bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib study of safety, tolerability, and efficacy of R1507 a monoclonal antibody to IGF-1R in combination with multiple standard chemotherapy regimens in patients with advanced solid malignancies.
Authors: Mahadevan Daruka , Sutton Gregory Ryan , Arteta-Bulos Rafael , Bowden Chris J. , Miller Paul J. E. , Swart Rachel Elizabeth , Walker Mark S. , Munster Pamela N. , Dees Elizabeth Claire , Marshall John , Hamid Omid , Kurzrock Razelle
Published: March 2020

e13574

Background: R1507 is a human IgG1 Mab that binds to the insulin-like growth factor-1 receptor (IGF-1R), implicated in the pathogenesis of several solid tumor types. IGF-1 or IGF-2 activate the IGF-1R and promote anchorage independent growth of malignant cells. A phase 1b study was conducted to establish the safety, tolerability and efficacy of R1507 in combination with multiple standard oncology regimens. Methods: This was an open-label, multi-center study in advanced stage cancer patients (pts). R1507 (3, 5, 9, 10 and 16 mg/kg IV, Q2W or Q3W) was added to 6 treatment regimens: gemcitabine + erlotinib (GE); paclitaxel + bevacizumab (PB); carboplatin + etoposide (CE); mFOLFOX6 + bevacizumab (FB); capecitabine + trastuzumab (CT); sorafenib (S). All arms started with R1507 dose lower than the recommended single agent dose (level -1). If tolerable, R1507 dose was escalated in subsequent cohorts of pts. Accrual to each regimen was dependent on the number of pts developing a DLT at dose level -1. The study used a 3 + 3 + 6 and a 3 + 9 design. Results: N=104 pts enrolled into regimens 1 to 6: 6% new diagnosis, 93% non-recent diagnosis, and 1% not classified. N=18 withdrew for safety [1 death, 17 AEs]. N=80 withdrew for non-safety reasons [n=61 PD, n=17 refused further treatment, n=1 insufficient response, n=1 ‘other’]. A total of 1337 AEs were reported: any grade, across regimens and doses were nausea, diarrhea, and vomiting. N=123 had grade ≥3 AEs (n=28 dose level -1; n=95 dose level 1) in 60 pts that were myelosuppression, fatigue and mucosal inflammation. ORR (partial response [PR] plus stable disease) of evaluable pts across 6 regimens was 36% with 5 PRs: regimens PB (non-small cell lung cancer, nasopharyngeal cancer), CE (melanoma), FB (colon cancer) and S (gastrointestinal stromal tumor: GIST). The GIST pt (>4 prior therapies) had a PR for 3 years. Three pts (breast cancer, melanoma, adenoid cystic carcinoma) were on study for >1 year. 71% pts had SD ≥ 4 months. Conclusions: R1507 added to 6 standard chemotherapy regimens was well tolerated with no significant safety issues. Trial was terminated early due to discontinued development of R1507. Clinical trial information: NCT00811993.
Trabectedin to induce mitochondrial membrane potential dissipation and reactive oxygen species generation in breast cancer cells.
Authors: Atmaca Harika , Bozkurt Emir , Cakar Burcu , Surmeli Zeki Gokhan , Uzunoglu Selim , Uslu Ruchan , Karaca Burcak
Published: March 2020

e13580

Background: Trabectedin (Yondelis; ET-743) is a tetrahydroisoquinoline alkaloid that was originally derived from the marine tunicate Ecteinascidia turbinata and is currently prepared synthetically. It ıs currently used for the treatment of soft tissue sarcomas. It has been shown that Trabectedin provides the production of superoxides near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis, however the apoptotic mechanisms of Trabectedin is still very limited. The objective of this study is to investigate the underlying mechanisms of apoptosis Trabectedin in two human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) and one human immortalized non-transformed breast epithelial cell line (MCF-10A), to see if similar oxidation processes take place in breast cancer. Methods: Cytotoxicity was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation, caspase 3/7 activation. Mitochondrial membrane potential (MMP) was evaluated by TMRE dye. Measurement of reactive oxygen species (ROS) was done by using Glutathione S-Transferase (GST) Assay Kit and CM-H2DCFDA dye. Results: Trabectedin induced the cytotoxicity in breast cancer cells in a time and dose dependent manner. Moreover, it increased DNA fragmentation and the MMP dissipation in tested breast cancer cells. The levels of ROS production in parallel with GST enzyme activity were sharply increased by Trabectedin treatment. Conclusions: This is the first study to investigate the role of Trabectedin activity and mechanisms of apoptosis in human breast cancer cells. These preliminary results might show us a way to use Trabectedin alone, or in combination for breast cancer treatment in near future.
A second-generation DNA-binding pyrrole-imidazole polyamide with antitumor activity.
Authors: Nickols Nicholas George , Yang Fei , Li Benjamin C , Szablowski Jerzy O , Wang Chieh-Mei , Dervan Peter Brendan
Published: March 2020

e13588

Background: Pyrrole-imidazole polyamides are synthetic minor groove binders with programmable sequence recognition. A polyamide that targets the DNA sequence 5’-WGWWCW-3’ (W=A/T) found in the Androgen Receptor (AR) response element inhibits a subset of AR driven transcripts and is cytotoxic in a number of cancer cell lines including LNCaP (prostate cancer), without evidence of DNA damage. Pharmacokinetic studies show bioavailability after intravenous or subcutaneous injection. This polyamide suppressed growth of LNCaP tumor xenografts in mice. However, escalated dosing resulted in significant weight loss that could deter further development. We now report a second-generation polyamide with decreased systemic toxicity that retains efficacy towards LNCaP xenografts. Methods: We investigated the toxicity of our lead polyamide in normal (C57BL/6)mice by necropsy. We then synthesized a focused library of four polyamides that retain the DNA-recognition sequence of our lead molecule, but with chemical substitutions at non-recognition elements. We treated groups of normal male mice (n=4 each) with escalating doses up to 10 mg/kg and observed them for 10 days or until signs of significant distress, after which mice were necropsied. The least toxic polyamide was then tested for suppression of LNCaP xenograft growth (n=14 per treatment arm: 1 mg/kg polyamide versus saline vehicle alone). Tumors were allowed to grow to 200 mm3 prior to treatment by subcutaneous injection every three days for a cycle of six injections. Tumors were then resected and measured. Results: The primary target organ of toxicity for our lead polyamide was the liver, which demonstrated toxicity at 3 mg/kg and dose-limiting toxicity at less than 10 mg/kg. One polyamide in our library demonstrated no evidence of toxicity by necropsy and serum analysis up to 10 mg/kg. This polyamide also suppressed growth of established LNCaP xenografts (T/C: 51%, p=0.0073) at a dose of 1 mg/kg. The other polyamides demonstrated greater toxicity and were not tested further. Conclusions: We report a second-generation polyamide with minimal systemic toxicity in rodents that retains in vivo antitumor activity in prostate cancer xenografts.
Efficacy and safety of every-2-weeks cetuximab combined with FOLFOX or FOLFIRI as first-line therapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC): An Asia-Pacific nonrandomized phase II study (APEC).
Authors: Cheng Ann-Lii , Cornelio Gerardo H. , Shen Lin , Price Timothy Jay , Yang Tsai-Shen , Chung Ik-Joo , Dai Guanghai , Lin Jen-Kou , Sharma Atul , Yeh Kun-Huei , Ma Brigette , Zaatar Adel , Guan Zhongzhen , Masood Nehal , Srimuninnimit Vichien , Yau Thomas Cheung , Sarholz Barbara , Lim Robert S.C.
Published: March 2020

e14501

Background: Randomized studies have shown that weekly cetuximab added to first-line FOLFOX or FOLFIRI improves clinical outcome in patients (pts) with KRAS wild-type (wt) mCRC. This Asia-Pacific multicenter study investigated FOLFOX or FOLFIRI + every 2 weeks cetuximab (C) as first-line therapy in pts with KRAS wt mCRC. Methods: Eligible pts received every 2 weeks cetuximab (d1 500 mg/m2 q14d) with, based on investigator’s choice, either FOLFOX (oxaliplatin 100 mg/m2, folinic acid [FA] 200 mg/m2 L-form or 400 mg/m2 racemic, then 5-fluorouracil [5-FU], as a 400 mg/m2 iv bolus and a 2400 mg/m2 infusion over 46 h) or FOLFIRI (irinotecan 180 mg/m2, FA 200 mg/m2 L-form, or 400 mg/m2 racemic, then 5-FU, as a 400 mg/m2 iv bolus and a 2400 mg/m2infusion over 46 h), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks. Results: Data cut-off was 86 weeks after the date of last patient included. The ITT/safety population comprised 289 pts; 65.1% received FOLFOX + C and 34.9% FOLFIRI + C. Baseline characteristics were generally well balanced. Leukocyte count >10000/mm3was more frequent (16.5% vs 7.9%) and prior adjuvant treatment less frequent (21.3% vs 46.5%) in pts receiving FOLFOX + C. Response (CR or PR) was observed in 170 (58.8%) pts. The overall R0 resection rate was 10.0%. Survival data are not mature. Cetuximab dose intensity was >80% in 77.7% (FOLFOX + C) and 74.3% (FOLFIRI + C) of pts. Most frequent grade 3/4 adverse events (>10% in either arm) were neutropenia, diarrhea, hypokalemia, neuropathy (FOLFOX + C only) and skin reactions. Conclusions: Efficacy and safety profiles of every 2 weeks cetuximab combined with FOLFOX or FOLFIRI were similar to those reported for either chemotherapy plus weekly cetuximab in pivotal studies. Clinical trial information: NCT00778830. [Table: see text]
CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.
Authors: van Engeland Manon , Cleven Arjen , Derks Sarah , Draht Muriel XG , Smits Kim M , Melotte Veerle , Weijenberg Matty P , Herman James Gordon , de Bruïne Adriaan P , Van Criekinge Wim
Published: March 2020

e14503

Background: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here we examine the prognostic impact of promoter methylation in CRC patients treated with surgery alone in the context of microsatellite instability (MSI), BRAF- and KRAS mutations. Methods: 173 CRCs were analyzed for promoter methylation of 19 tumor suppressor- and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 (CL1, 57% (98/173) of CRCs), cluster 2 (CL2, 25% (43/173) of CRCs) and cluster 3 (CL3, 18% (32/173) of CRCs). CL3 had the highest methylation index (0.25, 0.49 and 0.69 respectively, p=<0.01) and was strongly associated with CIMP (p<0.01). After stratification for tumor stage, MSI and BRAF status, no statistically significant differences in survival between CL1, CL2 and CL3 nor between CIMP and non-CIMP CRCs were detected. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, MSS, BRAF wild-type CRCs: HR=3.89 (95% CI =1.58-9.60, p=0.003) and HR=2.21 (95% CI =1.09-4.48, p=0.03) in a second population-based study (n=151). Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF wild-type CRCs.
Comparing KRAS mutation testing by pyrosequencing versus allele specific primary extension methods in colorectal cancer specimens.
Authors: Sampat Keeran Ravin , Patel Nirali , Deal Allison Mary , Weck Karen E , O'Neil Bert H.
Published: March 2020

e14522

Background: KRAS mutation status is an important clinical variable for targeting treatment in metastatic colon cancer. Many community practices send out mutational analysis to laboratories which utilize allele specific primer extension (ASPE) to identify mutations in only codons 12 or 13 of the KRAS gene. Our institutional molecular pathology laboratory performs pyrosequencing (PS) of KRAS codons 12, 13, and 61 which can potentially identify more KRAS mutations. We undertook this study to determine whether there were analytical differences in the results for specific mutations between these techniques. Methods: We obtained 77 sets of paraffin slides from a local practice from patients with metastatic adenocarcinoma of the colon whose KRAS mutation status had previously been analyzed by ASPE. After macrodissection for tumor enrichment, DNA was extracted from unstained paraffin slides and analyzed for KRAS codon 12, 13, and 61 mutations using the PyroMark KRAS v2.0 test. The results of KRAS testing by PS were then compared to those by ASPE. Exact 95% confidence intervals are reported. Results: None of the patients with KRAS codon 12 or 13 mutations called by ASPE (0/77, 0% [0%-4.7%]) changed to wild-type (WT) upon retesting by PS methodology. However, six patients had a discordant result between their ASPE-based testing and PS-based testing (6/77, 7.8% [2.9%-16.2%]). Two patients had differences in the amino acid (AA) at codon 12 (2/77, 2.6% [0.3%-9.1%]). Three patients were found to have a codon 61 mutation (3/77, 3.9% [0.8%-11.0%]), including two patients who were called KRAS WT by ASPE (2/30, 7% [0.8%-22%]). Finally, one patient with a call of a codon 13 mutation by ASPE changed to WT by PS (1/77, 1.3% [0.0% - 7.0%]). Conclusions: Almost 8% of patients who had KRAS testing by PS had a discrepancy in results compared with commercial ASPE testing alone. Although ASPE appears to be very accurate in detecting KRAS mutations, it missed KRAS codon 61 mutations in about 4% of the samples tested. This may have some clinical impact as we learn more about this subgroup of patients in the future.
Association of telomere length with clinical outcomes in patients with colorectal carcinoma.
Authors: Baig Mahadi Ali , Augustine Titto A , Merla Amartej , Atzmon Gil , Budagov Temuri , Goel Sanjay , Maitra Radhashree
Published: March 2020

e14540

Background: Telomeres (T) consist of thousands of copies of TTAGGG tandem repeats capping the ends of the chromosome. T along with enzyme telomerase provides protection against any threats to the genome that might arise as a consequence of “end replication problem”. Studies have linked short TL with premalignant and malignant stages of CRC carcinogenesis. However, the relation of TL to the clinical outcomes has not been conclusively determined. In this study we evaluated the association of TL with clinical outcomes in a cohort of 75 CRC patients. Methods: Tumor DNA was isolated from formalin fixed paraffin embedded specimens. TL was measured by using a qRT-PCR method that provided the relative T copy number, compared to reference copy number of the housekeeping gene, β-Globin, which resulted in a T/S ratio. One T/S ratio unit is equivalent to a mean TL of 4,270 base pairs (BP). Results: From 75 patients, 118 tissue samples were identified (66 primary, 52 metastases, 29 matched pairs). Age at diagnosis (>/< median) had a statistically significant difference in TL (mean BP 4700 vs. 4374; p=0.05) with shorter TL in the advanced age. Females had longer TL compared to men (mean BP 4722 vs. 3669 respectively; p=0.04). Stage at diagnosis (localized Vs Metastatic) had a statistically significant difference in TL (mean BP 4047 vs. 5704; p=0.03). Shorter TL was associated with shorter progression free survival (PFS) for patients treated with cetuximab/panitumumab (3963 vs 5295 p=0.022). Patients treated with cetuximab/panitumumab who had Shorter TL were also found to have significantly decreased Overall Survival (OS) (101.1 Months vs 153.02 Months p<0.0001). We failed to find a difference in the TL between primary and metastatic sites in the 29 patients with paired samples. There was no difference of TL seen with size of the tumor. Furthermore there was no difference in TL between various metastatic sites. Conclusions: TL is a potential biomarker predictive of clinical outcome (OS & PFS) for patients treated with cetuximab/panitumumab. Tumor TL reduces with advancing age and appears to be sex dependent. Further studies to validate TL’s predictive role in patient outcomes are underway.
Management of skin toxicity and cetuximab-based regimen compliance in first-line chemotherapy of metastatic colorectal cancer (mCRC) patients (pts): Results of observer study.
Authors: Pinto Carmine , Di Fabio Francesca , Rosati Gerardo , Lolli Ivan , Ruggeri Enzo , Ciuffreda Libero , Ferrari Daris , Tumolo Salvatore , Rosti Giovanni , Tralongo Paolo , Ferrara Raimondo , Alabiso Oscar , Chiara Silvana , Ianniello Giovanni Paolo , Di Costanzo Francesco , Frassoldati Antonio , Iacono Carmelo , Adamo Vincenzo , Mattioli Rodolfo , Valeri Michele
Published: March 2020

e14557

Background: Cetuximab significantly improves efficacy when added to chemotherapy in mCRC pts. The ObservEr Study evaluated quality of life (QoL), skin toxicity management and treatment compliance of cetuximab-based regimens in first-line treatment of mCRC pts. Methods: ObservEr is a non-interventional, multicenter, prospective study. Primary endpoint is change in QoL during first-line treatment, with focus on the impact of dermatological toxicity. QoL (Dermatology Life Quality Index/DLQI and EORTC QLQ C30) is assessed at baseline and weekly for the first 8 weeks of treatment, then at every evaluation visit until PD or withdrawal. Secondary endpoints are efficacy, rate of liver metastasis resections, incidence of serious adverse events. Results: Between Apr 2011 and Nov 2012, 29 Italian centers enrolled 233 pts, with 226 evaluable pts. Pt characteristics: 152(67.3%) males, 74(32.7%) females; median age 65 (39-81) years; PS ECOG 0-1 95.5%; potentially resectable liver metastasis 59(27.1%); irinotecan regimens 129(57.1%), oxaliplatin regimens 60(26.5%), other regimens 37(16.4%). Median interval between request and result of KRAS test was 10 (6-15) days. Prophylactic skin treatment with vitamin K1 cream was used in 159(70.4%) pts, reactive treatment included vitamin K1 in 59(26.1%). Grade (gr) 1-2 skin toxicity was observed in 128(56.6%) pts, gr 3 in 28(12.4%); no gr 4 was detected. No significant difference in gr 3 skin toxicity was observed between males vs females (13.8 vs 9.5%; p=0.351), age <60 vs ≥60 years (18.1 vs 9.7%; p=0.077), irinotecan vs oxaliplatin regimens (12.4 vs 18.3%; p=0.278), prophylactic vs reactive treatment (15.1 vs 6.8%; p=0.339). Dose reduction, temporary and permanent discontinuation of cetuximab due to skin toxicity was required in 9(4.0%), 32(14.2%) and 7(3.1%) pts respectively; cetuximab compliance ≥70% of dose was reached in 208(92.0%) pts. Conclusions: These results suggest that appropriate skin toxicity management and prophylactic or reactive treatment with Vitamin K1 cream can improve the gr 3 skin toxicity control and the cetuximab compliance. QoL results will be shown at the 2013 ASCO Meeting. Clinical trial information: ID239.
Primary tumor resection to improve survival in patients with metastatic colorectal cancer in the post-2000 era: A California Cancer Registry analysis.
Authors: Rodriguez Fahrni Ana Milena , Gong I-Yeh , Cress Rosemary , Chen Yingjia , Semrad Thomas John , Khatri Vijay P.
Published: March 2020

e14570

Background: Resection of primary tumors in the setting of metastatic colorectal cancer (MCRC) is controversial. Fewer primary tumor resections are being performed due to the improved tumor responses and disease control rates associated with modern systemic therapy. Recent studies suggest a survival benefit for patients with MCRC who had primary tumors resection prior to systemic therapy. This analysis evaluates the independent prognostic impact of primary tumor resection on overall survival (OS) for patients with MCRC using the California Cancer Registry (CCR). Methods: We queried the CCR for all patients with MCRC diagnosed between 2003 and 2010. Patients were categorized by whether or not they had primary tumor resection at time of diagnosis. Covariates included gender, age, race/ethnicity, socioeconomic status (SES), and rural-urban commuting area (RUCA) score of patients. Univariate comparisons were made using the Kaplan Meier method. Multivariate comparisons were performed using the Cox proportional hazards regression method. Results: 19,836 patients met the criteria for analysis of whom 11,566 (58%) had primary tumor resection. Primary tumor resection rates declined over this time period (63% in 2003 v. 52.8% in 2010, p<0.0001), varied by SES (55% v. 62%: lowest versus highest, p<0.001) and residence (63% in rural versus 58% for urban, P=0.0160). On multivariate analysis, overall survival was significantly better for patients that had primary tumor resection (HR: 0.467 [95% CI: 0.467-0.482]; p<0.0001). Survival was statistically longer in younger patients (HR: 1.385 for age 65-75, HR: 2.217 if greater than age 75), highest SES (HR: 0.869, p<0.0001), Hispanics (HR: 0.884, p<0001), and Asian/Pacific Islanders (HR:0.892, p<0.0001). Overall survival was worse for African Africans (HR:1.105, P=0.0001). Conclusions: Our study demonstrates the independent prognostic value on survival of primary tumor resection in patients with MCRC. There is significant variability of resection rates by SES and rural-urban residence. As analysis of CCR data cannot eliminate the influence of patient and provider biases, a prospective randomized trial is warranted.
A multicenter dose-finding study of irinotecan (CPT-11) based on UGT1A1 polymorphisms for metastatic colorectal cancer.
Authors: Sato Hirohiko , Shimada Mitsuo , Kurita Nobuhiro , Iwata Takashi , Yoshikawa Kozo , Miyatani Tomohiko , Kashihara Hideya , Mikami Chie , Matsumoto Noriko
Published: March 2020

e14572

Background: Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity such as severe diarrhea and neutropenia. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Here, we present the final report of prospective trial of safety and efficacy about FOLFIRI ± bevacizumab (Bev) therapy according to each gene type of UGT1A1for Japanese patients with advanced CRC in second-line setting. Methods: Between September 2008 and March 2012, 59 patients were enrolled in this study. Grouping was defined as follows: wild group; both *28 and *6 were wild types, hetero group; *28 and either *6 was hetero type, and homo group; 28/*28 and *6/*6* or a both hetero types. In the 59 patients with advanced CRC treated with FOLFIRI ± Bev as a second line, wild and hetero groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. The incidences of severe toxicities according to gene type of UGT1A1, the response rate and progression-free survival were investigated. Results: In the 59 patients, wild group was 28 (47%), hetero group was 26 (44.1%) and homo group was 5 (8.5%). 8 patients (29%) showed severe toxicities (grade 3 or more) in wild group, 5 patients (19%) in hetero group, 1 patient (20%) in homo group (P=0.71). Regarding the response rate, CR, PR, SD, PD was observed in 1 (4.0%), 1 (4.0%), 5 (20.0%) and 18 patients (72.0%), respectively in wild group, 0 (0.0%), 2 (8.3%), 5 (20.8%) and 17 patients (70.8%), in hetero group, 0 (0.0%), 0 (0.0%), 1 (20.0%) and 4 patients (80.0%), in homo group. The overall response rate (CR+PR) was 8.0% in wild group, 8.3% in hetero group, 0% in homo group (P=0.80). As for progression-free survival, the number of cycle to PD was 12.1 cycles (2-35 cycles) in wild group, 8.3 (2-20) in hetero group, 9.8 (6-14) in homo group (P=0.15). Conclusions: The dosages of 150mg/m2 irinotecan in hetero group, 100mg/m2 in homo group are safe and effective in FOLFIRI ± Bev therapy in the second line. Clinical trial information: UMIN000004773.
Quality of life in a multicenter phase II trial of metastasectomy for intra- and extra-hepatic metastases from colorectal adenocarcinoma.
Authors: Wei Alice Chia-chi , Serrano Aybar Pablo Emilio , Cleary Sean P. , Coburn Natalie G. , Greig Paul David , Law Calvin , Moulton Carol-anne , Gallinger Steven
Published: March 2020

e14573

Background: The combination of intra- and extra-hepatic metastases (IHM and EHM) from colorectal cancer (CRC) has traditionally been considered a contraindication for surgery. Currently there is a growing interest in resecting IHM and EHM. The purpose of this study was to evaluate the health related quality of life (HRQoL) of patients with IHM and EHM from CRC undergoing complete metastasectomy. Methods: Participants with any number of CRC IHM and up to 3 foci of EHM, resectable with RO intent were eligible for the HRQoL component of a Phase-II multi-institutional trial. The effects of therapy on HRQoL were evaluated using: EORTC-QLQ C30, EORTC-LMC21 and FACT-HEP at baseline, prior to surgery and at 4, 8 and 12 months following complete metastasectomy. Results were compared to baseline. >10% mean score change was considered a minimally important clinical difference (MICD). Results: Twenty-five participants were enrolled with a median age: 57 (range: 32-84) years. Protocol surgery was completed in 18/25 (72%) including 11/25 (44%) staged resections. Perioperative morbidity and mortality was 11/25 (44%) and 1/25 (4%), respectively. Median disease-free survival was 6 (range: 0-17) months. 22/25, 88% participants underwent perioperative chemotherapy. EORTC-QLQ C30 Global-HRQoL remained statistically and clinically unchanged compared to baseline at 4 and 8 months but had a MCID decrease at 12 months (mean score change: 15.3) that was not statistically significant. This was associated with a significant decrease in social and role functioning and an increase in fatigue, pain and dyspnea. FACT-Hep score was statistically lower at 4 months post surgery, without reaching a MICD. There was no difference in any of the subscales analyzed in regards to sex, age or the presence of peri-operative complications. Conclusions: Aggressive metastasectomy of multi-site CRC is feasible and safe. Despite disease recurrence in the majority of patients there was no significant deterioration of Global HRQoL as a result of treatment. There was a transient effect on symptoms including fatigue, pain dyspnea and role functioning, which improved by 12 months. Clinical trial information: NCT00606398.
Lung and colon cancer costs among chemotherapy patients after an FDA policy change.
Authors: Stroupe Kevin , Tarlov Elizabeth , Weichle Thomas , Zhang Qiuying , Lee Todd , Michaelis Laura Christian , Durazo-Arvizu Ramon , Ozer Howard , Hynes Denise Marie
Published: March 2020

e14578

Background: Emerging evidence of adverse events from erythropoietin-stimulating agents (ESAs) led FDA to add a black box warning to ESA labeling in March 2007, after which ESA use declined. We examined the impact on healthcare costs for lung and colon patients receiving chemotherapy in Department of Veterans Affairs (VA) healthcare facilities. Methods: Patients were newly diagnosed with lung or colon cancer during 2002-2008, had at least 2 chemotherapy visits, and did not have kidney disease. For each patient, we defined a chemotherapy episode as the time beginning with the first chemotherapy visit and ending with the last visit before a break of 90 days with no chemotherapy. We calculated outpatient anemia management (ESA and transfusion), cancer-related, and total healthcare costs from 30 days before to 90 days after the chemotherapy episode. We compared costs between patients with chemotherapy episodes before (PRE) and after (POST) March 2007 using multivariable regression analyses controlling for patient and facility characteristics. Costs were adjusted to 2010 dollars using the consumer price index. Results: There were 16,828 study patients: 13,630 lung and 3,198 colon. POST-period ESA use was markedly lower than PRE-period use for both groups (lung, 23% vs. 39%, P<0.01; colon, 11% vs. 23%, P<0.01). More lung cancer patients received transfusions in the POST than the PRE period, though the increase was small (27% vs. 25%, P=0.04). Consequently, adjusted POST-period anemia treatment costs were lower (lung, $526 lower, P<0.01; colon, $504 lower, P<0.01). Cancer-related and total costs were nonetheless higher in the POST period, due primarily to higher outpatient costs (adjusted cancer-related costs: lung, $4,500 higher, P<0.01; colon, $10,343 higher, P<0.01; adjusted total costs: lung, $4,706 higher, P<0.01; colon, $11,414 higher, P<0.01). Conclusions: Outpatient anemia management costs were lower during the period after the FDA policy change. There was no substitution effect of transfusion in place of ESAs. These declines in anemia management costs were not enough to offset the higher cancer-related costs, resulting in higher total healthcare costs.
Dachshund 2 protein, a novel neuroendocrine marker associated with favorable tumor characteristics and clinical outcome in colorectal cancer.
Authors: Wangefjord Sakarias , Brunnstrom Hans , Nodin Bjorn , Uhlen Mathias , Eberhard Jakob , Jirstrom Karin
Published: March 2020

e14580

Background: The dachshund (DACH) gene encodes a nuclear protein and transcription factor that regulates metazoan development of eyes, limbs, brain, gonads and endocrine tissue. DACH2, one of two human homologues, has recently been identified as a marker of poor prognosis in epithelial ovarian cancer, but its further role in tumorigenesis and expression in normal and cancerous human tissue has not been described. Methods: In this study, immunohistochemical expression of DACH2 was evaluated in tissue microarrays with tumours from 539 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Chi Square and Spearman’s correlation tests were used to explore the associations between DACH2 expression, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between DACH2 expression and cancer specific survival (CSS). Furthermore, given its distinct expression in various endocrine normal tissues and tumours in the Human Protein Atlas, we also compared DACH2 expression with a standard panel of neuroendocrine markers in 20 carcinoid tumours. Results: DACH2 expression correlated negatively with TNM-stage, differentiation grade, vascular invasion and microsatellite instability, and positively with older age, distal tumour location and expression of p27, cyclin D1, p53 Ki-67 and beta-catenin. DACH2 expression was significantly associated with an improved CSS in the whole cohort and in cases with tumour located in the colon but not rectum. These associations did however not remain significant in multivariable analysis, adjusted for established clinicopathological factors. Furthermore, DACH2 was highly expressed in all examined carcinoid tumours, with a better diagnostic performance than the majority of established markers. Conclusions: Our findings demonstrate a strong link between DACH2 expression and favourable clinicopathological characteristics and outcome in CRC. Moreover, DACH2 is abundantly expressed in neuroendocrine tumours, and its utility as a diagnostic tool for this entity warrants further study.
Biweekly gemcitabine and capecitabine in heavily pretreated patients with metastatic colorectal cancer (mCRC).
Authors: Solis Hernandez Maria Del Pilar , Jiménez Paula , Faez Garcia Laura , Alvarez Fernandez Carlos , Pérez Arnillas Quionia , Rodriguez Rubi David Jose , Ruiz Ana Lucrecia , Sánchez Lorenzo Luisa , Li Torres Walter Antonio , Uriol Esther , Menendez Prieto Maria Dolores , Vieitez de Prado Jose Maria
Published: March 2020

e14617

Background: Some patients with mCRC are still susceptible to continue with active therapy after progression to fluoropyrimidines, oxaliplatin, and irinotecan regimens due to their good performance status. Preclinical and clinical trials suggest that gemcitabine and fluoropyrimidines are synergic antimetabolites. Their major mechanism of action is to incorporate dFdCTP into DNA and to introduce FUTP into RNA, respectively, affecting their processing and function. This study aims to describe patients profile and response to gemcitabine-capecitabine (GemCap) in heavily pretreated mCRC, and so possible predictive factors for survival. Methods: Between June 2001 and July 2011, 119 evaluable patients pretreated with oxaliplatin and irinotecan regimens were enrolled: ECOG 0-1 97%, male 68%, median age 63yo, range: 36-79, rectum 57%, 3rd line: 61%. Patients received Gem 1000 mg/m2 d2 and Cap 1000 mg/m2BID x 7d q2w. Survival analysis was determined by Kaplan-Meier and log-rank test. Results: ORR and clinical benefit were: 5% and 36%. Median PFS and OS were 2.83m (0.43-35) and 6.53m (0.47m-10yrs in patient with complete response). Most frequent toxicities were anemia (22%), thrombocytopenia (10%), hand-foot syndrome (9%) and grade ≥3 were diarrhea in 5%. There were no treatment-related deaths. Predictive factors for PFS and OS are shown in Table. Statistic significance was registered in favor of clinical benefit achieved and for those who had not previously received monoclonal Abs, for SLP and OS respectively. Moreover, patients under 65yo tend to have a better survival. Conclusions: These data suggest GemCap is a tolerable regimen that achieves maintained responses for non selected heavily preated mCRC patients, especially in those reaching radiological clinical benefit, without previous use of monoclonal Abs and younger patients. [Table: see text]
Pathway redundancy and feedback loop as drivers of nonresponse in colorectal cancer treatments.
Authors: Kim Hee Cheol , Kim Phillip Sangwook , Lee Jeeyun , Park Joon Oh , Lee Tani Ann T. , Liu Xinjun , Park Se Hoon , Kuller Anne , Singh Sharat , Kang Won Ki , Park Young Suk
Published: March 2020

e14626

Background: There is urgent need for rational therapy selection based on functional-pathway characterization to achieve significantly improved clinical outcome. Methods: 207 CRC patients were evaluated for >100 signal transduction proteins. Receptor tyrosine kinases (RTKs, i.e. ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc) and non-RTKs (Src, FAK, etc) as well as Jak/Stat along with AKT and MAPK pathway proteins were analyzed for their level of expression and activation utilizing Collaborative Enzyme Enhanced Reactive (CEER) immunoarray. In addition to pathway profiling, samples were also molecularly characterized for 14 different mutations within the KRAS, BRAF and PIK3CA oncogenes. Results: Both ErbB/VEGFR driven and ErbB/VEGFR-independent signal transduction activation patterns were observed in the CRC patients with complex redundant pathway circuitry. Phosphorylated RTKs led to downstream AKT and MAPK pathway activation. Various mutations in KRAS, PIK3CA and BRAF were found in 42%, 11% and 4% of CRC patients, respectively. KRAS G12D and G13D mutations were the most frequent mutations. Percent of mutant alleles per input DNA increased in matching metastatic tumors when compared to the primary tumors. While downstream signal transduction via AKT and MAPK pathways were similar in both wild-type and mutant tumors, we observed higher levels of potential compensating non-ErbB driven RTK expression/activation in KRAS mutant patients. A significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Conclusions: CEER-based pathway analysis adds value towards understanding of CRC tumor¡&hibar;s potential response under various clinical scenarios. The comprehensive characterization of pathway redundancy allows for rational selection of a combination of targeted agents. A combination of Erbitux with anti-angiogenic therapy may provide most benefit for patients with concomitant EGFR and VEGFR2 activation. Based on pathway circuitry determined by CEER, clinicians can optimize clinical decisions in selecting more effective therapies that target relevant pathway proteins.
Thrombotic events in metastatic colorectal cancer patients treated with FOLFIRI plus bevacizumab.
Authors: Al-Shamsi Humaid O. , Anjum Mahraz , Al Farsi Abdulaziz Mohammed , Shen Hua , Cook Richard J. , Linkins Lori-Ann , Major Pierre
Published: March 2020

e14630

Background: To determine the incidence and risk factors for thrombotic events (TEs) (arterial and venous) in patients with metastatic colorectal cancer (mCRC) who received Bevacizumab and FOLFIRI (Leucovorin, Fluorouracil and Irinotican ) compared to FOLFIRI alone. Methods: Single institution retrospective study of 450 mCRC patients who received either Bevacizumab plus FOLFIRI or FOLFIRI alone between October 2006 and September 2012. Demographics , TE risk factors and treatment data were abstracted from patients records. Multivariate analysis was used to determine factors that contributed to increased TE incidence. Results: 261 mCRC patients received Bevacizumab plus FOLFIRI ( 64.8 % males , mean Body Mass Index (BMI) 26.1 ) compared to 189 control patients who received FOLFIRI alone ( 61.1 % males ,BMI 27). The incidence of TEs was 15 % (arterial 1.8% + venous 13.2%) in the Bevacizumab plus FOLFIRI group compared to 15.8% (arterial 2.1% + venous 13.7%) in the control groups. Multivariate analysis controlled for age, BMI, gender, malignancy, metastatic sites , line of treatment, and risk factors did not suggest a significant increase in risk of TE associated with Bevacizumab (OR=0.83 95% CI: 0.40 - 1.70; p=0.602). No difference in locations of TEs was observed between both groups . The only statistically significant factor for thrombosis in Bevacizumab group was increased BMI (OR=1.05; 95% CI: 1.01- 1.10; p=0.016). Conclusions: Our data suggest that bevacizumab did not significantly increase the rate of thrombosis in patients with mCRC when added to FOLFIRI. To our knowledge this is the first study reporting the rate of TEs (arterial and venous) in this population.Our data suggest that BMI may be a risk factor for increase risk of thrombosis in patients treated with bevacizumab . Clinician should consider risk factors assessment prior to initiating bevacizumab .
Association of increased levels of stem cell marker ALDH1 with overall survival in metastatic colon cancer.
Authors: Fitzgerald Timothy Louis , Partis William J , Starr Shane , Sigounas George
Published: March 2020

e14635

Background: The clinical relevance of cancer stem cells (CSC’s) in solid organ malignancies is unclear. ALDH1 is thought to be a universal marker of stemness and is expressed in normal and neoplastic stem cells. We sought to determine the effects of stemness, expressed as levels of ALDH1, on survival for similarly staged metastatic colon cancer patients. Methods: Patients with lymph node positive colon cancer and unresectable liver metastasis diagnosed from 2004-2009 were identified. Sections were prepared from paraffin blocks and stained with an ALDH1 antibody. To determine quantitative expression of ALDH1, morphometric analysis with a Nikon microscope, SPOT video camera, and ImagePro software was performed with expression defined as stained area/total area. Ten to twenty randomly selected fields from were assessed. Patients were determined to have high expression of ALDH1 if respective levels were above the mean. Data analysis was performed with JMP. Results: A total of 16 patients were identified, with a median age of 64 years. The majority of patients were female (63%) and black (69%). Few primary tumors were poorly differentiated (25%). Median survival was 21.5 months (range: 1-47). Mean expression of ALDH1 was 0.041+0.01 for normal crypts, 0.031+0.01 for lymph node metastases, and 0.062+0.02 for primary tumors. ALDH1 expression was high in 31.3%, 20%, and 31.3% of patients for normal colon crypts, lymph node metastases, and primary cancers, respectively. Increased expression ALDH1 in tumors was strongly correlated with mortality (p=0.0013) and male sex (p=0.0166), but not with age (p=0.71) or race (p=0.50). Increased expression of ALDH1 in primary tumors was associated with a decreased overall survival, 27 vs. 6 months (p=0.0015). Increased expression of ALDH1 in normal colon crypts and lymph node metastases was not associated with survival, 27 vs. 19 (p=0.18) and 21 vs. 22 months (p=0.35), respectively. Conclusions: Increased stemness in primary colon cancers, expressed as ALDH1 levels, is associated with poor survival for similarly staged metastatic patients. These data suggest that an increase in stem cell fraction predicts a more aggressive clinical course.
DNA mutation frequencies in metastatic small bowel adenocarcinoma (mSBA) in comparison to gastric (mGC), colon (mCC), and rectal cancer (mRC): Continuum or cutpoint?
Authors: Murphy Janet E. , Russo Andrea Lyn , Szymonifka Jackie , Kwak Eunice Lee , Allen Jill N. , Zhu Andrew X. , Blaszkowsky Lawrence Scott , Clark Jeffrey W. , Ryan David P. , Hong Theodore S. , Borger Darrell R.
Published: March 2020

e14636

Background: The small intestine is in continuity with the stomach and colon/rectum. However mGC and mCC/mRC differ in oncogene profiles. No study has evaluated the oncogene profile of mSBA on the continuum of mGC and mCC/mRC. This may give insight into biology and have implications for treatment. Methods: Respective analysis was performed on GI cancer patients who underwent tumor mutational profiling since 2010. Genotyping was performed on formalin-fixed and paraffin-embedded tumor tissue using a multiplexed mutational profiling platform. Here we report results for APC, BRAF, EGFR, IDH1, KRAS, NRAS, PI3K, PTEN, and TP53. Results: We identified 12 patients with mSBA (11/12 with clinical data, 11/12 with genotype data). Median age at stage IV diagnosis was 61.1y (49.3-71.5y). Four patients had duodenal, 3 jejeunal, 2 ileal, and 2 multiple/unknown primary sites. All patients received 5FU and ox, while 8/11 received irino, 5/11 bev, 3/11 cetux, 1/11 regorafenib and 1/11 capecitabine. Two patients had adjuvant RT (both duodenal) while 4/11 received palliative RT. Survival was calculated from the date of stage IV diagnosis until death, with data censored on 2/1/2013. Median survival was 24.0 months (95% CI 6.4 – 60.0 mo). We compared genotype frequencies of mSBA patients (11) with mGC (41), mCC (161), and mRC (64) using Fisher’s exact test for pairwise comparisons. Conclusions: While the small bowel sample size was small, a significant difference in KRAS mutation frequency was found when compared to gastric cancer. No significant differences in mutation frequencies were found when compared with colon or rectal cancer. [Table: see text]
Peripheral immunosuppressive cell levels as predictive marker for the clinical outcome in stage IV colorectal carcinoma.
Authors: Koutoulaki Anna , Zafeiriou Zafeiris , Skalidaki Dimitra , Aggouraki Despoina , Vetsika Kiriaki E , Mavroudis Dimitrios , Georgoulias Vassilis , Kotsakis Athanasios Panayotis
Published: March 2020

e14639

Background: Immune suppressive cells,Myeloid-Derived Suppressor Cells (MDSCs) and T Regulatory Cells (Tregs) have been identified as negative prognostic biomarkers in distinct solid tumors. In colorectal cancer (CRC), increased peripheral levels of MDSCs have been correlated to worse survival (Solito S et al.; Blood 2011). Although Tregs infiltrated in tumors have been associated with favourable clinical outcome (Salama P et al.; JCO 2009), their significance in peripheral blood remains unclear. The aim of the present study was to evaluate the role of these cells in the peripheral blood as a prognostic marker in CRC patients. Methods: Blood sample was collected from 49 CRC naïve patients (Stage IV) prior to 1st line treatment and 33 healthy donors. Flow cytometric analysis of MDSCs (HLA-DR-Lin-/lowCD33+CD11b+) and Tregs (CD3+CD4+CD25 highCD127low/-FoxP3+CD39+) was performed in fresh samples. MDSC and Treg levels of patients and normal controls were analyzed by using unpaired t-test. ROC analysis (area = 0.8539) was used to define high versus low MDSC levels, whereas the median value of Tregs in normal controls was used as a cut-off. Among patients that relapsed, Kaplan-Meier analysis was used to compare time to tumor progression (TTP) with high and low levels of MDSCs and Tregs. Results: The median percentages of MDSCs and Tregs in patients were significantly increased compared to controls (Mann Whitney test: p < 0.0001; p = 0.0111, respectively). MDSCs were positively correlated to Treg levels (Spearman's r2 = +0.408; p = 0.048). Patients with high levels of MDSCs at baseline, but not Tregs (p = 0.7165), relapsed earlier to those with low levels (p= 0.0348; 9.83 vs. 4.93 months, respectively). Conclusions: CRC patients have elevated peripheral levels of immunosuppressive cells. MDSCs seem to be an independent prognostic factor for TTP. The significance of the observed correlation of MDSCs with Tregs and the suppressive mechanisms of these cells will be further investigated. Updated survival data will be presented in an increased cohort of patients.
Use of surgery and chemoradiation in stage II and III rectal cancer: A retrospective comparison of treatment modalities in major insurance types using the NCDB.
Authors: Warlaumont Mary , Brin Lauren , Fuller Timothy , Whittaker Naomi , Silberstein Peter T.
Published: March 2020

e14641

Background: The preferred method of care for stage II/III rectal cancer is trimodal therapy: neoadjuvant chemoradiation plus surgical resection. We aim to compare the treatment practices for patients with stage II/III rectal cancer in major insurance types. Methods: Using data from the National Cancer Database (NCDB), we analyzed the treatment patterns of 91,782 patients diagnosed with stage II/III rectal cancer from 2000-2009. The NCDB includes data from 70% of all U.S. cancer patients. This is the largest study of this kind to date. Results: In stage II/III rectal cancer, patients with private insurance received more trimodal therapy (70.3%) than patients with VA Insurance (56.6%), Medicare (46.9%), Medicaid (66.5%), or no insurance (61.7%) (p<.0001). VA patients received less trimodal therapy than Medicaid or non-insured patients (p<.0001). Medicare patients (26.9%) were treated with surgery alone more often than patients with private insurance (9.8%), Medicaid (10.4%), VAH (12.2%) or no insurance (9.4%) (p<.0001). VA (4.8%) and Medicare (4.3%) patients were more likely to not receive any “First Course Treatment” than patients with private insurance (1.3%) (p<.0001). Patients over 70yo received less trimodal therapy (42.2%) than patients under 70yo (68.9%) (p<.0001) and received more surgery without chemotherapy or radiation (29.3%) than patients less than 70yo (9.2%) (p<.0001). Conclusions: Stage II/III rectal cancer patients with private insurance received more trimodal therapy than VA, Medicare, Medicaid, or uninsured patients. VA patients received less trimodal therapy than Medicaid or uninsured patients. [Table: see text]