bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of microsatellite instability (MSI) status in gastrointestinal (GI) tumor samples tested with comprehensive genomic profiling (CGP).
Authors: Hall Michael J. , Gowen Kyle , Sanford Eric M. , Ali Siraj Mahamed , Kaczmar John , Miller Vincent A. , Stephens Phil , Yelensky Roman , Daly Mary Beryl , Sun James
Published: February 2017

528

Background: PD-1 inhibitor therapy (pembrolizumab) has demonstrated promising activity in MSI-H (MSI-High) colorectal cancer (CRC) and MSI-H non-CRC compared to MSS tumors, supporting MSI as predictive of anti-PD-1/L1 therapy independent of tumor histology. We developed and validated a novel computational method to assess MSI status using next generation sequencing (NGS) data generated from CGP of clinical cases. We then sought to determine the frequency of MSI in a diverse sample of clinical cases of GI tumors previously assayed with CGP (FoundationOne). Methods: To determine MSI status, 114 intronic homopolymer repeat loci (10-20bp long in the human reference genome) with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. Translation of the MSI score to MSI-H or MSS (MSI-Stable) was established using a training data set. Results: Our methodology was validated in 69 samples with MSI status (20 MSI-H, 49 MSS) previously determined by standard clinical testing, either PCR or immunohistochemistry staining. Our concordance was 97% (65/67). We then applied our method to 2545 GI cancers assayed with CGP in the course of clinical care, with small bowel carcinoma having the highest rate of MSI-H (Table). The 3.5% frequency of MSI-H in CRC is lower than expected, possibly attributed to sampling bias against MSI-H CRC in the cohort. In CRC, we discovered significant differences in mutational profile: histone methyltransferase MLL2/3 mutations were enriched in MSI-H CRC (P<0.0001, Fisher’s Exact test), while TP53mutations were enriched in MSS CRC (P<0.0001, Fisher’s). Conclusions: CGP can be used to detect MSI with high accuracy. In addition, application of this approach to the 2545 GI cancers demonstrates the use of CGP to identify differences in mutational profiles between MSI-H and MSS cancers. Broadened application of these methods to more tumor types may provide target enrichment for emerging immunotherapies. [Table: see text]
Clinical outcomes of three-dimensional versus two-dimensional laparoscopic surgery for gastric cancer: A single center, prospective, randomized trial—An interim report.
Authors: Lin Jian-Xian , Huang Changming , Zheng Chaohui , Li Ping , Xie Jianwei , Wang Jiabin , Lu Jun , Chen Qiyue , Cao Longlong , Lin Mi
Published: February 2017

53

Background: Laparoscopic surgery is more challenging compared with open surgery, in part because surgeons must operate in three-dimensional (3D) space through a two-dimensional (2D) projection on a monitor, which results in loss of depth perception. To counter this problem, 3D imaging for laparoscopic was developed. However, there is limited evidence regarding its efficacy and safety. We therefore conducted a phase III, single center, prospective, randomized study to validate the efficacy and safety of 3D laparoscopic gastrectomy for gastric cancer compared with 2D laparoscopic surgery. Methods: The eligible criteria were pathologically-proven adenocarcinoma, 18 to 75 years of age, no history of other malignant tumor, chemotherapy, or radiotherapy, and clinical stage T1-4aN0-3M0 with R0 resection. The primary end point was to determine whether there is a difference in operation time between the two groups. The morbidity and mortality were compared to evaluate the safety of this trial. Results: A total of 196 patients were randomized (97 cases in 3D Group; 99 cases in 2D Group) between January 1, 2015 and August 31, 2015. There were no significant differences between the two groups in clinicopathological characteristics. The mean number of retrieved lymph nodes was similar in the 3D and 2D groups (35.6±14.1 vs. 36.1±13.5 per case). The operation time was similar in 3D and 2D groups (183.6±34.1 vs. 180.0±37.2 min). The blood loss in 3D Group was 59.6±45.6 ml, which was less than that in 2D Group (69.9±62.4 ml) without statistically different. There were no significant differences in times to resumption of activities, first flatus, resumption of soft diet, and post-operative stay between the two groups (P > 0.05, respectively). The morbidity of the 3D and 2D groups were 21.6% (21/97) and 17.1% (17/99), respectively (P = 0.428). There was no patient died during the postoperative stay in both groups. Conclusions: 3D laparoscopic gastrectomy is a safe and feasible procedure for gastric cancer. However, compared with 2D group, there was no so much benefit from 3D laparoscopic gastrectomy for gastric cancer. Clinical trial information: NCT02327481.
Thrombocytosis as a predictor of poor prognosis in colorectal cancer patients.
Authors: Ramjeesingh Ravi , Jones Amie , Orr Christine , Bricks Corey Sean , Hopman Wilma M , Hammad Nazik
Published: February 2017

540

Background: Thrombocytosis has been identified as a prognostic factor in many cancer types including ovarian, breast, and lung cancers. In colorectal cancer (CRC), the literature is divided. Several smaller case studies suggest a negative prognosis in CRC patients with pre-operative thrombocytosis, a larger population study contradicts this. Methods: We performed a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from January 2005 to December 2011. 1304 confirmed CRC patient charts were identified and patient, tumor, blood work and treatment variables were extracted. Results: 1,096 patients had platelet count available at the time of oncology consult. 222 (20.3%) were characterized as having thrombocytosis (>400x109/L). No difference was identified between those with normal and with thrombocytosis with regards to age, sex, comorbidities, and BMI. However, a statistically significant difference was identified when looking at several pathological characteristics. Significantly more patients with thrombocytosis presented with stage 4 disease (p<0.0001). Additionally less early T-stage (T1: p<0.05, T2: p<0.001), lymph node positivity (p<0.05) and LVI (p<0.05) was identified. Univariate analysis identified a significant difference in survival (1yr: 71.6% vs 88.1%, p<0.0001; 2 yr: 58.1% vs 78.1%, p<0.0001; 5yr: 48.2% vs 64.7%, p<0.0001). Multivariate Cox regression analysis, identified a statistically significant effect of thrombocytosis on risk of dying (HR=1.434, C.I 1.153-1.784, p=0.001). A survival difference was primarily identified in the Stage 4 population (1yr: 55.8% with thrombocytosis vs 72.9% with normal platelet count, p=0.0058; 2 yr: 36.0% vs 50.2%, p=0.0388; 5yr: 26.7% vs 32.0%, p=0.4042). There were no differences in the number of metastatic sites or the number of days on chemotherapy to account for the survival difference. Conclusions: Thrombocytosis, at the time of oncology consultation appears to predict a lower chance of survival in CRC patients, especially in the stage 4 population. Further work is required to elucidate the mechanism of action between elevated platelet counts and survival.
Treatment patterns and outcomes in patients with KRAS wild type (WT) metastatic colorectal cancer (mCRC) treated in first line with bevacizumab (B) or cetuximab (C) containing regimens.
Authors: Houts Arthur C. , Ogale Sarika , Sommer Nicolas , Walker Mark Stephen
Published: February 2017

550

Background: Patients with KRAS WT mCRC treated with B or C plus standard chemotherapy backbones had comparable outcomes in the Phase III CALGB 80405 trial; comparative effectiveness in a real-world community setting remains unknown. Methods: This retrospective study examined PFS and OS in a US community sample of adult, KRAS WT, mCRC patients treated 1st line with B or C containing regimens. Medical records from the Vector Oncology and Affiliate Data Warehouse were used. Disease progression was determined from patient charts. OS was measured from start of 1st line treatment until death; patients were censored at the last observed office visit. Results: B and C samples were comparable on patient characteristics (Table). Oxaliplatin-based and Irinotecan-based backbones were used more frequently with B and C, respectively. Median PFS and OS did not differ significantly between B and C, and were of similar magnitude as in CALGB 80405. In Cox models, number of metastatic sites was a significant predictor of PFS and OS, p < 0.01. Outcomes did not differ significantly with different chemotherapy backbones. Conclusions: Consistent with CALGB 80405, 1st line PFS and OS for KRAS WT mCRC patients treated with B or C were comparable in this real-world analysis. Further analyses will focus on treatment sequences. [Table: see text]
A pilot study of AMP-224, a PD-L2 Fc fusion protein, in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic colorectal cancer.
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Pratt Drew , Kleiner David E , Fioravanti Suzanne , Walker Melissa , Carey Stephanie , Figg William Douglas , Steinberg Seth M. , Anderson Victoria , Levy Elliot , Krishnasamy Venkatesh , Wood Bradford J. , Jones Jennifer , Citrin Deborah E. , Greten Tim F.
Published: February 2017

560

Background: AMP-224, a PD-L2 Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not PD-1LO cells which represent the normal activated T cell population. Preclinical studies have documented an increase in antitumor immunity following radiation therapy (RT), but also tumor PD-L1 expression as an escape mechanism. The aim of the study is to evaluate whether inhibition of PD-1/PDL-1 axis could improve anti-tumor immunity effects of RT. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver were treated with SBRT to a site of liver metastasis at 8Gy in a single fraction (DL1) or 8Gy in 3 daily fractions (DL2). All patients received AMP-224 10mg/kg IV beginning Day 1 after SBRT preceded by cyclophosphamide 200mg/m2 (D0). Primary objective was to determine the safety and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Mandatory pre- and post-treatment biopsies were attempted on all patients. Results: N = 17 patients with refractory metastatic CRC were enrolled. N = 2 pts were unevaluable. 6pts were treated at DL1 (8Gy x 1fraction SBRT, AMP-224 10mg/kg q2-weekly) and 9pts were treated at DL2 (8Gy x 3fractions SBRT, AMP-224 10mg/kg q2-weekly) No DLT was encountered. The most common toxicity was fatigue (G1/2) in all patients in DL2. N = 3 patients experienced G2 infusion reaction which responded to standard interventions. 5/15 pts did not complete treatment due to rapid PD. No objective responses have been seen, although N = 6 pts remain on study. Pre- and post-tumor biopsies were performed on 7 of first 11 pts. Conclusions: AMP-224 in combination with SBRT to site of colorectal hepatic metastases is safe and feasible. Preliminarily no objective responses have been seen. Full clinical and correlative data including post-therapeutic radiated and non-radiated tumor biopsies will be presented. Clinical trial information: NCT02298946.
BRAF mutations in patients with large cell neuroendocrine carcinoma of the colon (LCNECC).
Authors: Ganesh Karuna , Raj Nitya Prabhakar , Yaeger Rona D. , Berger Michael F. , Shia Jinru , Reidy Diane Lauren
Published: February 2017

567

Background: LCNECC is a rare, poorly differentiated neoplasm with a median survival of 13 months. The cell of origin, genetic mediators and optimal clinical management of LCNECC are unknown. Current guidelines recommend treatment with platinum and etoposide, but nearly all patients rapidly fail therapy. Identification of actionable genomic alterations in LCNECC may lead to improved outcomes. Methods: We identified 123 patients (1.1%) with LCNECC or non-small cell high-grade neuroendocrine carcinoma of the colon or rectum, out of 11134 colorectal cancers treated at MSKCC from 1991-2015. Genomic testing had been performed on 8 tumors: 5 using mass spectrometry based genotyping of 8 genes and 3 using hybridization exon capture of 341 cancer-associated genes (MSK IMPACT). Results: BRAF V600E mutations were identified in 5/8 (62.5%) LCNECCs. One patient each had KRAS Q61H and G12V mutations. Only 2/8 patients had TP53 mutations. All 5 patients with BRAF V600E mutations had non-regional lymphadenopathy, consistent with the metastatic pattern seen in BRAF-mutant colorectal adenocarcinoma (CRC). One patient, a 52-year old female with metastatic LCNECC, was first treated with cisplatin/irinotecan but progressed after 2 cycles. She was treated with FOLFOX, with dramatic clinical and radiological response lasting 7 months. BRAFV600E mutation was identified, and she was treated with dabrafenib+trametinib with radiologically stable disease at 2 months. In sum, 4/6 evaluable patients treated with first line FOLFOX, and 3/3 patients receiving second line FOLFOX after disease progression on cisplatin-based therapy achieved radiological responses. Conclusions: BRAF and KRAS hotspot mutations are near universal features of LCNECC, suggesting that LCNECC is an ERK driven tumor. BRAF inhibitor therapy was associated with clinical benefit in one LCNECC patient. Mutations in TP53, RB1 and PTEN, frequent in small cell cancer, are uncommon in LCNECC. Moreover, several patients responded to FOLFOX, a standard of care for CRC. Together, the mutation patterns and therapy responses suggest some similarities between LCNECC and CRC. MSK IMPACT analysis of further LCNECCs is underway and will be reported at the meeting.
Molecular mechanism of secondary-resistant for trastuzumab in gastric cancer.
Authors: Iwatsuki Masaaki , Kojiro Eto , Baba Hideo
Published: February 2017

58

Background: The ToGA trial demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2-positive GC. Although trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. The aim of this study was to identify molecular mechanism that regulates the sensitivity of HER2-positive GC cells to trastuzumab. Methods: (i) Establishment of trastuzumab-resistant GC cell: We cultured the HER2-positive cell line in the presence of trastuzumab (ii) microRNA array: We examined the miR expression profile in the parent and resistant cells using miR array analysis. (iii) Identification of novel miR-gene pathway: We focused on miR-223-FBXW7 pathway based on miRarray analysis. Results: (i) We established resistant cell without significant changes in HER2 or p-HER2 in the presence of trastuzumab continuously for 6 months. (IC 50: 0.17 vs. 988.8μg/ml) (ii) We identified 23 miRs up-regulated in the resistant cells as compared with the parental cells. Of these identified miR, 40% miRs are located on 19q13.42. (iii) the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive gastric cancer cell line to trastuzumab through the modulation of apoptosis. Conclusions: This study suggested that the miR-223-FBXW7 pathway can be a crucial clue to the mechanism of resistance to trastuzumab in GC, leading to the development of individualized treatment in clinical practice.
The occurrence of mutant KRAS clones in the blood of RAS wild type colorectal cancer patients: Impact of response or failure under anti-EGFR therapy.
Authors: Berger Andreas W. , Schwerdel Daniel , Welz Hanna , Ettrich Thomas Jens , Moeller Peter , Seufferlein Thomas
Published: February 2017

600

Background: Colorectal cancer (CRC) is characterized by a high level of genetic heterogeneity. In addition, changes in the genetic profile induced by chemotherapy affect treatment results. Acquired resistance of tumors is defined as a result of clonal evolution and clonal selection under systemic chemotherapy. Repeated tumor tissue biopsies are difficult to obtain and cannot be easily used for dynamic monitoring of therapy response or failure due to marked tumor heterogeneity. Promising data for circulating cell-free tumor DNA (ctDNA) as a tool for studying tumor evolution were recently published. Methods: In this study we analyzed ctDNA from patients with metastatic CRC during treatment with anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab/panitumumab). By droplet digital PCR we performed genotyping of CRC tissue and tracking of clonal evolution of the most frequent KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61R, A146T and A59T) in plasma ctDNA. Results: In initial KRAS wild type tumors several mutated KRAS clones occurred in plasma under the course of anti-EGFR-therapy indicating an increasing acquired resistance to the given therapy leading to a disease progression. Some of these mutations declined upon discontinuation of anti-EGFR therapy. Conclusions: Based on these results we hypothesize that the initial state of KRAS wild type situation seems to be restored in some cases. This opens up the possibility to reinduce anti-EGFR therapy in later therapy lines.
Trifluridine to enhance cytotoxicity by DNA mismatch repair deficiency and subsequent MBD4 frameshift mutation in colorectal cancer.
Authors: Suzuki Satoshi , Iwaizumi Moriya , Hamaya Yasushi , Takagaki Kosuke , Osawa Satoshi , Furuta Takahisa , Sugimoto Ken
Published: February 2017

608

Background: TAS-102 is composed of trifluridine (FTD) and tipiracil hydrochloride and was shown to prolong survival of patients with refractory metastatic colorectal cancer (CRC). FTD is the active antitumor component of TAS102 and its metabolite TF-TTP chemically resembles 5FU-derived metabolite FdUTP in that both of them are misincorporated into DNA and lead to cytotoxicity. Several groups have reported that stage II-III colorectal cancer patients with tumors that lost DNA mismatch repair (MMR) function do not derive a benefit from 5-FU based chemotherapy. Although FTD is reported to be misincorporated into DNA, it is not known if MMR deficient CRC cells have chemoresistance for FTD. Methods: We first utilized human colorectal cancer cell lines HCT-116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-retained cells), and compared cytotoxicity for FTD by clonogenic assay. To further analyze if 5FU refractory CRC cells have chemosensitivity for FTD, we established 5FU refractory HCT116 cells by continuous 5FU treatment for 10 month and analyzed cytotoxicity for FTD. Finally we constructed an expression plasmid of truncated DNA grycosylase MBD4, (MBD4tru) by frameshift mutation with MMR deficiency and stably transfected the construct into HCT116 CRC cells and selected HCT116MBD4tru cell clones. The HCT116MBD4tru cells were treated with FTD and analyzed for cytotoxicity by clonogenic assay. Results: In hMLH1-deficient cells, the number of colony was reduced by FTD treatment to a same degree of hMLH1-proficient cells whereas the number of colony by 5FU treatment is higher in hMLH1-deficitent cells than hMLH1-retained cells (p< 0.05). In 5FU refractory cells, treatment of FTD showed cytotoxicity to the same degree of non-5FU refractory cells. Interestingly, HCT116MBD4tru cells led to cytotoxicity with a higher sensitivity than control cells (p< 0.05). Conclusions: FTD induces cytotoxisity independently of MMR status as well as under 5FU refractory condition, and MBD4 frameshift mutation by MMR deficiency enhances FTD sensitivity. These results suggest that FTD may be useful for patients with MSI-H/MBD4 mutant CRC as well as for those with 5FU refractory CRC.
A pooled analysis of the secondary resection for colorectal cancer liver metastases: Comparison of bevacizumab (Bmab) and anti-EGFRs.
Authors: Ichikawa Wataru , Sunakawa Yu , Nakayama Hirofumi , Ikusue Toshikazu , Kaneta Toshikado , Imataka Hiromi , Sekikawa Takashi , Sasaki Yasutsuna
Published: February 2017

610

Background: Systemic chemotherapies can convert irresectable liver metastases (LM) to resectable in some cases of metastatic colorectal cancer (mCRC). Secondary surgical resection is now considered to be a worthwhile therapeutic aim in mCRC with LM. There is a clear correlation between radiological response and secondary resection rate (SRR) (Jones RP et al. Eur J Cancer 2014). However, it remains unclear which monoclonal antibodies contribute the improvement of SRR, Bmab or anti-EGFRs. Methods: We performed a systematic review of literature published between Jan 1998 and Aug 2015 to analyze the relationship between SRR and antibodies in mCRC treated with 1st-line chemotherapy. Phase II or III trials which obtained the information of response rate (RR) and resection of LM were included in this analysis. The RR, SRR, and R0 SRR were compared between Bmab- and anti-EGFR (cetuximab or panitumumab)-containing regimen groups using Mann–Whitney U test. The correlation between RR and R0 SRR was assessed by Spearman's rank correlation coefficient. Results: A total of 40 studies were enrolled: 33 treatment arms from 16 trials for liver-limited disease (LLD) and 31 arms from 24 trials for non-LLD. The result is shown below. No difference was observed in SRR and R0 SRR between Bmab and anti-EGFR groups. In addition, a preliminary analysis showed that RR had significantly positive association with R0 SRR in anti-EGFR group (R2 0.74, P=0.027 for non-LLD; R2 0.88, P=0.018 for LLD) but not in Bmab group (P=0.27 for non-LLD, P=0.12 for LLD). Conclusions: The SRR and R0 SRR were comparable between Bmab and anti-EGFRs, even in mCRC with LLD, while RR correlated with R0 SSR in anti-EGFRs but not in Bmab. These findings warrant validation in ongoing trials to compare the targeted-agents. [Table: see text]
Association of isocitrate dehydorgenase-1 (IDH-1) mutations with elevated oncometabolite 2-hydroxyglutarate (2HG) in advanced colorectal cancer.
Authors: Fallah-Rad Nazanin , Bedard Philippe L. , Siu Lillian L. , Kamel-Reid Suzanne , Chow Helen , Weijiang Zhang , Jang Raymond , Krzyzanowska Monika K. , Razak Albiruni R. A. , Chen Eric Xueyu
Published: February 2017

627

Background: IDH-1 mutations are common in AML, gliomas, and intrahepatic cholangiocarcinoma. The enzyme product of the IDH-1 R132 variant preferentially catalyzes the NADPH-dependent reduction of alpha-ketoglutarate to the oncometabolite R-2-Hydroxyglutarate (R-2HG), resulting in accumulation of R-2HG, relative to its enantiomer, S-2HG. Elevated plasma levels of 2HG and/or higher ratios of R/S have been observed in AML and intrahepatic cholangiocarinoma, but not in gliomas. Only a few cases of IDH-1/2 mutations have been reported in advanced colorectal cancers (CRC). We investigated plasma levels of 2HG and relative ratios of R/S in CRC patients harboring IDH-1/2mutations. Methods: Between 2012 and 2015, 428 patients with advanced CRC were molecularly profiled through the COMPACT and IMPACT programs at the Princess Margaret Cancer Centre. Tumor DNAs were isolated from FFPE archived samples and genotyped using a customized Sequenom panel or Illumina MiSeq TruSeq Amplicon Cancer Panel in a CLIA-certified laboratory. Plasma samples from patients harboring IDH-1/2mutations and 4 gender/age matched control patients were analyzed for 2HG, R-2HG and S-2HG using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC R column. Results: Of 428 patients with advanced CRC, 4 (0.9%) patients were identified to harbor IDH-1 mutation. No IDH-2 mutations were detected. The variants identified were R132C (2 patients), R132S, and R132H. 3 of 4 patients also harbored KRAS mutations. Patients with IDH-1 mutations had higher levels of 2HG (319 ± 102 ng/ml vs 195 ± 43 ng/ml, p = 0.043). The ratio of R/S were 0.44, 0.75, 1.59, and 2.60 in 4 patients with IDH-1 mutations and 1.3, 0.90, 0.41 and 0.67 in 3 patients without IDH-1mutations. Conclusions: IDH-1 mutations are rare in advanced CRC. 3 of 4 patients in our study had concurrent KRAS mutations. Patients with IDH-1 mutations had higher levels of oncometabolite 2HG compared with controls with no difference in R/S ratio.
Evaluation of circulating VEGF based biomarkers in INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG).
Authors: Yip Sonia , Harvie Rozelle , Martin Andrew James , Sjoquist Katrin Marie , Tsobanis Eric , Kang Yoon-Koo , Bang Yung-Jue , Alcindor Thierry , O'Callaghan Christopher J. , Burnell Margot J. , Tebbutt Niall C. , Rha Sun Young , Lee Jeeyun , Cho Jae Yong , Lipton Lara Rachel , Strickland Andrew , Zalcberg John Raymond , Simes John , Goldstein David , Pavlakis Nick
Published: February 2017

64

Background: The INTEGRATE study evaluated activity of regorafinib (REG) v placebo (PBO) in 147 eligible patients with refractory AOGC. REG was highly effective in prolonging progression free survival (PFS). Differences between regions (i.e. Australia New Zealand/Canada (ANZ/CAN) vs Korea) were found in the magnitude of effect, but REG was effective across all regions and subgroups. We report on an exploratory analysis of VEGF biomarkers to identify predictive/prognostic markers. Methods: Protein biomarkers IL8, VEGF-A,-B,-C-D, soluble(s)VEGFR-1,-2-3 were analysed in plasma at baseline (BL) by multiplex immunoassays (Bio-Plex,BioRad) or ELISA (Abnova). Spearman statistics were used to quantify correlations between markers. Wilcoxon Rank-Sum tests were used to compare markers across regions. The prognostic and predictive value of markers was determined using cox proportional hazards analysis of PFS. Results: There were moderate-to-strong correlations between BL levels of IL8 and VEGF-C (ρ = 0.68), IL8 and VEGF-D (ρ = 0.66), VEGF-A and VEGF-C (ρ = 0.68), VEGF-A and sVEGFR-1 (ρ = 0.54); and a modest negative correlation between VEGF-D and sVEGRF-1 (ρ = -0.33). The regions differed according to BL levels of: VEGF-A (higher in ANZ/CAN; p = 0.0015), VEGF-B (higher in Korea; p = 0.0003), VEGF-D (higher in Korea; p <.0001), and sVEGFR-1 (higher in ANZ/CAN; p <.0001). Adjusting for treatment group, there were statistically significant negative associations between PFS and BL IL8 (p = 0.047), VEGF-A (p = 0.037) and sVEGFR-1 (p = 0.045). There was no convincing statistical evidence that any BL plasma biomarker modified the effect of REG. The effect of region on effectiveness of REG was maintained when evaluated in conjunction with BL biomarkers individually and in combination. Conclusions: Highplasma IL8, VEGF-A and sVEGFR-1 may be adverse prognostic factors. A predictive VEGF blood based biomarker remains elusive. A broader biomarker study including markers beyond the VEGF axis and tissue based markers is ongoing. Clinical trial information: ACTRN12612000239864.
How are colorectal cancer (CRC) patients treated following cancer recurrence during follow-up?
Authors: Van Loon Katherine , Hu Chung-Yuan , Cuddy Amanda , Bekaii-Saab Tanios S. , Benson Al Bowen , Hall Michael J. , Lai Lily L. , Nurkin Steven J. , Skibber John Michael , Weiser Martin R. , Schrag Deborah , Chang George J.
Published: February 2017

645

Background: A major goal of surveillance following curative resection for CRC is identification of treatable recurrence. However, there is a paucity of data regarding optimal frequency or duration of surveillance or potential for salvage therapy following detection of recurrence. The aim of this study was to examine treatment patterns following recurrence of CRC. Methods: Patients ≥ 18 years who presented to 8 participating NCCN institutions between 2005-2012 with resected stage I, II, or III CRC were identified. Time to recurrence was determined by the Kaplan-Meier method and descriptive statistics were used to report treatments following recurrence. Results: Of 5653 patients who underwent resection for locoregional CRC (2984 colon, 2669 rectal and rectosigmoid), median age was 60 [IQR: 50-70]. 53.5% were male. With a median follow-up time after diagnosis of 23.5 months (11.0-45.2), 641 recurrences (6.9% local; 93.1% distant) were identified. Median time to local recurrence was 16.1 months [IQR: 12.5-27.3]. Median time to distant recurrence was 15.6 months [IQR: 11.2-23.9]. Among 325 recurrences of a colon primary, 18 (5.5%) were local and 307 (94.5%) were distant; liver and lung were most common sites (30.8% and 13.9%, respectively). Among 316 recurrences of a rectal primary, 26 (8.2%) were local and 290 (91.8%) were distant; lung and liver were most common sites (35.8% and 21.8%, respectively). Of 597 patients who developed a metastatic recurrence, 227 (38.0%) underwent metastectomy (79 liver and 76 lung resections) and 26 (4.3%) underwent ablation. 414 (64.6%) received chemotherapy and 64 (10%) received radiation. 133 (20.7%) died without treatment < 1 year after recurrence. Of 641 patients,113 (17.6%) had synchronous sites of recurrence and 152 (23.7%) developed recurrence at a second site within 12 months. Conclusions: A high rate of metastectomy was observed following detection of recurrence within the NCCN hospitals. However, a significant proportion of patients had a second site of recurrence < 12 months after initial recurrence. Further inquiry into optimal surveillance and management of recurrence for patients following curative resection of CRC is needed. (Support: U10CA180821, CE-1304-6543).
Phase III RECOURSE trial of TAS-102 versus placebo with best supportive care in patients with metastatic colorectal cancer: Geographic subgroups.
Authors: Ohtsu Atsushi , Yoshino Takayuki , Wahba Mona M. , Benedetti Fabio M. , Falcone Alfredo , Garcia-Carbonero Rocio , Tabernero Josep , Sobrero Alberto F. , Peeters Marc , Zaniboni Alberto , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Mayer Robert J. , Van Cutsem Eric ,   on behalf of the RECOURSE Study Group
Published: February 2017

646

Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase inhibitor, tipiracil hydrochloride, at a molar ratio of 1:0.5 (weight ratio, 1:0.471). The efficacy and safety of TAS-102 in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial; enrollment criteria included ≥ 2 prior lines of standard chemotherapy. Primary results of RECOURSE demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (PBO) (hazard ratio [HR] = 0.68 and 0.48 for OS and PFS, respectively; both P< 0.0001). Methods: RECOURSE data were evaluated for efficacy and safety, including rate of hospitalizations, of TAS-102 vs PBO by each geographic subgroup of US, EU, and Japan (JP). Results: Of 768 pts, 99 US (mean age, 60 y), 403 EU (mean age, 62 y), and 266 JP (mean age, 62 y) pts were randomized to receive TAS-102 or PBO. Median OS with TAS-102 vs PBO was 6.5 mo vs 4.3 mo in US pts, 6.8 mo vs 4.9 mo in EU pts, and 7.8 mo vs 6.7 mo in JP pts. HRs for OS and PFS for US, EU, and JP pts all favored TAS-102 (Table). There were no marked differences among the US, EU, and JP subgroups with respect to overall incidence of adverse events (AEs), ≥ Grade 3 AEs, serious AEs (SAEs), or hospitalizations. Conclusions: Similar to the overall RECOURSE population, OS and PFS benefits were observed in each geographic subgroup randomized to TAS-102 vs PBO, with an acceptable safety profile. Clinical trial information: NCT01607957. [Table: see text] [Table: see text]
Outcomes after noncurative locoregional treatment in patients with unresectable metastatic colorectal carcinoma.
Authors: Yang Qiong , Liao Fangxin , Liu Shousheng , Jiang Chang , He Wen-zhuo , Xia Liang-ping
Published: February 2017

654

Background: A curative hepatic or pulmonary metastasectomy for colorectal carcer is a generally accepted procedure. However, the value of noncurative locoregional therapy for unresectable metastatic colorectal carcer was not well defined. Methods: Of 1,174 patients with unresectable colorectal cancer from 2003 to 2014 retrospectively reviewed, 62 patients received curative regional treatment, 290 patients received locoregional therapy, and 822 patients received standard chemotherapy. Propensity score matching was used to adjust the balance of baseline data between locoregional therapy arm and chemotherapy arm. Kaplan-Meier survival analyses were based on data after propensity score matching. Factors possibly influencing survival were evaluated by univariate and subsequently by multivariate analyses. Results: After propensity score matching, 544 patients were included in this study, 272 in locoregional therapy arm and 272 in chemotherapy arm, respectively. Locoregional therapy included metastasectomy, radiofrequency ablation, percutaneous microwave coagulation therapy and radioactive particle implantation. The addition of locoregional therapy to chemotherapy significantly improved the overall survival with median overall survival 38.73 months (95%CI 34.93-42.54 months) in locoregional therapy arm versus 19.8 months (95%CI 18.06-21.54 months) in chemotherapy arm, respectively, p<0.001. 9 factors were associated with overall survival by univariate analysis, which include primary tumor site, initial stage at first diagnosis, pathological grading, target organ of regional treatment, CA199 and LDH at diagnosis of advanced disease, CEA, CA199 and LDH before regional treatment. Furthermore, CEA (>5ng/ml) and LDH (>245U/L) before regional treatment were identified as independent poor prognostic factors by multivariate analysis. Median overall survival according to the presence of 0, 1, or 2 factors was 49.4 months, 35.7 months, and 27 months. Conclusions: Unresectable metastatic colorectal cancer also benefited from locoregional therapy. Two pre-locoregional treatment risk factors could select the patients most likely to benefit from this strategy.
Multiple immunological mechanisms of cancer cachexia in patients with solid tumors.
Authors: Gonda Kenji , Shibata Masahiko , Nakamura Izumi , Ohki Shinji , Kono Koji , Shimura Tatsuo , Takenoshita Seiichi
Published: February 2017

667

Background: Cancer cachexia is a mixed and multiple factorial condition and commonly seen in patients with advanced cancer, and has long been reported that host-immune function is critically participated. Chronic inflammation plays a key role in the progress of malignant diseases and has been reported to relate with immune suppression and nutritional impairment seen in patients with advanced diseases. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 18 normal healthy volunteers and 112 patients with gastrointestinal cancer. These cells were used for the detection of MDSC (myeloid-derived suppressor cells: CD11b+CD14-CD33+) by flow cytometry. PBMC was also used for the PHA-blastogenesis of lymphocytes which is a marker of cell mediated immunity (stimulation indices: SI) and for the production assay of cytokines including IFN-G, IL-6 and IL-10. Serum levels of soluble cytokine receptors including sIL-2R and sTNF-R1, and anti-inflammatory molecules such as IL-10 and IL-1 receptor antagonist (IL-1RA) were also measured. For the evaluation of nutritional status, serum concentrations of rapid turnover protein (RTP) including prealbumin, transferrin and retinol binding protein was measured. NLR (neutrophil/lymphocyte ratio) was calculated and used as a marker of chronic inflammation. Results: The circulating levels of MDSC was significantly increased in esophageal, gastric and colorectal carcinomas than in normal volunteer and significantly inversely correlated with serum concentration of RTP and with SI, and correlated with markers for inflammation. The levels of sIL-2R and sTNF-R1 were increased in patients with gastric and colorectal and inversely correlated with the levels of RTP and SI. In patients with cachexia, serum concentrations of IL-10 were increased and the production of IFN-G was decreased. Conclusions: It is suggested that suppression of cell-mediated immune function exists in patients with cancer cachexia and the immunological mechanisms of nutritional damages in these patients are even partially driven by Th2-dominant condition of CD4(+) cells and MDSC. These complicated mechanisms are also involved in inflammation-related immunological condition such as SIRS and CARS.
Analysis of plasma protein biomarkers from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC).
Authors: Teufel Michael , Kalmus Joachim , Rutstein Mark Daniel , Koechert Karl , Seidel Henrik , Reischl Joachim , Skubala Adam , Vonk Richardus , Wilhelm Scott , Kobina Svetlana , Qin Shukui , Xu Rui-hua , Kim Tae Won , Li Jin
Published: February 2017

672

Background: In the randomized phase 3 CONCUR trial (NCT01584830), regorafenib significantly improved overall survival (OS) and progression-free survival (PFS) vs placebo (PBO) in Asian patients (n = 136 regorafenib; n = 68 PBO) with treatment-refractory mCRC (HR [95% CI]: OS 0.55 [0.40‒0.77]; PFS 0.31 (0.22‒0.44]). Protein biomarker data from the phase 3 CORRECT trial of mostly Western patients with mCRC identified TIE-1 as a potential predictor of clinical response to regorafenib; however, this association was not significant in multivariable analyses. We present an exploratory protein biomarker analysis of patients in CONCUR. Methods: Sixteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in plasma samples collected at study entry from 121/204 (59%) patients (n = 83 regorafenib; n = 38 PBO). Potential predictive and prognostic effects were evaluated. Results: The biomarker cohort was representative of the overall study population in major baseline demographic factors, OS (HR 0.61; 95% CI 0.40‒0.93), and PFS (HR 0.25; 95% CI 0.16‒0.39). Elevated levels of ANG-2 (HR 2.46; p = 0.0016) and VEGF-A (HR 1.38; p = 0.03) were associated with poor OS prognosis; however, no significant association with treatment OS benefit for regorafenib vs PBO was observed for either marker (ANG-2: HR 0.76; p = 0.3307; VEGF-A: HR 0.83; p = 0.20). Elevated levels of five plasma proteins were associated with poor PFS prognosis: ANG-2 (HR 1.73; p = 0.0085), VEGF-A (HR 1.30; p = 0.0308), IL-8 (HR 1.67; p = 0.0014), VWF (HR 2.39; p = 0.0029), and IGF-BP2 (HR 1.71; p = 0.0384). Elevated levels of IL-8 (HR 0.70; p = 0.019), VWF (HR 0.53; p = 0.0312), and IGF-BP2 (HR 0.60; p = 0.0336) showed a modest interaction with regorafenib PFS; however, these results did not reach statistical significance after adjustment for multiple testing (p = 0.0045). Conclusions: None of the plasma proteins analyzed were predictive of regorafenib clinical benefit as measured by both OS and PFS in Asian patients with mCRC. These results, as well as those in CORRECT, suggest that rationally selected protein markers are not suitable to predict treatment benefit of regorafenib. Clinical trial information: NCT01584830.
Safety and efficacy of regorafenib in Japanese patients with metastatic colorectal cancer (mCRC) in clinical practice: Interim result from postmarketing surveillance (PMS).
Authors: Komatsu Yoshito , Muro Kei , Yamaguchi Kensei , Uetake Hiroyuki , Satoh Taroh , Yoshino Takayuki , Nishida Toshirou , Yamazaki Naoya , Takigawa Hajime , Hamada Yoko , Chosa Masayuki , Sunaya Toshiyuki , Yamamoto Yuka , Ito Yuichiro , Watanabe Toshiaki , Sugihara Kenichi
Published: February 2017

680

Background: The oral multikinase inhibitor regorafenib (REG) was approved for unresectable mCRC in Japan in 2013 based on results of the global CORRECT phase 3 trial of 760 patients (pts), which included 100 Japanese pts. A Japanese PMS (NCT01843400) has been conducted since approval, to assess the safety and efficacy of REG for the treatment of mCRC in clinical practice. Methods: Pre-registration was applied in the PMS. Adverse events (AEs), laboratory tests, drug exposure and anti-tumor effects were prospectively monitored for 6 months after initiating REG. One-year survival data was also collected. The target enrollment was 1,250 Japanese pts. Results: A total 1,307 pts were enrolled in the PMS from March 2013 to May 2015. At the interim analysis as of June 2014, 545 pts were evaluable for safety and efficacy: male 59%; age ≥ 65 yrs 48%; Eastern Cooperative Oncology Group Performance Status 0/1/2 40%/51%/9%; KRAS status wild-type/mutant 50%/47%; treatment line of REG 3rd/4th/ ≥ 5th line 33.8%/37.6%/27.7%; initial dose of REG 160 mg/120mg 76%/17%. Drug related AEs were reported in 483 patients (89%). The most common events were hand foot skin reaction [(HFSR) 57%], liver dysfunction [31.8% (including hepatic laboratory abnormalities (15%)], hypertension (28%), platelets count decreased (16%) and fatigue (15%). The incidence of major AEs of any grade typically peaked the first 2 months after starting REG and was relatively stable afterwards. Median time to treatment failure was 2.3 months [range 2.1– 2.4]; median overall survival (OS) was 6.9 months [range 6.0– 7.7]. Exploratory analysis suggested that pts who experienced HFSR had a significantly longer OS than pts who did not (hazard ratio 0.351; 95% confidential interval0.253– 0.488; p < 0.0001). Conclusions: Interim results suggested that the safety and efficacy profile of REG in Japanese pts in clinical practice was consistent with those of Japanese pts in the CORRECT trial. Follow-up and data collection are ongoing. Updated data will be presented. Clinical trial information: NCT01843400.
Impact of first-line bevacizumab therapy on the efficacy of subsequent anti-epidermal growth factor antibodies (anti-EGFR) in metastatic colorectal cancer (mCRC).
Authors: Burge Matthew E. , Wong Hui-Li , Lee Belinda , Tie Jeanne , Kosminder Suzanne , Field Kathryn Maree , Tran Ben , Desai Jayesh , Ananda Sumitra , Gibbs Peter
Published: February 2017

685

Background: The FIRE3 study reported that cetuximab added to first line combination chemotherapy versus the addition of bevacizumab to the same chemotherapy backbone, with a planned switch to the alternative biologic in second line therapy, resulted in improved overall survival. One possible explanation is that the sequence of biologic administration in mCRC impacts on treatment benefit. Examination of the efficacy of anti-EGFR therapy in cohorts where patients have and have not received prior bevacizumab will inform this. Methods: We interrogated our prospective database (ACCORD), which records comprehensive detail on demographics, treatments received and patient outcomes for consecutive mCRC patients in real world practice across multiple institutions in Australia. We included patients receiving 2nd and subsequent line anti-EGFR monotherapy. Disease control rate (DCR) (partial response plus stable disease), progression free survival (PFS) and overall survival (OS) from the start of anti-EGFR were determined as a function of prior bevacizumab use. Results: From a total of 1511 patients treated between 01/10/2002 and 31/12/2014,129 patients treated with single agent anti- EGFR were identified, 75 had received prior bevacizumab. Demographics, performance status and tumour characteristics were similar between the 2 groups. 84% were confirmed KRAS exon 2 wild type. Prior treatment with bevacizumab did not impact DCR (35% vs 40%, p = 0.5065), median PFS (3.0 vs 3.0 months, p = 0.9460) or OS (8.6 vs 8.4 months, HR 0.95, p = 0.8073). Similarly, for bevacizumab treated patients, the time since last dose of bevacizumab to start of anti-EGFR ( < 3 months (n = 26) vs 3-6 months (n = 17) vs > 6 months (n = 32)) did not impact PFS (2.3 vs 3.6 vs 3 months) or OS (8.9 vs 10.1 vs 7.1 months, HR: 0.88, p = 0.82). Conclusions: There was no evident impact of previous bevacizumab treatment, or time from previous bevacizumab treatment, on the efficacy of single agent anti-EGFR therapy in a routine clinical practice cohort. Our data do not support the notion that prior bevacizumab renders tumors more or less sensitive to subsequent anti EGFR therapy.
Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475).
Authors: Doi Toshihiko , Piha-Paul Sarina Anne , Jalal Shadia Ibrahim , Mai-Dang Hieu , Saraf Sanatan , Koshiji Minori , Csiki Ildiko , Bennouna Jaafar
Published: February 2017

7

Background: PD-L1 and PD-L2 expression have been associated with poor prognosis in esophageal cancer. Pembrolizumab (pembro) is a humanized monoclonal antibody against PD-1 that blocks interaction with PD-L1 and PD-L2. The multicohort, phase Ib KEYNOTE-028 (NCT02054806) trial was designed to evaluate the safety and efficacy of pembro in patients (pts) with PD-L1+advanced solid tumors. We report updated results from the esophageal carcinoma cohort of this study. Methods: Key eligibility criteria included advanced squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction, PD-L1 expression in tumor or stroma determined centrally by IHC, failure of standard therapy, and ECOG PS 0-1. Pts received pembro 10 mg/kg every 2 wk for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end point was ORR per RECIST v1.1 by investigator review. Results: Of the 23 pts enrolled, median age was 65 y, 82.6% were men, 73.9% had squamous histology, and 87.0% received ≥ 2 prior therapies for metastatic disease. As of the Aug 4, 2015 data cutoff date, median follow-up duration was 31 wk (range 5.7-71). Nine pts (39.1%) had drug-related adverse events (DRAEs), most commonly decreased appetite (n = 3, 13.0%). Four pts (17.4%) had grade 3 DRAEs, with only decreased lymphocytes reported in > 1 pt (n = 2, 8.7%). No pts died or discontinued pembro due to a DRAE. Immune-mediated AEs, regardless of attribution by investigator, were grade 2 hypothyroidism (n = 2, 8.7%) and adrenal insufficiency (n = 1, 4.3%). ORR was 30.4% (95% CI 13.2-52.9), and the stable disease rate was 13.0% (n = 3, 95% CI 2.8-33.6); 6-mo and 12-mo PFS rates were 30.4% and 21.7%. Five of 7 responses were ongoing at data cutoff, with a median duration of response of 40.0 wk (range 24.1+ to 46.1+). Analysis of the relationship between PD-L1 expression level and antitumor activity is ongoing. Conclusions: Pembro continued to show manageable toxicity and durable antitumor activity in pts with heavily pretreated, PD-L1+ advanced esophageal carcinoma. Phase II and III trials of pembro in pts with esophageal carcinoma are ongoing. Clinical trial information: NCT02054806.