020 was a phase IB study of axitinib + bevacizumab + FOLFOX vs. FOLFIRI to evaluate potential overlapping toxicities. In cohorts 8 and 9, A4061020 was expanded to determine the MTD of 7 days of intermittent pulse dosed axitinib at 14mg vs. 20mg + FOLFIRI or FOLFOX. Enrollment was open to mCRC with progression on both oxaliplatin and irinotecan-based regimens. The primary outcome was MTD; while secondary outcomes included: PFS, TTP, and OS.

Results: Preliminary data of 10 mCRC subjects show intermittent pulse dosed axitinib at 14mg and 20mg in combination treatment is safe and tolerable (few grade 3 and one grade 4 AE). We observed PFS up to 16.8 mos (avg 8.7 mos, 6 subjects) and TTP up to 17.1 mos (avg 11.8 mos, 4 subjects) vs. average 6 mos on the last line of chemotherapy. To date, the OS endpoint has not been achieved ( Table ).

Conclusions: In 10 heavily pre-treated mCRC subjects, intermittent pulse dosed axitinib demonstrates safety, tolerability, and improved PFS and TTP. Intermittent pulse-dosed VEGF receptor inhibition may enhance tumor response that warrants further exploration.

[Table: see text]
Phase II multicenter study of second-line FOLFIRI plus cetuximab (FLIER) in patients with KRAS wild-type metastatic colorectal cancer: Final analysis of survival and additional analysis of BRAF, PI3CA mutations.
Authors: Miyake Yasuhiro , Iwamoto Shigeyoshi , Hazama Shoichi , Goda Fuminori , Matsuda Chu , Amagai Kenji , Bandou HIroyuki , Fukunaga Mutsumi , Nagata Naoki , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

481

Background: Survival advantage of second line FOLFIRI plus cetuximab in patients with KRAS wild-type metastatic colorectal cancer has not been well reported. Since mutations in codons 12 and 13 of the KRAS gene predict lack of response to Cetuximab, mutations of V600E BRAF and PI3CA have been controversial.

Methods: The aim of this study was to assess the efficacy of second-line FOLFIRI plus cetuximab in KRAS wt mCRC. Primary endpoint was response rate, other secondary endpoints were PFS, OS and safety. KRAS, BRAF, PI3CA tests by direct sequence were performed in Yamaguchi University. The starting dose of irinotecan was 150mg/ m2 (approved dose in Japan), but decreased to 100mg/m2 with UGT1A1 *28,*6 homozygous or both heterozygous.

Results: From December 2008 to November 2009, 112 pts were preregistered. 67 (59.8%) pts were KRAS codon 12, 13 wt, and 60 pts were enrolled: 39 males (65%), 21 females (35%); median age was 62 years (range 37-82). The incidence of UGT1A1*28, *6 homozygous was 2.8%, 4.7% respectively. Grade 3/4 adverse events were leucopenia 26.7%, neutropenia 43.3%, paronychia 10.0%, skin toxity (fissure) 10.0% and acne 5.0%. The confirmed response rate (RECIST) was 31.7% (19/60). The median progression free survival and overall survival were 7.5 (C.I. 5.2-10.1) and 19.5 (C.I. 11.7-22.2) months respectively. Three pts had BRAF mutations and tumor shirinkage were +50.9%, +12%, +85.6% respectively. Two pts had PI3CA mutations and tumor shirinkage were +4%, +44%, respectively.

Conclusions: FLIER was the first multicenter phase II trial with prospective analysis of KRAS as a predictive biomarker for cetuximab in second-line mCRC in Japan. Second-line FOLFIRI+cetuximab is well-tolerated and active. Mutations in BRAF and PI3CA gene seemed to be lack of response to cetuximab.
Effect of PIK3CA and KRAS mutations on sensitivity to ATP-competitive mTOR inhibitors in a primary xenograft model of colorectal carcinoma.
Authors: Ducker Gregory S. , Atreya Chloe Evelyn , Simko Jeffrey , Nakakura Eric K. , Bergsland Emily K. , Donner David B. , Shokat Kevan M. , Warren Robert S.
Published: February 2017

483

Background: The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and has been strongly implicated in cancer. Mutations in KRAS and the PI3K pathway are upstream of mTOR and are common in colorectal carcinoma (CRC). Currently approved mTOR inhibitors are derivatives of the natural product rapamycin and have shown little clinical efficacy in CRC. A new and potentially more efficacious class of ATP-competitive mTOR inhibitors has now entered clinical trials.

Methods: Seeking a more representative preclinical model of CRC, we generated primary xenografts in nude mice of surgically resected specimens of human hepatic colorectal cancer metastases. We then treated xenograft tumors with the selective ATP-competitive mTOR inhibitor PP242 and monitored response by inhibition of tumor growth, changes in histopatholgy, and alterations in signaling pathways. Cell line experiments were performed to support observations made in the patient derived xenografts.

Results: We demonstrate that in contrast to rapamycin, the mTOR inhibitor PP242 is highly effective at inhibiting tumor growth in both the primary xenograft model and in colorectal cancer cell lines. The inhibition of tumor growth in the xenografts and cell lines depended upon the strong inhibition of phosphorylation of mTOR substrate eIF4E binding protein 1 (4EBP1) but was not correlated with inhibition of phosphorylation of S6 kinase (S6K). Cells with mutant KRAS were relatively resistant to PP242 induced growth inhibition and this correlated with reduced inhibition of 4EBP1 phosphorylation. However, these effects were partially rescued in cells in which a co-mutation in PIK3CA resulted in AKT activation.

Conclusions: Our studies reveal the first mTOR inhibitor resistant cell line, the genetic basis for its resistance and most importantly, these findings were revealed through the use of a primary xenograft mouse model which recapitulates morphologically the features of the tumors isolated from patients. We believe ATP-competitive inhibitors may be of limited clinical utility in mutant KRAS tumors, except for those that have concomitant activation of AKT.
The prognostic implication of phosphoinositide 3-kinase/Akt pathway in gastric carcinomas.
Authors: Begnami Maria D. , Chiappini Paula , Costa Jr. Wilson L. , Fregnani José Humberto , Coimbra Felipe José Fernandez , Diniz Alessandro Landskron , Pinto Clovis
Published: February 2017

49

Background: The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB) signaling pathway plays a critical role in cell growth and survival. Dysregulation of this pathway has been found in a variety of cancer cells. Recently, constitutively active PI3K/Akt signaling has been firmly established as a major determinant for cell growth and survival in an array of cancers. Blocking the constitutively active PI3K/AKT signaling pathway provides a new strategy for targeted cancer therapy. The purpose of our present study was to investigate the expression of activated mTOR (p-mTOR), PTEN, and pAKT in non-neoplastic gastric tissue and in gastric cancer patients to determine their pattern of expression in gastric tumors and their prognostic significance.

Methods: The expression of p-mTOR, pAKT, and PTEN was detected in specimens of 239 gastric cancers who underwent radical resection (R0) and in 200 non-neoplastic gastric tissues by immunohistochemistry. Slides were scanned and analyzed with an automated cellular imaging system (ACIS III, Dako). The correlation of p-mTOR, pAKT, and PTEN expression to clinicopathologic features and survival of gastric cancer was studied.

Results: Overexpression of pMTOR in the cytoplasmic pattern, nuclear pAKT, and nuclear PTEN was observed in the non-neoplastic tissues when compared with gastric tumor tissues (all, p<0.001). Overexpression of pmTOR, pAKT, and PTEN in gastric tumors was closely correlated with pTNM stage (p<0.001, p=0.008, p=0,036, respectively). Patients with p-AKT positive showed significantly longer disease-free survival (DFS) and overall survival (OS) rates than those with pAKT-negative tumors in univariable analyses. In multivariable analyses, higher expression rates of pMTOR and losses of PTEN were significantly associated with worse overall survival.

Conclusions: Taken together, the observations indicate the PI3K/Akt pathway plays an important role in the gastric carcinogenesis. A new strategy for combined chemotherapy of gastric cancer should be designed to more specifically block PI3K/Akt pathway for selected patients.
Copy number differences in EGFR and other amplicons between primary colon tumors and paired lymph node metastasis.
Authors: Tsikitis Vassiliki Liana , Larson David , Preece Christina , Tsavaridis Spyros , Thompson Patricia
Published: February 2017

498

Background: Prior study, demonstrating differential immunohistochemical EGFR expression between the primary colon cancer and the liver metastasis, suggested possible molecular differences between the two tumor sites. This questions the relevance of obtaining genomic information from the primary tumor to guide adjuvant treatment. In this study we examine whether there are genomic differences specific to metastatic nodes versus the paired colon primary samples.

Methods: Using 30 primary and lymph node metastasis pairs (dissected for >80% tumor from paraffin embedded tissue), we obtained a dataset of copy number derived from the Affymetrix Oncoscan Molecular Inversion Probe platform. Using the Nexus Copy Number software for processing, we used the default automatic segmentation of the copy number data with a threshold for calling copy number gains/losses of 2.3/1.7. Subsequently we applied the Wilcoxon signed-rank test in order to find regions showing copy number imbalance that differ between the paired nodes and tumors correcting for multiple comparisons by performing permutation-based estimation of the false discovery rate permuting the samples 100 times.

Results: Using 40 ng of total DNA from paraffin embedded tumor from primary and tumor in positive nodes, we obtained high quality, genome wide copy number data. Using FDR < 0.1, we identified four chromosomal segments that showed statistically significant increased likelihood of copy number gains in the primary tumor compared to the tumor-containing node. Thirty five percent of tumor-bearing lymph nodes were copy number normal at the EGFR locus whereas the corresponding primary tumor showed amplification at 7p11.2 (includes the EGFR gene). A similar pattern was observed for 8q24, 14q11.2, and 20q12-q13; regions associated with aggressive tumor behavior.

Conclusions: Our results demonstrate four significant differences between the primary tumor and lymph node metastasis and in all cases the metastasis were copy number normal compared to the copy number gain observed in the primary tumor. These results support the importance to examine differences at the genome level between the metastatic tumor site and the primary.
Gene expression analysis of EAC in association with PET response.
Authors: Wayte Nicola , Nancarrow Derek , Walpole Euan Thomas , Lampe Guy , Gotley David , Smithers Bernard Mark , Barbour Andrew
Published: February 2017

50

Background: Esophagectomy with preoperative chemotherapy or chemoradiotherapy are standard treatment regimens for localized esophageal adenocarcinoma (EAC). Early metabolic response to preoperative therapy (determined by FDG-PET scan) has been shown to predict histological response and survival. We present preliminary data from a randomized phase II trial of pre-operative cisplatin (C), 5-fluorouracil (F) and docetaxel ± radiotherapy based on early response to standard chemotherapy for resectable EAC. We present gene expression data for 22 patients with early FDG-PET response.

Methods: Samples that were histologically proven invasive EAC and clinical stage T2/3 tumors were included in the analysis. All patients received C (day1) and F (days 1-4) chemotherapy. Early metabolic response was defined as >35% reduction in SUVmax on day 14 FDG-PET scan compared with baseline scan. Whole genome mRNA expression was obtained for pre-treatment biopsies using HumanHT-12v4 expression chips. Expression data was log2 transformed prior to robust spline normalization conducted with the lumi R package. Statistical analysis was performed in BRBarray.

Results: There were 8 early PET responders and 14 early nonresponders to CF chemotherapy. Differentially expressed genes among PET responders and non-responders were identified using a random-variance t-test; 57 genes were identified as significantly differentially expressed between the two classes (p ≤ 0.001). A global test indicated significantly different expression profiles between the classes (p = 0.031). A gene classifier to predict PET response was explored and Support Vector Machines correctly classified 82% of samples with the prediction error estimated using leave-one-out cross-validation (p = 0.05). Epigenetic and apoptotic processes were significantly overrepresented in the gene list based on Gene Ontology analysis.

Conclusions: This preliminary work supports a biological basis for the association between early metabolic PET response to preoperative therapy and survival in EAC patients. The list of differentially expressed genes may include potential biomarkers of treatment response and requires further investigation at the maturation of the phase II clinical trial for EAC.
New biomarkers to predict response to oxaliplatin-based chemotherapy in metastatic colorectal cancer: KRAS and ERCC1.
Authors: Strippoli Antonia , Basso Michele , Orlandi Armando , Schinzari Giovanni , Calegari Alessandra , Cursio Olga Elisabetta , Barile Rosalba , Amoruso Alessia , Pozzo Carmelo , Cassano Alessandra , Barone Carlo
Published: February 2017

500

Background: In the present study we have evaluated the possibility that KRAS mutational status might be predictive of the efficacy of oxaliplatin-based chemotherapy. In addition, we explored the possible role of excision repair cross complementing group-1 (ERCC-1) that is envolved in repair of oxaliplatin (OXA) produced DNA-adducts.

Methods: We performed a retrospective analysis of 90 patients with metastatic colorectal cancer, who received FOLFOX-6 schedule and FOLFIRI schedule ± Bevacizumab, in first or second line therapy. In sixty out of 90 patients the expression of ERCC-1 was also determined by fluorescence-based real-time detection method.

Results: Among 90 patients, 42 (47%) wild-type (wt) and 48 (53%) mutated (mt) KRAS tumors were found. Twenty-two out of 42 wt KRAS patients received FOLFOX-6 as first-line therapy and the other 20 patients as second-line treatment; in the mt KRAS population, 27 and 21 patients received FOLFOX-6 as front-line or second-line, respectively. One complete response (CR) and 10 partial responses (PR) were observed in the wt KRAS group (RR 26%), whereas 2 CR and 25 PR were obtained in the mt KRAS group (56%); the difference is statistically significant in the total sample (p=0.003) and when only patients receiving FOLFOX-6 in first-line are considered (p=0006). PFS was longer in mt than in wt KRAS patients in the entire group of patients (10 vs 8 months, respectively; p=0.001) and in those treated in front-line (10 vs 8 months, respectively; p=0.003). ERCC-1 was over-expressed in 30 out of 60 patients, but the efficacy of FOLFOX-6 was not different in patient showing high ERCC-1 levels in comparison to those with low level of the gene. In ERCC-1 over-expressing patients, however, RR and PFS were higher in mt than in wt patients (40% vs 13% and 10 vs 8 months, respectively); a similar, not significant, trend was also observed in patients not over-expressing ERCC-1.

Conclusions: Our data, if confirmed in larger series and in a prospective setting, suggest that activating mutation of KRAS oncogene could be a predictive biomarker of response to oxaliplatin. Basal tumor expression of ERCC-1 doesn’t explain the high efficacy of FOLFOX-6 in mt KRAS patients.
The expression of multiple proteins as prognostic factors in human colorectal cancer: The correlation between cathepsin D, p53, Cox-2, EGFR, C-erbB2, and Ki-67 expression.
Authors: Lee In Kyu , Kim Hyung Jin
Published: February 2017

502

Background: This study aimed to establish a correlation between the expression of cathepsin D; p53; Cox-2; EGFR; C-erbB2; Ki-67 protein and the prognosis of colorectal cancer patients.

Methods: Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer from January 2006 to December 2007. The expression of the six proteins was determined using immunohistochemical staining of paraffin-embedded tissue specimens.

Results: Cathepsin D, p53, Cox-2, EGFR, C-erbB2, and Ki-67 expression was detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expression of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and overall survival (p=0.003), whereas the expression of the other proteins could not be correlated. In a multivariate analysis, after adjusting for age, sex, and stage, cathepsin D expression was found to be an independent prognostic factor for a short overall survival(HR=8.55, 95% CI 1.07–68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and overall survival rate (p=0.002), when compared with patients expressing fewer than four of the proteins

Conclusions: In this study, the expression of CD was correlated with a poor prognosis in terms of the cancer-free survival and the overall survival rate. Importantly, the high hazard ratio (HR=8.55) associated with CD expression from the multivariate analysis, even after adjusting for the tumor stage, demonstrates its potential as an independent, single-gene prognostic factor. The expression of four or more of the examined proteins was significantly correlated with a poor prognosis, even after adjusting for the stage. Currently, the prognostic value of a single gene marker in CRCA is very controversial, but based on these results, we believe that the number of expressed genes/proteins may be helpful in identifying patients with both early-stage cancer and a potentially poor prognosis, which will help to determine if adjuvant chemotherapy is necessary.
Clinical implications of polymorphisms in UDP-glucuronosyl transferase (UGT) in patients with metastatic colorectal cancer (mCRC) who were treated with oxaliplatin, irinotecan, and S-1.
Authors: Kim Sun Young , Jang Mi Song I , Kim Hyun Mi , Baek Ji Yeon , Hong Yong Sang , Jung Kyung Hae
Published: February 2017

503

Background: The three-drug regimen with oxaliplatin, irinotecan and fluoropyrimidine is an effective therapeutic option for patients with mCRC, but is associated with high rate of toxicity. Pharmacogenetic profile might be helpful for selection of proper patients for this intensive regimen.

Methods: Forty-two patients were enrolled to our phase II trial and were given irinotecan 150mg/m2 plus oxaliplatin 85mg/m2 on D1 and S-1 80mg/m2/day on D1-14 every 21 days as their front-line therapy for mCRC. Genomic DNA was extracted from peripheral blood, where the presence of germline polymorphisms of UGT including UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A6*2, and UGT1A7*3 were tested.

Results: Patients with UGT1A1*6 allele had a tendency of more frequent grade 2-3 vomiting (p = 0.06) compared to those without UGT1A1*6. The presence of a haplotype containing UGT1A6*2 and UGT1A7*3 was associated with grade 2-3 vomiting (p = 0.014) and grade 2-3 diarrhea (p = 0.063). Higher objective response rate (18/20, 90%) was noted in patients without UGT1A*60 compared to those with UGT1A1*60 (11/22, 50%; p = 0.008). The absence of UGT1A1*60 was also associated with marginally improved progression-free survival (10.3 mo v 7.7 mo, p = 0.081) and overall survival (26.8 mo v 15.1 mo, p= 0.044) compared to the presence of the variant allele.

Conclusions: UGT1A1*6 and a haplotype containing UGT1A6*2 and UGT1A7*3 may be associated with irinotecan-related gastrointestinal toxicities. Phenotypic association of UGT1A1*60 and efficacy of the three-drug regimen requires further investigation.
Estrogen as a prognostic factor on liver metastasis from colorectal cancer.
Authors: Zhang Sen , He Zhen Hua , Zhang Xue Lei , Wu Zhen Jie , Ouyang Jun
Published: February 2017

506

Background: Estrogen plays an important role in some cancer. However, previous studies about the influence of estrogen on colorectal cancer (CRC) have been conflicting, especially rare reports on liver metastasis. This study tries to explore the prognostic impact of estrogen on CRC with liver metastasis.

Methods: Eighty six patients with CRC including 43 synchronous liver metastases were studied. Estrogen receptor-beta (ER-beta) were assayed by immunohistochemistry (IHC) in liver metastasis tissues, colorectal cancer tissues and normal tissues. And the serum estrogens were detected by radioimmunoassay (RIA) in 30 patients with CRC including 14 synchronous liver metastases. After follow-up, the relationship between ERβ, estrogen and survival time were analyzed.

Results: The positive rates of ER-beta in liver metastases tissues, CRC tissues and normal tissues were 39.5% (17/43), 39.5% (34/86) and 62.8% (54/86), respectively; and significant differences were found between liver metastasis (P=0.012) or CRC (P=0.002) with normal tissues. The 1-, 2-, 3-and 5-year survival rates for ER-beta positive patients were 97%, 79%, 71% and 51%, respectively comparing with 82%, 59%, 55% and 40%, respectively for ER-beta negative patients (P=0.190). In contrast, the 1-, 2-, 3- and 5-year survival rates in liver metastasis group were 77%, 37%, 31% and 23%, respectively; and 93%, 64%, 57% and 57%, respectively for ER-beta positive patients comparing with 67%, 19%, 14% and 7%, respectively for ER-beta negative patients (P=0.004). Serum estrogen levels in patients with liver metastases were significantly lower than those without liver metastasis (P=0.012) and Pearson Correlation showed that there was a moderate positive correlation between level of serum estrogen and survival time (P=0.006).

Conclusions: CRC liver metastasis patients with positive ER-beta have a better survival, which indicates estrogen is a protective factor for CRC liver metastasis patients. But more study is needed to show estrogen would be a protective factor for CRC patients.
Association of peripheral blood guanylyl cyclase C (GCC) expressions with prognostic parameters and response to therapy in patients with colorectal cancer.
Authors: Camci Celalettin , Sevinc Alper , Sahin Akif , Kalender Mehmet Emin , Oztuzcu Serdar , Sever Ozlem nuray , Ozyazgan Esma , Demiryurek Abdullah Tuncay
Published: February 2017

508

Background: Guanylyl cyclase C (GCC) is expressed exclusively in normal intestinal mucosal cells, primary and metastatic colorectal cancers (CRC). The aim of this study was to determine the possible association between the GCC expressions in peripheral blood, prognostic parameters and response to chemotherapy in CRC patients.

Methods: Forty-nine metastatic CRC patients and 41 healthy controls with similar age and sex were included to this study. Peripheral blood GCC expressions are measured by the reverse transcriptase-polymerase chain reaction (RT-PCR) method.

Results: No GCC expression was measured in healthy controls but GCC expressions of the patients were detectable. Although there was a significant reduction in GCC expressions in 30 patients with regression (from 5.46 ± 4.12 to 0.06 ± 0.03, p < 0.0001), marked increase in GCC expressions was observed in 19 patients with progression following chemotherapy (from 0.43 ± 0.19 to 1.38 ± 0.52, p = 0.0174). Significant correlation was found between the GCC expressions and carbohydrate antigen 19-9 (CA19-9) levels (p = 0.0041) in 30 patients with regression before chemotherapy. Marked correlation was also detected between the GCC expressions and carcinoembryonic antigen (CEA) levels (p = 0.0072) in 19 patients with progression before chemotherapy.

Conclusions: The results of the present study suggest that peripheral blood GCC expressions along with CEA and CA19-9 can be used to determine the early respose to chemotherapy in patients with metastatic CRC. These findings imply that higher expression of GCC in peripheral blood seems to be an indicator of good therapeutic response to chemotherapy and remission. Monitoring the peripheral blood GCC expressions may allow employing different treatment options to metastatic CRC patients.
The single-nucleotide polymorphism T>C rs4353229 in CASP7 gene and mir-224 as new biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer.
Authors: Villa Guzman José Carlos , Zarate Ruth , Boni Valentina , Gomez A. , De la Haba Juan R. , Bandres Eva , Garcia-Foncillas Jesus , Aranda Enrique
Published: February 2017

513

Background: Oxaliplatin represents a central component of colorectal (CCR) cancer treatment. It is known that the ways in which oxaliplatin is neurotoxic include not only DNA damage, but also the modulation of specific molecules, such as caspases 3 and 7, involved in regulating the cellular equilibrium between apoptotic death and the cell cycle. MiRNAs are non-coding RNAs that can block mRNA traslation. Recent evidences indicate that variations in miRNA binding sites may contribute to the susceptibility to CCR. However, the effect of these SNPs on miRNA-target interaction remains to be determined. The SNP T>C rs4353229 in CASP7 gene is binding site of miR-224. We hypothesize that miR-224 and the SNP T>C rs4353229 could be new predictive biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer.

Methods: We examined the SNP T>C rs4353229 in CASP7 gene in 62 patients with advanced CCR. All patients had received first line of chemotherapy based in fluoropirimidines plus oxaliplatin. The Oxaliplatin-Specific Neurotoxicity Scale was utilized to assess oxaliplatin-related symptoms. Time to progresion (TTP) and objetive response rate (ORR) were calculated. Genomic DNA was extracted from peripheral blood and genotyped by allelic discrimination. We explored the possible correlation of rs4353229 with neurotoxicity, DCR and TTP using and Chi-cuadrado test and Kaplan-Meier model (log rank) respectively.

Results: SNP distribution was 3,2% (ancestral homozygous CC), 46,7% (variant homocygous TT) and 43,7% (heterocygous CT). Median TTP was 10 months (IC95%: 7,4-12,5); regarding CASP7 polymorphism, there were not differences (p=0,41; log rank). ORR was 64,5% and there are not differences between CC, CT and TT patients (p=0,50). Fifteen patients experienced neurotoxicity grade III/IV (24,19%) and it was correlated significantly with ancestral homoygous CC patients (p=0,003).

Conclusions: The SNP T>C rs4353229 in CASP7 gene and miR-224 may be new candidates predictor of oxaliplatin-induced neurotoxicity. Further characterization of CASP7 SNPs and miR-224 may open new avenues for the study of cancer and therapeutic interventions.
High-resolution melting analysis (HRMA) for KRAS mutational study in patients with metastatic colorectal cancer (mCRC pts).
Authors: De Stefano Alfonso , Malapelle Umberto , Carlomagno Chiara , Bianco Roberto , Marciano Roberta , Cimminiello Carolina , Colantuoni Maria , De Placido Sabino , Troncone Giancarlo
Published: February 2017

515

Background: The use of anti EGFR monoclonal antibodies cetuximab and panitumumab is restricted to KRAS wild-type (WT) mCRC pts. Standard method for KRAS testing is direct sequencing. To overcome its limited sensitivity, novel techniques have been developed. However there is little concordance on the clinical significance of more sensitive tests. HRMA is very sensitive and economic and allows rapid detection of DNA sequence variations based on specific sequence-related melting profile. Here we report the evaluation of therapeutic effects of cetuximab in direct sequencing tested WT pts, according to their HRMA mutational status.

Methods: We retrospectively evaluated 50 (35 males, 15 females) mCRC pts with WT KRAS status by direct sequencing. Median age was 61 years (range 29 – 77). Most (40%) pts had liver metastases and 24% had multi-organ disease. They received second- or third-line cetuximab-containing chemotherapy, with irinotecan (n=25) or with combination regimen (22 FOLFIRI and 3 FOLFOX). Twenty-eight pts were treated in second-line and 22 in third-line. KRAS mutation status was reassessed in all pts using HRMA.

Results: All 50 pts were evaluated for tumor response, PFS and OS. In 4 (8%) pts, KRAS mutations were only identified by HRMA. The response rate of HRMA KRAS WT pts was 28.3%, with 1 complete (2.2%) and 12 partial (26.1%). No response was observed in HRMA KRAS MT (3/4 with a progression as best response). Stable disease rates were 30.4% (14/46 pts) and 25% (1/4 pts) in HRMA WT and MT cases respectively. Disease control rate (objective responses plus stable disease) was 58.7% in HRMA KRAS WT pts and 25% in HRMA KRAS MT. No significant correlation was found between HRMA-KRAS status and response rate (p=0.287) or disease control rate (p=0.219). However, median PFS (5.1 versus 2.5 months; HR=0.34, p=0.04) and median OS (11.3 versus 3.2 months; HR=0.11, p=0.03) were significantly longer for HRMA KRAS WT pts compared to HRMA KRAS MT.

Conclusions: These data show a significant difference in clinical outcome between HRMA KRAS WT and MT pts receiving a cetuximab-containing second- or third-line treatment, suggesting that techniques more sensitive than direct sequencing could better select pts for cetuximab-based treatment.
Association of temporary blood pressure drop after bevacizumab administration with clinical course of advanced colorectal cancer.
Authors: Kanai Masashi , Ishiguro Hiroshi , Mori Yukiko , Kitano Toshiyuki , Nishimura Takafumi , Matsumoto Shigemi , Yanagihara Kazuhiro , Chiba Tsutomu , Toi Masakazu
Published: February 2017

528

Background: Hypertension is a common adverse event of bevacizumab and recent data demonstrates that this event is associated with a better clinical course. However, a blood pressure drop after bevacizumab administration and its clinical significance have not yet been reported.

Methods: Between August 2007 and October 2010, 85 patients with colorectal cancer underwent palliative chemotherapy using bevacizumab at Kyoto University Hospital. For these patients, we obtained data using both the designated database system (CyberOncology, CyberLaboratory Co. Ltd., Ibaragi, Japan) and the hospital’s electronic medical records system on blood pressure values at 0 min (before administration), at 90 min and 180 min after the initiation of bevacizumab during the first three cycles of bevacizumab treatment. Out of the 85 patients, there were 81 for whom two or more sets of blood pressure data from the first three cycles were available. Therefore, we retrieved data from a total of 162 bevacizumab administrations in 81 patients (data from 2 separate administrations per patient).

Results: Twenty-five patients (30%) demonstrated an average temporary drop of 20 mm Hg or more in systolic blood pressure between 0 and 90 min. We classified these 25 patients as group A and the others as group B. In group A the mean blood pressure drop between 0 and 90 min was 25 and 30 mm Hg in the first and second monitoring, respectively, compared with 3 and 5 mm Hg in group B. There were no significant differences between the 2 groups in their baseline characteristics. Interestingly, median time to treatment failure (TTF) was significantly longer in group A compared to group B (291 vs. 162 days; hazard ratio, 0.53; 95% CI, 0.31 – 0.89; P = 0.02). Furthermore, the proportion of patients who required intervention with antihypertensive drugs during bevacizumab treatment was significantly higher in group A compared to group B (36% vs 4%; P < 0.01).

Conclusions: Our current study suggests that a temporary blood pressure drop after bevacizumab administration could be a predictive marker for bevacizumab treatment.
Effectiveness and safety of second-line (2L) irinotecan- and oxaliplatin-based regimens after first-line (1L) bevacizumab (BV)-containing treatment (tx) for metastatic colorectal cancer (mCRC): Results from the ARIES observational cohort study.
Authors: Bekaii-Saab Tanios S. , Grothey Axel , Bendell Johanna C. , Kozloff Mark , Cohn Allen Lee , Mun Yong , Fish Susan , Flick Elizabeth Dawn , Dalal Darshan , Hurwitz Herbert
Published: February 2017

535

Background: Prior ARIES analyses showed that BV-treated mCRC patients (pts) receiving chemotherapy (CT)/biologics + BV within 2 months (mo) after 1st progressive disease (PD) had longer post-progression survival (PPS) than pts receiving only CT/biologics. The present analysis evaluated whether this effect of BV was consistent when used with common 2L CT regimens— irinotecan- (iri-) and oxaliplatin- (ox-) based—in mCRC pts exposed to 1L BV in ARIES.

Methods: ARIES enrolled mCRC pts receiving 1L CT + BV. No tx regimens or assessments were protocol specified. This analysis evaluated 1L BV-treated mCRC pts who had PD, survived ≥2 mo after PD, and received 2L iri- or ox-based tx. PPS was estimated by Kaplan-Meier methods. Cox regression was used to estimate hazard ratios (HRs), while adjusting for covariates (eg, 1L time to progression).

Results: Of 1550 1L pts in ARIES, 1074 had 1st PD and survived ≥2 mo after PD. Of these 1074, 390 and 114 received 2L iri- and ox-based tx, respectively, ± BV ( table ). Baseline characteristics were generally similar between groups. The incidence of targeted adverse events (TAEs) was as expected and similar between the BV and No BV groups over time. In pts receiving 2L iri- or ox-based CT tx, PPS in BV-treated pts was longer compared to those not on BV. Analyses may be limited by small pt numbers in some groups.

Conclusions: Consistent with prior ARIES analyses, the continued use of BV after 1st PD was associated with prolonged PPS regardless of the 2L CT backbone used.

[Table: see text]
A 21-year analysis of lymph node trends in colon cancer: Do quality measures really matter?
Authors: Hari Danielle M. , Stojadinovic Alexander , Chiu Connie G. , Leung Anna M. , Sim Myung-Shin , Bilchik Anton J.
Published: February 2017

539

Background: Lymph node (LN) number has been endorsed as a quality measure (QM) in colon cancer (CC) because of the impact on survival. However, the current mandate requiring > 12 LNs has been questioned. We evaluated whether compliance of this QM has improved and whether this has impacted overall survival (OS).

Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to identify patients (pts) with pathologically confirmed, localized and regional CC (Stage I-III) diagnosed between 1988 and 2008. Interval trends in lymph node (LN) harvest and OS were evaluated over time (Year Strata (YS): 1988-1993, 1994-1998, 1999-2003 and 2004-2008).

Results: For pts with local and regional CC, 181,035 had confirmed LN examinations. For Stages I-III, there has been a dramatic improvement in compliance for pts with > 12 LNs harvested over the recent two 5-yr periods (19, 21, 18% respectively, p<0.0001) whereas previously only a 5-7% increase occurred over time (see Table ). This rise in compliance had the greatest effect on the increased survival trend for stage II CC with minimal change for those with Stage I and Stage III CC. Irrespective of LN examined there has been a significant increase in OS for all stages over time (p<.0001).

Conclusions: In the largest time-dependent assessment of lymph node examination in colon cancer, significant improvements in surgical quality measures have occurred over the past decade for Stage I, II and III. These measures have translated into improvements in overall survival particularly for Stage II disease. Lymph node yield alone is not an adequate quality measure for patients with stage I and III colon cancer.

[Table: see text]
Association of NCCN guideline adherence with improved survival in high-risk stage II and stage III colon cancer.
Authors: Boland Genevieve Marie , Chiang Yj , Chagpar Ryaz , Xing Yan , Hu Chung-Yuan , Feig Barry W. , Chang George J. , You Y. Nancy , Cormier Janice N.
Published: February 2017

543

Background: Evidence-based treatment guidelines have been proposed as a quality metric for cancer care. There is significant variability in the treatment of high-risk stage II (defined by tumor depth, histologic grade, margin status, and # of nodes retrieved) and stage III colon cancer patients in the National Cancer Database (NCDB). This study examines whether adherence to guidelines is associated with improved outcomes.

Methods: Patients with colon adenocarcinoma (1998-2002) were identified from the NCDB. The stage-specific NCCN guidelines were used to classify patients into two groups based on adherence to guidelines (adherent or non-adherent). Overall survival (OS) and relative survival (RS) were calculated for both groups. Relative survival was used as a surrogate for disease-specific survival and calculated using the methods of Dickman et al.

Results: A total of 77,350 patients were included in the analytic cohort. Stage-specific outcomes were compared and stage is an independent predictor of survival. As reported in our previous analyses, nonadherence as a result of omission of chemotherapy, was noted in 64.3% and 26.4% of high-risk stage II and stage III patients, respectively. Nonadherence was associated with decreased OS and RS with a hazard ratio for death of 1.43 (95% CI: 1.33, 1.54) for high-risk stage II and 1.89 (95% CI: 1.82, 1.95) for stage III (p < 0.001, Table) RS. Additionally, regression analysis demonstrated that gender, age, race, insurance, income, and type of facility were associated with differences in RS.

Conclusions: Guideline-based practice, particularly for high-risk stage II and stage III colon cancer, is associated with improved survival outcomes. Therefore, these guidelines may be appropriate as a metric of performance comparable across various institutions. Additionally, factors associated with deviations from guidelines can be used to focus improvements in the access to and delivery of cancer treatment.

[Table: see text]
What determines adjuvant chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer?
Authors: Chang George J. , Hu Chung-Yuan , You Y. Nancy , Eng Cathy , Rodriguez-Bigas Miguel A. , Skibber John Michael
Published: February 2017

546

Background: The treatment standard for rectal cancer patients after neoadjuvant chemoradiotherapy (CXRT) and radical resection includes adjuvant chemotherapy (CT). The purpose of this study was to evaluate patient demographic and clinicopathologic characteristics in relation to adjuvant CT use.

Methods: A retrospective cohort study of patients ≥ 65 years old with rectal cancer treated by neoadjuvant CXRT and radical resection in the Surveillance, Epidemiology, and End Results-linked Medicare database (1998-2007, Medicare Part A/B only) was performed. Multivariate logistic regression was used to assess CT utilization in relation to patient, tumor and treatment response characteristics.

Results: Among 1344 patients who met study criteria, 748 (55.6%) received adjuvant CT with 5-fluorouracil (FU) including 189 (25.3%) who also received oxaliplatin (Ox). ypStage was the strongest determinant of both any post-operative CT (43.1% stage I, 51.3% stage II, 73.4% stage III). Other associated factors included age, comorbidity, marital status and surgery type. In addition, age, socioeconomic status, and grade were associated with Ox use. These effects persisted even after exclusion of patients with comorbidities.

Conclusions: Although standard treatment guidelines for locally advanced rectal cancer include postoperative CT for all patients after neoadjuvant CXRT and radical resection, nearly 1 in 2 patients failed to receive adjuvant CT. Despite the absence of established evidence, treatment decisions appear to be influenced by the findings at surgical pathology.

[Table: see text]
A randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: The LARCID trial.
Authors: Hoff Paulo Marcelo , Saragiotto Daniel Fernandes , Barrios Carlos H. , Del Giglio Auro , Coutinho Anelisa Kruschewsky , Andrade Aline C , Dutra Carolina , Forones Nora , Correa Mariangela , Portella Maria Socorro , Passos Vanessa Q. , Chinen Renata N , van Eyll Brigitte
Published: February 2017

549

Background: Chemotherapy-induced diarrhea (CID) is a relatively common adverse event in the treatment of colorectal cancer patients. The LARCID trial evaluated the efficacy and safety of long-acting release octreotide (octreotide LAR) for the prevention of CID in this population.

Methods: Colorectal cancer patients starting adjuvant or first-line treatment with a chemotherapy combination containing fluorouracil (5-FU), capecitabine and/or irinotecan were randomized to receive octreotide LAR, 30 mg intramuscularly every 4 weeks, (experimental arm) or the physician’s treatment of choice in case of diarrhea (control arm).

Results: A total of 139 patients were randomized, most of which received 5-FU- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n=68) and 78.9% in the control group (n=71). Treatment with octreotide LAR did not prevent nor reduced the severity of CID. Treatment choices for diarrhea management included loperamide in the majority of cases. No benefit from octreotide LAR was identified in terms of need for diarrhea treatment, opioids, or intravenous hydration, nor in the rate of hospitalization, or quality-of-life.

Conclusions: Octreotide LAR is not indicated for the prevention of CID.
Effect of postoperative complications on adjuvant chemotherapy use in stage III colon cancer.
Authors: Merkow Ryan P. , Bentrem David J , Chow Warren B. , Cohen Mark E , Ko Clifford Y. , Bilimoria Karl Y.
Published: February 2017

551

Background: The National Quality Forum has endorsed the use of adjuvant chemotherapy in stage III colon cancer yet a substantial treatment gap exists in the United States. Our objective was to evaluate the contribution of postoperative complications on the use of adjuvant therapy after colectomy for cancer.

Methods: Patients from the ACS NSQIP and the NCDB who underwent colon resection for cancer were linked (2006-2008) to create a novel dataset containing robust information on comorbidities, complications, and oncologic variables. The association of complications on adjuvant chemotherapy use was assessed using multivariable regression models.

Results: From 140 hospitals, 2414 patients underwent resection for stage III colon adenocarcinoma (open colectomy: 64%, laparoscopic colectomy: 36%). Overall, 896 (37.1%) patients were not treated with adjuvant therapy, of which 116 (12.9%) had documented severe comorbidities or advanced age as the reason for no adjuvant therapy receipt. Of the remaining 780 patients, 202 (25.9%) had a potential complication that could account for not receiving adjuvant therapy: 33 perioperative deaths and 169 patients with ≥1 serious complications including organ space infection (n=32), wound dehiscence (n=12), respiratory failure (n=48), pneumonia (n=45), renal failure (n=22) and septic shock (n=38). The remaining 611 patients did not have a documented reason for not receiving adjuvant chemotherapy. Complications independently associated with decreased adjuvant therapy use were renal failure (OR 0.17, 95% CI 0.0-0.59), respiratory failure (OR 0.23, 95% CI 0.11-0.51) and pneumonia (OR 0.36, 95% CI 0.18-0.75). Organ space infection was not associated with decreased use of adjuvant therapy, but significantly increased time to treatment (69 vs. 45 days, P<0.05). Superficial SSI did not decrease adjuvant therapy use or delay treatment.

Conclusions: Serious postoperative complications explained one quarter of the adjuvant chemotherapy treatment gap among stage III colon cancer patients and should be considered in quality assessment of colon cancer care. Judging provider performance on quality metrics is challenging without clinical data.
Assimilation of evidence-based medicine into clinical practice: Adjuvant radiotherapy in the multidisciplinary treatment of rectal cancer.
Authors: Fitzgerald Timothy Louis , Brinkley Jason , Zervos Emmanuel E. , Wong Jan H.
Published: February 2017

552

Background: Implementation of evidence based standards is recognized to be problematic. Level 1 evidence supports the superiority of neoadjuvant therapy for stage II/III rectal cancer. The purpose of this study was to determine to what extent evidence based medicine has impacted clinical practice.

Methods: Stage II/III rectal cancer patients undergoing surgery from 1998-2007 were identified in the SEER tumor registry using SEER*Stat 6.2. Variables were extracted and analyzed in SPSS; trends were evaluated with regression models and survival with log rank test.

Results: A total of 25,129 patients were identified, 15,769 (63%) were treated with adjuvant radiotherapy. A majority were > 60 years old (56%), white (82.8%), male (60.9%), had stage III cancers (59.2%) and treated with neoadjuvant radiotherapy (54.5%). Significant changes in timing of adjuvant radiotherapy were noted over the study period. In 1998 28.1% of patients were treated neoadjuvantly, this increased to 74% in 2007, a 263% increase. Scatter plot best fit lines intersect in approximately year 2002, p value of trend <0.001. On univarate analysis race (p=0.018), sex (p<0.001), year of diagnosis (p<0.001), age (p<0.001), and stage (p<0.001) were associated increased likelihood of neoadjuvant radiotherapy. Logistic regression found male sex (OR 1.14, p<0.001), year (OR 1.223, p<0.001) and stage II (OR 1.39, p<0.001) were predictors of neoadjuvant therapy. Significant increases in preoperative radiotherapy were observed for all races and cancer stages (p<0.001). There was a significant survival advantage for those treated with adjuvant radiotherapy, median survival 39 vs. 93 months p<0.0001. There, however, was no survival advantage to neoadjuvant vs. postoperative radiotherapy, median survival 94 vs. 93 months, p=0.749.

Conclusions: When adjuvant radiotherapy is utilized, there has been rapid adoption of evidence based standards for Stage II/III rectal cancer. However, substantial numbers of patients are not receiving care recognized to improve outcomes.