bluuebunny/crossref_metadata_2025_split huggingface dataset:
PEGylated human IL-10 (AM0010) monotherapy in refractory metastatic colorectal cancer.
Authors: Infante Jeffrey R. , Papadopoulos Kyriakos P. , Naing Aung , Autio Karen A. , Ott Patrick Alexander , Wong Deborah Jean Lee , Bendell Johanna C. , Bauer Todd Michael , Pant Shubham , Van Vlasselaer Peter , Brown Gail Linda , Oft Martin 
Published: September 2018

3571 Background: Colorectal Cancer (CRC) has been refractory to immune therapies. The clinical benefit of immunotherapy is thought to depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells which are low in most CRCs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Patients with CRC who have progressed on SOC first and second line of therapy have a reported 7.1 months OS with TAS-102 (Meyer et al. NEJM372;20, 2015). In this Phase 1 study the efficacy of AM0010 was studied in refractory metastatic CRC patients. Methods: CRC pts progressing on a median of 4 prior therapies (range 2-7) were treated daily with AM0010 in doses of 1 ug/kg SQ daily to 40 ug/kg in a dose escalation design. Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+T cells. Results: AM0010 was tolerated with reversible TrAEs. 10 pts (of 27) had a G3/4 TrAE. There were no objective responses. 11 patients were treated in dose escalation cohorts (1-10 ug/kg) and 16 pts were treated at or above RP2D (20 ug/kg or 40 ug/kg). Seven of 25 pts with at least one radiographic response evaluation had stable disease at 8 weeks. One patient had SD for 19.4 months. The mPFS (ITT n = 27 pts) was 1.6 months, mOS was 11.7 (range 2.4 – 32+) months. The median follow-up is 25.2 months (range 13-35). AM0010 increased Th1 cytokines IL-18 and IFNg in the serum of patients, while decreasing mediators of chronic, tumor promoting inflammation (Th17 cytokines) and TGFb. Tumor infiltrating granzyme B+ CD8+ T cells increased during the treatment. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients. Conclusions: AM0010 is well tolerated in patients with refractory CRC. Although objective tumor responses were not seen in this very advanced CRC population, the observed immune activation including clonal T cell expansion, prolonged stable disease, and the mOS of 11.7 months is encouraging in this advanced CRC population. Future study of AM0010 in combination with FOLFOX in a second – line of therapy colorectal cancer patients is being planned. Clinical trial information: NCT02009449.
Impact of overall severity of adverse events (AEs) on long-term outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first line systemic chemotherapy: Findings from 3,971 pts in the ARCAD database.
Authors: Zalcberg John Raymond , Shi Qian , Ferraro Danielle Angela , Meyers Jeffrey P. , Saltz Leonard , Goldberg Richard , Van Cutsem Eric , Hurwitz Herbert , Fuchs Charles , Bokemeyer Carsten , Sargent Daniel J. , De Gramont Aimery , Price Timothy Jay , Adams Richard 
Published: September 2018

3582 Background: The prognostic importance of the incidence, severity, type and duration of AEs pts experience during chemotherapy varies between tumor types, and the available evidence across the board is often conflicting. Here we investigated the impact of the overall severity of AEs among pts with mCRC receiving first-line oxaliplatin (Oxa)- and/or irinotecan(Iri)-based regimens. Methods: The overall severity of AE data (i.e., max grade (G) of all AEs) were available on 3,971 pts (median age 61; 60% male, 47% ECOG PS 1+; 57% 2+ metastatic sites) enrolled onto 6 1st-line randomized trials. Around 46%, 45%, and 9% of pts had received Oxa-, Iri-, and Oxa+Iri-based regimens, respectively. Pts receiving biologic agents were excluded. Stratified multivariate Cox models were used to assess the associations with overall survival (OS) and progression-free survival (PFS); adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Pts who only received Oxa-based treatment reported the lowest rate of G3+ AEs (p < .0001) compared to pts treated with Iri- or Oxa+Iri-based regimens. Older age, female gender, and PS 1 or 2+ were associated with higher grade AEs (all p < .0001). Considering AEs experienced within 6w after randomization, 10% and 61% of pts experienced G4+ and G2-3 AEs, respectively. G3+ AEs were associated with a shorter OS for both pts receiving Oxa- (HRadj= 1.2, 95% CI, 1.1-1.3, padj < .0001) and Iri-based regimens (HRadj= 1.4, 95% CI, 1.2-1.5, padj < .0001). For the entire treatment course, 19% and 72% of pts experienced G4+ and G2-3 AEs, respectively. For Oxa-based regimens, pts with G3+ AEs had a longer OS (HRadj= 0.86, 95% CI, 0.78-0.94, padj = .0016), whereas G3+ AEs were associated with a shorter OS (HRadj= 1.2, 95% CI, 1.1-1.4, padj = .0004) for pts treated with Iri-based regimens. Similar patterns were seen for PFS. Conclusions: Pts who reported higher grade AEs during initial treatment (≤6w) have significantly worse outcome than those who do not. Further analyses with treatment exposure/detailed dose-AE profile and its impact on survival are warranted.
Prognostic signatures of oligometastasis in colorectal cancer liver metastasis.
Authors: Khan Sajid A. , Paty Philip , Zeng Zhaoshi , Lu Jun 
Published: September 2018

3588 Background: Knowledge of molecular differences between limited metastasis (oligometastasis) and widespread metastases may provide biomarkers for selection of patients who will benefit from curative metastasis resection and provide useful prognostic information. In this study, we detect messenger RNA expressional patterns in patients with colorectal cancer liver metastasis (CRCLM) and identify networks of coding and noncoding RNAs corresponding to oligometastatic phenotype. Methods: RNA was prepared from frozen tumor tissue of 55 patients with CRCLM patients treated with liver resection and/or biopsy of their metastatic tumors with greater than 15 years of follow-up. Survival was calculated and stratified according to risk of recurrence. Cases were subject to RNA-Sequencing experiments with paired end sequencing. Results: RNA analysis with TopHat and Cuffdiff found significant differences in transcript expression according to recurrence for 667 genes (P < 0.05). Of these transcripts, 166 had a greater than 2-fold gene expression between groups when comparing mean Fragments Per Kilobase of transcript per Million mapped reads (FPKM) (P < 0.05). Unsupervised hierarchical clustering revealed distinct genomic patterns based on clinical outcome. A supervised gene expression analysis revealed a differential expression of genes in the Homeobox ( HOX) family (P < 0.05). Overexpression of individual members of the HOX gene family are associated with prognosis. Upregulation of the HOXD11 gene was associated with cure in 60% of cases while downregulation was associated with 5-year overall survivals of 16% (P = 0.023). Furthermore, when clusters of HOX family members were compared, we found that expression correlated with survival, underlining the importance of this gene family in oligometastasis biology. A high ratio of the HOXD cluster to HOXA cluster was associated with a long recurrence free survival (P = 0.002). Conclusions: Common genomic signatures characterize patients with liver oligometastasis from primary colorectal cancer. The HOX gene family strongly correlates with prognosis and represents a unique molecular subtype of patients. Further mechanistic studies of the HOX gene family in metastases are underway.
Monitoring the effect of first-line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.
Authors: Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Lindebjerg Jan , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller 
Published: September 2018

3593 Background: Personalized medicine calls for an early indicator of treatment failure. Circulating tumor DNA (ctDNA) is a promising marker in this setting and our prospective study explored the association between disease control and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). Methods: The present study included 138 mCRC patients receiving standard first line combination chemotherapy. In patients with a RAS/RAF mutated tumor the same mutation was quantified in the plasma using droplet digital PCR (ddPCR). The fractional abundance of ctDNA (ctDNA level) was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease (PD). Results: RAS/RAF mutations were detected in the plasma from 77 patients (94% of patients with a tumor mutation). Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of a RAS/RAF mutation in plasma correlated to overall survival (OS) with a median of 24.2 months for patients with a wild-type tumor compared to 12.7 months for patients with a mution in plasma. A substantial increase in ctDNA level was highly associated with progression on treatment (risk ratio = 4.58, 95%CI = 1.99-10.51, p < 0.0001). Furthermore, with a stable ctDNA level the chance of non-progression was 88.2% (range 76.1-95.6%). The first substantial increase in ctDNA level occurred at a median of 51 days (range 14-133 days) before radiologically confirmed PD. Conclusions: The results indicate that ctDNA level may be predictive of treatment effect in patients with mCRC. An increase was observed to correlate with high risk of progression with a relevant lead time, whereas an unchanging ctDNA level related to stable disease.
Emergence of KRAS mutations and acquisition of resistance to EGFR blockade.
Authors: Yamada Takeshi , Takahashi Goro , Iwai Takuma , Takeda Kohki , Ueda Kohji , Koizumi Michihiro , Shinji Seiichi , Yokoyama Yasuyuki , Hara Keisuke , Matsuda Akihisa , Matsumoto Satoshi , Ohta Keiichiro , Eiji Uchida 
Published: September 2018

3598 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in patients with metastatic colorectal cancer (CRC). However, most patients who benefit from EGFR blockade acquire resistance. Although RAS mutation is established as a main cause of primary resistance, the mechanisms of this acquired resistance remain unclear. Here, we aimed to identify the mechanisms underlying acquired resistance to EGFR blockade by using circulating cell-free (ccf)DNA to track emerging KRAS, BRAF and S492R mutations during chemotherapy. Methods: We enrolled 33 patients with metastatic CRC and no RAS mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy that included EGFR blockade. We obtained ccfDNA from each patient before they started chemotherapy, and every 2–3 months during chemotherapy until disease progression. We detected KRAS (codons 12, 13, 61, and 146), BRAF (V600E) and S492R mutations using digital polymerase chain reaction. Results: KRAS mutations were detected in the ccfDNA of 4 of the 33 patients (12%) before chemotherapy. The response rate was 88% (29/33); all four non-responders had KRAS mutations in their ccfDNA and one of the four had both KRAS and BRAF mutations before starting chemotherapy. A response was detected in all patients (29/29) with no KRAS or BRAF mutations in their ccfDNA before chemotherapy. Of the 29 initial responders, 14 (48%) acquired resistance. Emerging KRAS mutations were detected in the ccfDNA of 13 of these 14 patients (93%); eight of these patients had multiple mutations (e.g. G12D and G12V; G13D and Q61H). BRAF mutations were also detected in six patients (43%); none of the patients had solo BRAF mutations. Six patients (43%) had S492R mutations; none of the patients had solo S492R mutations. Only one patient had no KRAS, BRAF or S492R mutations. Conclusions: Emergence of KRAS, BRAF or S492R mutations that were undetectable before the start of chemotherapy may be a mechanism underlying acquisition of resistance to EGFR blockade. Notably, emerging KRAS mutations were detected in most of the patients (93%) who acquired resistance. This indicates that KRAS mutation emergence may play a major role in the acquisition of resistance to EGFR blockade.
The feasibility and efficiency of wait and see policy for patients with complete clinical response following neoadjuvant therapy in rectal cancer: A prospective cohort study from China.
Authors: Gu Jin , Du Changzheng , Li Ming , Peng Yifan , Yao Yunfeng , Zhao Jun , Zhan Tiancheng , Cai Yong , Li Yongheng , Jin Jing 
Published: September 2018

3610 Background: It has been reported that non-operative treatment (wait and see) is feasible for the selected rectal cancer cases with a complete clinical response (cCR) following neoadjuvant therapy (NT). The aim of this study is to determine whether "wait and see" policy is efficient for the cCR patients in China. Methods: We designed a prospective cohort study in China (ChiCTR-TRC-12002488). From Jul 2012 to August 2016, totally 45 patients with locally advanced rectal cancer who were cCR following NT were enrolled in the study; within whom, 32 patients were assigned to wait and see group, and the remaining 13 patients were assigned to surgery group (intent-to-treat grouping). Results: The median follow-up time was 24 months (range: 3-51). Of the patients who were followed up more than 12 months (n=37), 8 patients developed tumor progression (7 in wait and see group and 1 in surgery group, respectively). In the wait and see group, the local regrowth took an account of 23.1% (6/26), while the distant metastasis rate was 3.8% (1/26). In the surgery group, there were 23.1% (3/13) of patients who has residual cancer confirmed by postoperative pathological assessment. All the patients with tumor regrowth underwent radical surgery and no body died of cancer. Conclusions: Wait and see policy has an acceptable safety and efficiency, it may become an alternative treatment for the patients who were cCR following NT. Clinical trial information: ChiCTR-TRC-12002488. [Table: see text]
ABSOLUTE: A phase 3 trial of nanoparticle albumin-bound paclitaxel (nab-PTX) versus solvent-based paclitaxel (sb-PTX) in patients with pre-treated advanced gastric cancer (AGC)—Efficacy and QOL results.
Authors: Koeda Keisuke , Shitara Kohei , Takashima Atsuo , Fujitani Kazumasa , Tsujimoto Hironori , Tsuji Akihito , Oki Eiji , Takagane Akinori , Takagi Masakazu , Hamamoto Yasuo , Baba Hideo , Omuro Yasushi , Okuda Hiroyuki , Nakano Yasuyuki , Sugimoto Naotoshi , Nakamura Michio , Imamura Kazuhiro , Ichikawa Daisuke , Kuwano Hiroyuki , Koizumi Wasaburo 
Published: September 2018

4010 Background: Sb-PTX is a standard second-line treatment for patients (pts) with AGC. Nab-PTX was developed to avoid the toxicities with use of solvents in sb-PTX and potentially improve efficacy. Based on ABSOLUTE trial, we conducted the additional analysis to evaluate the efficacy and QOL of nab-PTX and sb-PTX. Methods: Pts who were refractory to a fluoropyrimidine-containing first-line treatment were randomly assigned (1:1:1) to receive intravenous q3w nab-PTX (260 mg/m2) on day 1 of a 21-day cycle, and q1w nab-PTX (100 mg/m2) or q1w sb-PTX (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle. The primary objective was to evaluate whether q3w nab-PTX and q1w nab-PTX were non-inferior to q1w sb-PTX in terms of overall survival (OS). Tumor shrinkage at 8 weeks and at the time of the best response were also investigated. For the QOL analysis, EQ-5D score were collected at baseline and every 8 weeks during the first 24 weeks, and thereafter at every 24 weeks. Time to deterioration of EQ-5D score was compared between each arm as a minimally important difference of 0.05. Results: 741 pts were randomly assigned to q3w nab-PTX, q1w nab-PTX, or q1w sb-PTX. Median OS (months) were 10.3, 11.1, and 10.9, respectively. Q1w nab-PTX was non-inferior to q1w sb-PTX (hazard ratio 0.97, 97.5% CI 0.76-1.23; non-inferiority one-sided p = 0.0085), whereas q3w nab-PTX was not non-inferior to q1w sb-PTX (1.06, 95% CI 0.87-1.31; non-inferiority one-sided p = 0.062).The response rate of target lesions at 8 weeks and at the time of the best response (%) were 22.1 and 27.7 for q3w nab-PTX, 28.2 and 34.9 for q1w nab-PTX, and 18.0 and 25.6 for q1w sb-PTX. Median time to deterioration of EQ-5D score (months) were 2.1 in q3w nab-PTX, 3.8 in q1w nab-PTX, and 3.7 in q1w sb-PTX. Conclusions: Q1w nab-PTX was non-inferior to q1w sb-PTX in terms of OS. In addition, q1w nab-PTX showed favorable effect in comparison with q1w sb-PTX in terms of response rate of target lesions and time at best response. QOL was similar between q1w nab-PTX and q1w sb-PTX. These results suggest that q1w nab-PTX is a useful second-line treatment for pts with AGC. Clinical trial information: 132059.
SWOG S1310: Randomized phase II trial of single agent MEK inhibitor trametinib vs. 5-fluorouracil or capecitabine in refractory advanced biliary cancer.
Authors: Kim Richard D. , McDonough Shannon L , El-Khoueiry Anthony B. , Bekaii-Saab Tanios S. , Stein Stacey , Sahai Vaibhav , Keogh George P. , Kim Edward Jae-hoon , Baron Ari David , Siegel Abby B. , Barzi Afsaneh , Guthrie Katherine , Javle Milind M. , Hochster Howard S. 
Published: September 2018

4016 Background: No standard treatment options are available for patients with advanced BC who fail gemcitabine/platinum therapy. The rationale for evaluation of trametinib was based on the presence of MAPK alterations and on earlier promising results with other MEK inhibitors in BC. Methods: Pts with histologically proven BC who progressed on gemcitabine/platinum were randomized to trametinib (2mg qd) (Arm A) vs infusional 5FU at 2400 mg/m2 over 46 hours or capecitabine (1000 mg/m2PO days 1-14 BID) (Arm B). Patients were stratified by planned chemotherapy 5FU/LV vs capecitabine; and disease site: cholangiocarcinoma vs gallbladder. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS) and response rate (RR). 80 eligible patients (40 for each arm) were needed to detect an improvement in median OS from 5 months to 8.25 months (1.65 HR). A planned interim futility analysis of objective response was performed on the first 14 pts registered to the trametinib arm. Results: The study was stopped early based on the lack of measurable response in the trametinib arm. 53 pts were randomized (27 pts in Arm A vs 26 pts in Arm B). Median age was 62 years and the primary sites of tumor were cholangiocarcinoma (77%) and gallbladder (23%). Median OS was 4.3 months (95% CI 3.1-5.1) for Arm A, and 8.0 months (95% CI 3.2-14.6) for Arm B with a HR of 2.02 (95% CI 1.01-4.03, p=0.05). The median PFS was 1.3 months (95% CI 1.2-1.5) for arm A and 2.8 months (95% CI 1.4-6.9) for arm B with a HR of 2.95 (95% CI 1.38-6.30, p=0.01). Overall RR was 8% (95% CI 0%, 19%) in Arm A vs 10% (95% CI 0%, 23%) in Arm B (p>0.99), and 8% vs 45% had stable disease. Eight pts in Arm A experienced treatment-related ≥ grade 3 toxicities, including one death due to vomiting/dehydration. Seven pts in Arm B experienced treatment-related grade 3 toxicities; no higher grade toxicities were reported. Conclusions: To our knowledge, this is the first prospective randomized study of a targeted agent versus chemotherapy for the second line treatment of BC. In this unselected population, the lack of response to trametinib resulted in early closure. The PFS and OS for trametinib were inferior to 5FU. Clinical trial information: 02042443.
Association of a DNA damage response deficiency (DDRD) assay with prognosis in resected esophageal and gastric adenocarcinoma.
Authors: Turkington Richard C. , Knight Laura A , Douglas Rosalie V. , Blayney Jaine K. , Stevenson Leanne , McManus Damian , McCavigan Andrena , Walker Steven M. , Bornschein Jan , MacRae Shona , Noble Fergus , Underwood Timothy J , O'Neill Robert , McQuaid Stephen , Arthur Ken , James Jacqueline , Eatock Martin McKinlay , Harkin Paul D , Fitzgerald Rebecca C. , Kennedy Richard D. 
Published: September 2018

4026 Background: Current strategies to guide the selection of neo-adjuvant or adjuvant therapy in esophageal and gastric adenocarcinomas (EAC/GAC) are inadequate. We assessed a clinically validated 44 gene DNA Damage Response Deficiency (DDRD) assay to predict prognosis following neo-adjuvant DNA damaging chemotherapy (CT) in EAC and adjuvant CT or chemo-radiotherapy (CRT) in GAC. Methods: Transcriptional profiling of 273 formalin fixed paraffin embedded pre-treatment endoscopic EAC biopsies was performed using the Almac Diagnostics Xcel array. All EAC patients were treated with cisplatin-based neo-adjuvant chemotherapy followed by surgical resection between 2003 and 2014 at four UK centers in the OCCAMS consortium. Further validation was performed using a publically available dataset of 270 resected gastric cancers treated with adjuvant platinum-based CT, CRT or surgery alone at the Samsung Medical Centre, Seoul, Korea. The association between the DDRD score and prognosis was assessed by Kaplan-Meier analysis and Cox Proportional Hazards regression. Results: A total of 66 EAC samples (24%) were characterized as DDRD positive with the remaining 207 samples (76%) being DDRD negative. DDRD assay positivity was associated with improved DFS (HR 0.58; 95% CI 0.36-0.93; p = 0.024) and OS (HR 0.56; 95% CI 0.34-0.92; p = 0.023) following multivariate analysis. DDRD positive patients had a higher pathological response rate (p = 0.033) and a higher rate of loco-regional versus distant relapse (30% vs 20%; p = 0.013). For GAC, 132 samples (49%) were characterized as DDRD positive with the remaining 138 (51%) being DDRD negative. DDRD positivity was associated with improved DFS (HR 0.48; 95% CI 0.25-0.96; p = 0.037) following D2 gastrectomy and adjuvant CT or CRT. DDRD status was not associated with DFS in the surgery alone cohort (HR 0.87; 95% CI 0.55-1.38; p = 0.562). Conclusions: The DDRD assay is strongly predictive of benefit from DNA damaging neo-adjuvant CT and esophagectomy in EAC and gastrectomy and CT/CRT in GAC and can be applied to routine diagnostic material.