bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.
Authors: Falcone Alfredo , Cremolini Chiara , Masi Gianluca , Lonardi Sara , Zagonel Vittorina , Salvatore Lisa , Trenta Patrizia , Tomasello Gianluca , Ronzoni Monica , Ciuffreda Libero , Zaniboni Alberto , Tonini Giuseppe , Buonadonna Angela , Valsuani Chiara , Chiara Silvana , Carlomagno Chiara , Boni Corrado , Marcucci Lorenzo , Boni Luca , Loupakis Fotios 
Published: March 2020

3505 Background: Doublets plus bev are a standard option for the first-line treatment of mCRC. First-line FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The objective of the TRIBE trial was to confirm the superiority of FOLFOXIRI vs FOLFIRI when bev is added to chemotherapy (CT). Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior CT for advanced disease. Pts were randomized to either FOLFIRI/bev (arm A) or FOLFOXIRI/bev (arm B). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Primary endpoint was PFS. Results: Between July 2008 and May 2011 508 pts were randomized. Pts characteristics were (arm A/arm B): median age 60/61, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79%, multiple sites of disease 74%/70%, liver-only disease 18%/23%, prior adjuvant (adj) 12%/12%. At a median follow-up of 26.6 mos 424 pts progressed and 244 died. Median PFS and OS in the intention to treat (ITT) population were 10.9 and 30.9 mos. FOLFOXIRI/bev significantly increased PFS (median 9.7 vs 12.2 mos, HR 0.73 [0.60-0.88] p=0.0012). Subgroup analyses based on stratification factors (PS, prior adj) and baseline characteristics (site of primary, liver only disease, resection of primary, Kohne score) did not evidence significant interactions between treatment and analyzed factors. A trend toward a more consistent effect of FOLFOXIRI/bev was reported in no prior adj (HR 0.68 [0.55-0.83]) compared to prior adj group (HR 1.18 [0.67-2.08], p for interaction=0.071). Response rate (RECIST) was also significantly improved (53% vs 65% p=0.006). FOLFOXIRI/bev did not increase the R0 secondary resection rate in the ITT population (12% vs 15%, p=0.327), or in the liver-only subgroup (28% vs 32%, p=0.823). Conclusions: FOLFOXIRI/bev compared to FOLFIRI/bev, significantly increases PFS and response rate. Subgroup analysis suggests a possible interaction between prior adj CT and PFS benefit. Secondary resection rate does not differ between treatment arms. Clinical trial information: NCT00719797.
Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC).
Authors: Corcoran Ryan Bruce , Falchook Gerald Steven , Infante Jeffrey R. , Hamid Omid , Messersmith Wells A. , Daud Adil , Kwak Eunice Lee , Ryan David P. , Kurzrock Razelle , Atreya Chloe Evelyn , Luan Jennifer , Sun Peng , Schaeffer Megan , Motwani Monica , Bleam Maureen R , Moy Christopher H , Patel Kiran , Orford Keith W. , Kopetz Scott , Venook Alan Paul 
Published: March 2020

3507 Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ≥ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ≥ 1 biologic therapy. Among 34 pts with >1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study >12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ≥6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ±29%) and relative (69% ±28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.
A randomized, placebo-controlled, phase I/II study of tivantinib (ARQ 197) in combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy.
Authors: Eng Cathy , Hart Lowell L. , Severtsev Aleksey , Gladkov Oleg , Mueller Lothar , Kopp Mikhail V. , Vladimirov Vladimir Ivanovich , Langdon Robert M. , Kotiv Bogdan , Barni Sandro , Hsu Ching , Bolotin Ellen , Von Roemeling Reinhard , Schwartz Brian E. , Bendell Johanna C. 
Published: March 2020

3508 Background: Tivantinib (ARQ 197) selectively inhibits the MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, and metastasis. Resistance to EGFR inhibitors has been associated with activation of alternative pathways including MET. Methods: Pts with advanced KRAS WT CRC that progressed on or after 1 prior line of chemotherapy and no previous treatment with an EGFR inhibitor were eligible. Pts were randomized 1:1 to receive cetuximab (500 mg/m2) and irinotecan (180 mg/m2) on days 1 and 15 every 28 days, plus oral tivantinib (360 mg twice daily [BID]) or placebo. The primary endpoint was progression-free survival (PFS); additional endpoints include safety, objective response rate, overall survival (OS) and exploratory biomarker analyses. Results: Between Jul 2010 and Feb 2012, 122 pts were randomized; 117 pts were eligible for analysis (60 tivantinib, 57 placebo). Mean age was 57 years (range, 27-79 years); ECOG PS 0/1 55%/45%; and 81% received prior oxaliplatin. Median PFS was 8.3 months in the tivantinib arm vs 7.3 months in the placebo arm (hazard ratio [HR] = 0.85; 95% CI, 0.55-1.33; P = 0.38). Objective response rate (95% CI) was 45% (33%-58%) in the tivantinib arm and 33% (23%-46%) in the placebo arm. Median OS has not yet been reached but is trending in favor of tivantinib vs placebo (HR = 0.67). Among pts with prior oxaliplatin therapy, median PFS was 8.4 months for tivantinib and 7.2 months for placebo (HR = 0.67; 95% CI, 0.44-1.00; P= 0.1). The most common grade 3/4 adverse events (≥ 10%) were neutropenia, diarrhea, and nausea. Correlation of clinical outcomes with additional factors including mutation status and immunohistochemical analysis of tumor MET expression will be presented. Conclusions: Outcomes in this trial trended towards improvement with tivantinib (360 mg BID) plus cetuximab and irinotecan, particularly in the subgroup who had previous oxaliplatin. Further studies are needed to identify the CRC population most likely to benefit from addition of tivantinib to standard therapy. Clinical trial information: NCT01075048.
Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer.
Authors: Lenz Heinz-Josef , Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Jeffers Michael , Grothey Axel 
Published: March 2020

3514 Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p<0.001; PIGF: HR 1.81, p=0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p<0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.
Treatment outcome according to tumor ERCC1 expression status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab.
Authors: Bokemeyer Carsten , Köhne Claus-Henning , Bondarenko Igor , von Heydebreck Anja , Grote Hans Juergen , Stroh Christopher , Lenz Heinz-Josef 
Published: March 2020

3537 Background: The OPUS study showed that the addition of cetuximab to infusional 5-fluorouracil/folinic acid + oxaliplatin (FOLFOX4) significantly improved progression-free survival (PFS) and response in the first-line treatment of patients (pts) with KRAS wild-type (wt) mCRC. High level expression in tumors of ERCC1, a protein involved in nucleotide excision repair, has been associated with resistance to platinum-based chemotherapy in a range of tumor types. This analysis assessed outcome according to ERCC1 expression level and treatment group in OPUS study pts. Methods: ERCC1 expression level was assessed by immunohistochemistry (IHC) in all available formalin-fixed paraffin-embedded tumor samples from OPUS study pts. An ERCC1 IHC score on a continuous scale of 0–300 was calculated for each tumor, based on the intensity of nuclear staining and proportion of positive cells. The median IHC score was used to define low (<median) and high (≥median) ERCC1 expression levels and outcome was assessed in low vs high expression groups in both treatment arms. Results: Of 337 OPUS study intention to treat pts, 97 (29%) were evaluable for ERCC1 expression. Pts in the FOLFOX4 arm in the high ERCC1 expression group (n=27) had shorter PFS (median 5.8 vs 9.2 months; hazard ratio, HR 1.63, 95% CI 0.80–3.34) and overall survival (median 11.5 vs 18.5 months; HR 1.75, 95% CI 0.90–3.40) and a lower response rate (33.3% vs 39.1%) compared with those in the low ERCC1 expression group (n=23). To assess the effect of adding cetuximab to FOLFOX4 according to ERCC1 expression level, outcome was assessed in the KRAS wt subgroup of pts. Although low pt numbers precluded the drawing of definitive conclusions, PFS in the high ERCC1 expression group was longer in the FOLFOX4 + cetuximab arm (n=14) compared with the FOLFOX4 arm (n=13; median 7.7 vs 5.8 months), survival was longer (median 19.7 vs 12.0 months) and the response rate was higher (71.4% vs 30.8%). Conclusions: High tumor ERCC1 expression was associated with poor outcome in pts with mCRC receiving first-line platinum-based chemotherapy. The addition of cetuximab to FOLFOX4 may mitigate this effect in those with KRAS wt tumors. Clinical trial information: NCT00125034.
Proof-of-concept study of Sym004, an anti-EGFR monoclonal antibody (mAb) mixture, in patients (pts) with anti-EGFR mab-refractory KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Dienstmann Rodrigo , Tabernero Josep , Van Cutsem Eric , Cervantes-Ruiperez Andres , Rosello Keranen Susana , Benavent Viñuales Marta , Kjær Ida , Pedersen Mikkel W , Skartved Niels Jorgen Ostergaard , Flensburg Mimi F , Horak Ivan David , Garcia-Carbonero Rocio 
Published: March 2020

3551 Background: KRAS wt mCRC pts progressing on chemotherapy and anti-EGFR mAbs have limited treatment options. Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR, causing its internalization and degradation. With this unique mechanism of action, Sym004 overcomes acquired resistance to anti-EGFR mAbs in preclinical studies. Methods: Open-label, multicenter trial assessing safety (primary endpoint) and efficacy of 2 dose levels of Sym004 in KRAS wt mCRC pts with prior clinical benefit to anti-EGFR mAbs and subsequent progression during or within 6 months after treatment cessation. Sym004 was administered until disease progression or unacceptable toxicity. Tumor responses were evaluated centrally according to RECIST criteria. Paired skin and tumor biopsies were obtained at baseline and week 4. Results: In total, 42 pts were enrolled at 9 mg/kg (13) and 12 mg/kg (29). Median age was 66 years and median number of prior treatment lines 3. Central radiology review was performed in 12/13 (92%) pts at 9 mg/kg and 27/29 (93%) pts at 12 mg/kg. Tumor shrinkage > 10% was documented in 4/12 (33%) pts at 9 mg/kg, with partial response (PR) in 1/12 (8%) and stable disease (SD) in 9/12 (75%). At 12 mg/kg, 7/27 (26%) pts had > 10% tumor shrinkage, with PR in 3/27 (11%) and SD in 15/27 (56%). Median progression-free survival was 13.6 weeks (95% CI: 5.3-23) and 13.7 weeks (95% CI: 5.9-18.6), respectively. Duration of response for pts with PR was 5.6-17.6 weeks. Grade 3 or higher toxicity included skin rash in 26/42 (62%), hypomagnesemia in 16/42 (38%) and diarrhea in 2/42 (8%). Adverse events were manageable with dose reduction and supportive medication. There were no indications of immunogenicity. Pharmacodynamic analysis in serial tumor samples showed profound down-regulation of EGFR and reduction in proliferation marker Ki67. Conclusions: Sym004 at weekly doses of 9 and 12 mg/kg showed significant clinical activity in anti-EGFR treatment-refractory KRAS wt mCRC pts, clearly demonstrating proof-of-concept. Serial biopsies confirmed its mechanism of action. No unexpected adverse events were observed. Clinical trial information: NCT01117428.
Regular statin users and colorectal cancer (CRC) prognosis.
Authors: Ma Wei-li , Shao Yu Yun , Hsu Chih-Hung , Yeh Kun-Huei , Chen Ho-Min , Yeh Yi-Chun , Lai Chiu-Lin , Lin Zhong-Zhe , Cheng Ann-Lii , Lai Mei-Shu 
Published: March 2020

3554 Background: Statins are frequently used for the control of hyperlipidemia. Statins have multiple anti-cancer properties and may be associated with lower CRC risks among their users. This study tries to go a step further and explores whether statin use affects the prognosis of curatively resected CRC. Methods: We established a population cohort with patients (age ≥ 40 y) who were diagnosed as having stage I or II CRC from 2004 to 2008 and received curative surgery from the database of Taiwan Cancer Registry. Data of medication prescription and co-morbidities were retrieved from the database of National Health Insurance, Taiwan. Regular statin use was defined as taking statins for > 180 days within the observation period from one year before the cancer diagnosis to one year afterward. The database of National Death Registry was used for survival outcomes. Another similar cohort consisting of patients with hepatocellular carcinoma (HCC) was used for comparison. Results: In total, 10762 patients with CRC were enrolled; 891 (8%) patients were regular stain users, 812 (8%) patients took statins but were not regular users, and 9059 (84%) patients never used statins. Regular statin users, compared to never users, were more likely to be female (p < 0.001), older (p < 0.001), have stage I disease (p < 0.001) and co-morbidities such as diabetes, coronary artery disease, and renal disease. Adjuvant therapy was less frequently administered in regular statin users. In univariate analysis, cancer-specific survival (CSS) of regular stating users was significantly longer than that of never users (5-y CSS, 87% vs. 84%, p = 0.022), but overall survival (OS) was not significantly different (5-y OS, 80% vs. 77%, p = 0.156). In multivariate analysis adjusting for age, gender, stage, adjuvant therapy, co-morbidities, and the use of aspirin, regular stating use was an independent predictor both for better CSS (hazard ratio [HR] 0.72, p < 0.001) and for better OS (HR 0.71, p< 0.001). In contrast, no associations were found between statin use and CSS or OS in the HCC comparison cohort. Conclusions: Regular statin use was associated with better prognosis in CRC patients who received curative therapy. (This study was supported by grants DOH-101-TD-B-111-001 and DOH-102-TD-B-111-001).
Use of genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with cetuximab-based therapy.
Authors: Schultheis Anne Maria , Volz Nico Benjamin , Zhang Wu , Yang Dongyun , Ning Yan , Stintzing Sebastian , Wakatsuki Takeru , El-Khoueiry Rita Elie , Li Joseph Ethan , Kardosh Adel , Barzi Afsaneh , El-Khoueiry Anthony B. , Lenz Heinz-Josef 
Published: March 2020

3567 Background: Cetuximab is a monoclonal antibody targeting the EGF receptor. One of its anti-tumor mechanisms is the stimulation of the immune system via ADCC (Antibody-Dependent-Cell mediated Cytotoxicity). Immune response through T-cell activation may also play a role in antitumor efficacy of chemotherapy. CTLA4, PDL1, IDO1 and CD24 are inhibitory co-receptors or ligands that may downregulate the immune system through suppression of T-cell response. We tested whether Germline polymorphisms in these genes are involved in the cetuximab dependent immune response pathway and thus predict outcome in mCRC patients treated with cetuximab. Methods: DNA was isolated from blood of 108 patients with mCRC treated with either irinotecan+cetuximab (n=73) or single agent cetuximab (n=35). Twelve prospectively functionally relevant SNPs; IDO1(rs9657182, rs3739319, rs1010866), PD1(rs2227981, rs7421861), PDL1(rs2297137, rs2297136, rs10122089, G>C), CTLA4(rs231777, rs231775), and CD24(rs8734) were analyzed by PCR-based direct sequencing and evaluated for association with tumor response, overall survival (OS), and progression free survival (PFS). Results: Results are attached. There were 65 men and 43 women with a median PFS of 3.7 (95%CI: 2.8, 4.6) months and a median OS of 10.5 (95%CI:7.7, 13.3) months. Median follow up was 16.3 (range:1.2, 42.4) months. Conclusions: Our results show that immune response related SNPs may predict efficacy of cetuximab treatment in patients with mCRC. To the best of our knowledge this is the first data linking PDL1(rs2297137) to cetuximab efficacy in mCRC patients. [Table: see text]
Influence of sex and anthropometric factors on tumor biologic characteristics of colorectal cancer: A cohort study.
Authors: Brandstedt Jenny , Wangefjord Sakarias , Borgquist Signe , Nodin Bjorn , Eberhard Jakob , Jirstrom Karin 
Published: March 2020

3579 Background: How body size influences risk of molecular subtypes of colorectal cancer (CRC) remains unclear. In this study, we investigated the relationship between height, weight, BMI, WHR and risk of CRC according to expression of beta-catenin, cyclin D1, p53 and microsatellite instability (MSI) status. Methods: Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status was assessed in tissue microarrays with tumours from 584 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Four anthropometric factors: height, weight, body mass index (BMI), waist- hip ratio (WHR) were categorized by quartiles of baseline anthropometric measurements, and relative risks of CRC according to expression of betacatenin, cyclin D1, p53 and MSI screening status were calculated using multivariate Cox regression models. Results: Expression of cytoplasmatic and nuclear betacatenin, cyclin D1, p53 and MSS all revealed a positive association with increased weight and BMI in the overall analysis. Negative expression of the above mentioned factors was more frequently associated with increased height. MSI was not associated with any of the anthropometric factors in overall analysis and according to gender.Gender specific analysis revealed no association between any anthropometric factors and positive and negative cytoplasmatic beta-catenin expression, beta-catenin nuclear negativity, cyclin D1 negativity and p53 positivity. Nuclear beta-catenin positivity, cyclin D1 positivity, p53 negativity and MSS were all associated with increased weight in women. In men, positive expression of cytoplasmatic and nuclear beta-catenin, cyclin D1 positivity and p53 positivity were all associated with increased WHR. Negative expression of betacatenin was associated with increased weight, while there were no associations between any anthropometric factors and cyclin D1 negativity, MSS or MSI status in men. Conclusions: Findings from this large prospective cohort study demonstrate an association between obesity, measured as weight and BMI, and risk of CRC according to the expression of beta-catenin, cyclin D1, p53 and MSI status.