bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational proof of mechanism (PoM) for sorafenib with bevacizumab: Endpoint analysis and clinical activity
Authors: Azad N. S. , Henning R. , Yu M. , Davidson B. , Figg W. D. , Calvo K. , Venkatasen A. , Annunziata C. , Meltzer P. , Kohn E. 
Published: August 2020

3574 Background: We hypothesized that molecular targeting of tumor and its microenvironment with rational combination therapy would yield improved outcome. Bevacizumab (B) is a monocolonal antibody to vascular endothelial growth factor (VEGFF) and sorafenib (S) is a small molecule inhibitor of the VEGF receptor-2 and RAF-kinase.We have previously reported that S 200mg bid with B 5mg/kg q2wk resulted in partial responses and prolonged disease stabilization (ovarian cancers, renal cell cancer, leiomyosarcoma). Serial tumor biopsies were obtained for translational proof of mechanism analysis. Methods: Percutaneous core biopsies of metastatic sites were obtained at baseline, after 2wk of S (group A) or B (group B), and at 6wks (2 wk into S+B combination therapy). Tissue was used for: lysate array (TLA) proteomic analysis of signaling proteins, IHC for CD31, VEGF, and Ki67, Raf/Ras mutation, and SNP analysis. Results: 18 sets of 3 biopsies were obtained, assessed for morphologic response (MR; decrease to <60% viable tumor seen), and processed for TLA and IHC. 11 pts had morphologic response including all 4 PR and 6/12 SD pts. Greater reduction in change in phospho(p)-ERK was seen at 2wk in group A pts (starting with sorafenib only) (p = 0.003). 9/11 MR pts had inhibition of ERK or AKT activation (p < 0.03). OvCa pts were more likely to have reduction in bRaf (p = 0.02). Pts in group B (starting with bevacizumab only) had lower microvessel density as measured by CD31 IHC (p = 0.05) at 2 wks; there was also a trend to lower VEGF expression by IHC in that group.These effects were muted at time 3, after combination treatment. No relationships to clinical outcomes were found, every pt had at least 1SNP in >1 tested gene; there were no Ras mutations and 1 V600KRaf mutation . Conclusions: These exploratory results demonstrate proof of mechanism in the tumor and its microenvironment for the combination of S and B. Randomization of initial exposure for the first 4 wks allowed interrogation of the role of the independent agents; the Raf/ERK axis was inhibited by S treatment first and there was reduction in tissue angiogenesis markers with B first. The molecularly targeted combination of sorafenib and bevacizumab is biologically active and on target. Phase II studies in multiple tumor types are ongoing. No significant financial relationships to disclose.
Clinical, pharmacokinetic (PK), and pharmacodynamic findings from a phase I trial of an Eg5 inhibitor (AZD4877) in patients with refractory acute myeloid leukemia (AML)
Authors: Borthakur G. , Faderl S. , Ravandi F. , Padmanabhan S. , Stock W. , Wu K. , Li J. , Curt G. , Tallman M. , Minden M. 
Published: August 2020

3580 Background: AZD4877 is a potent, specific inhibitor of Eg5 (kinesin spindle protein). The only known function of Eg5 is to separate the centromeres during mitosis. Eg5 inhibition is thus specific for dividing cells, resulting in monoastral mitotic spindles (monoasters) and apoptotic cell death. Preclinically, hematologic tumor cell lines were generally more sensitive to AZD4877 than those derived from solid tumors. Methods: AZD4877 was administered IV daily x 3 as induction for up to 2 cycles, followed by consolidation (daily x 2) for up to 4 cycles. Eligibility criteria were standard. Results: Cohorts of 3–6 patients (pts) were treated at doses of 2, 4, 7, 10, 13, 16, and 18 mg/day. To date, 24 evaluable pts have received 33 induction and 3 consolidation cycles of treatment. Monoasters were detected at all dose levels evaluated (2, 7, 10, 13, and 18 mg/day). The T1/2 of AZD4877 ranged from 26 to 42 hr; PK were linear and drug levels non-cumulative. Myelosuppression, the dose limiting toxicity (DLT) in solid tumor studies, was not considered a DLT in this trial. Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose. Bone marrow biopsies were undertaken at screening and as clinically indicated. In pts with evaluable biopsies, marrow blasts decreased by 60–80% in 2 pts, and by 30–50% in 3 pts, with no response in 3 pts. Conclusions: Enrollment is ongoing at 16 mg, the likely Phase 2 dose. Preliminary results suggest possible clinical activity in AML. An expansion phase at the MTD is planned. [Table: see text]
Advancement to the clinic of an RNAi therapeutic for solid tumors
Authors: Bumcrot D. , Toudjarska I. , Judge A. , Brodsky J. , Ambegia E. , Buck T. , Racie T. , Jeffs L. , MacLachlan I. , Gollob J. , Sah D. W. 
Published: August 2020

3585 Background: Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated short interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. Efficacy was demonstrated in a mouse liver tumor model. Methods: To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP01) was tested in an orthotopic liver tumor model in which human hepatoma cells (Hep3B) are implanted directly into the livers of immunocompromised mice. Results: Intravenous administration of ALN-VSP01 leads to dose-dependent inhibition of both KSP and VEGF expression in established liver tumors. This was accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, tumor growth was significantly inhibited by a course of ALN-VSP01 treatment, and ALN-VSP01 treatment provided a clear survival benefit even when treatment was initiated in animals with a significant tumor burden. As a control, a SNALP-formulated siRNA targeting Luciferase was administered and shown to have no effect in these studies. Conclusions: Systemic administration of ALN-VSP01 exhibited clear efficacy in a mouse orthotopic liver tumor model. Clinical testing of ALN-VSP01 is expected to initiate in early 2009. [Table: see text]
Interim efficacy analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan (CPT-11) in resected stages II-III rectal cancers
Authors: Piedbois P. , Ychou M. , Zawadi A. , Douillard J. , Guérin-Meyer V. , André T. , Dupuis O. , Rougier P. , Faroux R. , Quinaux E. ,   AERO, GERCOR, FFCD, and FNCLCC Intergroup
Published: August 2020

4015 Background: The R98 trial tests the hypothesis that irinotecan (CPT-11) combined with 5FU/LV is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: 600 pts were planned to be randomized between 5FU/LV (control arm) or 5FU/LV + CPT-11. Recruitment was slow, with only 357 pts included in the study between 03/1999 and 12/2005 (178 in control arm and 179 in CPT-11) at which time the IDMC recommended closure of accrual. The primary endpoint was disease free survival (DFS), relevant events being death (whatever its cause), local or distant recurrence, and any new primary cancer. The trial was stratified by choice of control arm: either a Mayo-Clinic regimen (A: LV 20 mg/m2, 5FU 425 mg/m2 bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m2 over 2-hour, 5FU 400 mg/m2 bolus and 600 mg/m2 22-hour infusion, d1–2, q2w for 12 cycles), depending on centre decision. The experimental arm (B) consisted of LV5FU2 + CPT-11 180 mg/m2 d1 of every cycle. Results: Safety analysis was reported last year (P. Piedbois et al. Proc. ASCO 2008). We present here a first interim analysis of efficacy on half the numbers of events planned per protocol. Median follow-up is 55 months. Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. There was a trend in favor of 5FU/LV + CPT-11 in terms of DFS (77 vs 62 events in control and CPT-11 arms, hazard ratio=0.75, p=0.089) with similar effect in the Mayo-Clinic stratum (31 vs 25 events, hazard ratio=0.77) and in the LV5FU2 stratum (46 vs 37 events, hazard ratio=0.74). Conclusions: This interim efficacy analysis shows a trend in favor of 5FU/LV + CPT-11. If performed when at least 220 events are observed (projected in 2010), the next efficacy analysis would have a conditional power of about 60% to detect a true benefit of 5FU/LV + CPT-11 if the treatment effect remained the same as observed today. Study supported by Pfizer, France. [Table: see text]
High epiregulin (EREG) gene expression plus K-ras wild-type (WT) status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer (ACRC): Results from NCIC CTG CO.17—A phase III trial of cetuximab versus best supportive care (BSC)
Authors: Jonker D. J. , Karapetis C. , Harbison C. , O’Callaghan C. J. , Tu D. , Simes R. J. , Xu L. , Moore M. J. , Zalcberg J. R. , Khambata-Ford S. 
Published: August 2020

4016 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p<0.0001) but not for low EREG patients (HR 0.77, p=0.28). The test for interaction showed a non-significantly larger treatment effect in the high EREG group (HR 0.62, p=0.13). High EREG AND K-ras WT status (“Combimarker”) was present in 139 (36%). Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months (HR, 0.31; p<0.0001), and median OS 9.8 vs 5.1 months (HR, 0.43; p<0.001) in the cetuximab vs BSC arms, respectively. In the rest (n=246, 64%) cetuximab was not associated with improved PFS (HR, 0.82; p=0.12) or OS (HR, 0.90; p=0.45). The test for treatment-Combimarker interaction showed a larger cetuximab effect on OS (HR 0.52; p=0.007) and PFS (HR 0.49; p=0.001) in the Combimarker positive group. Conclusions: In the setting of pre-treated ACRC, patients with both high EREG gene expression and K-ras wild- type status may benefit from cetuximab therapy. Determination of EREG gene expression levels should be prospectively evaluated in patient selection for EGFR targeted therapy. [Table: see text]
The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer
Authors: Lambrechts D. , De Roock W. , Prenen H. , De Schutter J. , Jacobs B. , Biesmans B. , Claes B. , De Hertogh G. , Van Cutsem E. , Tejpar S. 
Published: August 2020

4020 Background: KRAS mutations (MUT) negatively affect outcome after cetuximab (CTX) in metastatic colorectal cancer (mCRC). As only 40% of KRAS wild-type (WT) respond it is possible that other MUT, constitutively activating the Ras/Erk or PI3K/Akt pathways, are present in the non-responding KRAS WT. We analyzed the KRAS, BRAF, NRAS & PIK3CA MUT status in 276 chemorefractory CRC treated with CTX +- irinotecan and correlated the MUT status with outcome. Methods: KRAS codon 12,13, 61&146, BRAF V600E, NRAS codon 12&13, PIK3CA E542K, E545K, A, G, V (exon 9), H1047Y, R, L (exon 20), N345K, R88Q and Q546K MUT were evaluated on FFPE primary CRC using the Sequenom MALDI TOF MassArray system. A two- sided Fisher's exact test was used to evaluate the association between PIK3CA, KRAS, BRAF & NRAS MUT and objective response (OR). Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: 116/276 (42%) CRC had a KRAS MUT, 96% of which occurred in codon 12 or 13. KRAS WT was associated with OR (p<.0001), longer median PFS (p<.0001) and OS (p<.0001). 15/153 (9.8%) KRAS WT had a BRAF MUT. BRAF WT was associated with OR (p=.01), longer PFS (p<.0001) and OS (p=.007). 5/98 (5%) KRAS WT had an NRAS MUT and none of these showed OR. KRAS, BRAF and NRAS MUT were mutually exclusive. The combined KRAS/BRAF/NRAS WT state was associated with OR (p<.0001), longer PFS (p<.0001) and OS (p<.0001). 23/200 (12%) CRC carried a PIK3CA mutation: 5/39 (13%) of responders and 18/160 (11%) of non-responders (p=.781). Median PFS and OS were not associated with PIK3CA MUT state (p=.760 & p=.698) overall, nor in the KRAS/BRAF/NRAS WT subgroup (p=.946 & p=.509). 5/13 (38.5%) PIK3CA MUT KRAS/BRAF/NRAS WT CRC showed an OR. 13/107 (12%) of KRAS/BRAF/NRAS WT and 10/93 (11%) of KRAS/BRAF/NRAS MUT tumors harbored a PIK3CA MUT (p=.826). Conclusions: KRAS, BRAF & NRAS MUT are mutually exclusive and occur in at least 47% of CRC. Like KRAS WT, BRAF WT state of the primary is significantly associated with outcome in mCRC treated with CTX. The combined KRAS/BRAF/NRAS WT state is significantly associated with outcome. PIK3CA MUT occur independently of the KRAS/BRAF/NRAS MUT status. We cannot provide any evidence for a strong role of PIK3CA MUT as a marker in determining outcome to CTX. [Table: see text]
Amphiregulin (AR) expression in the prediction of benefit from cetuximab plus irinotecan in KRAS wild-type metastatic colorectal cancer (mCRC) patients
Authors: Loupakis F. , Cremolini C. , Perrone G. , Stasi I. , Salvatore L. , Vincenzi B. , Ruzzo A. , Ronzoni M. , Bencardino K. , Falcone A. 
Published: August 2020

4021 Background: AR is an endogenous ligand of Epidermal Growth Factor Receptor (EGFR), whose binding is prevented in the presence of cetuximab. Methods: We retrospectively assessed KRAS mutational status and AR expression at immunohistochemistry (IHC) in 86 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. AR-IHC was performed on tissue sections from paraffin-embedded primary tumors. Specimens were defined AR-low or AR-high according to a score (range 0–300) obtained multiplying intensity (0 to 3+) by percentage of stained cells (0–100%). According to the results of a ROC analysis, we identified a cut-off value of 18. The association between AR-IHC and treatment outcome in terms of response rate (RR), PFS, and OS was investigated in the subgroup of KRAS wild-type patients. Results: Eighty-six consecutive patients were included. M/F = 44/42, median age = 67 (41–78), median number of previous lines of chemotherapy = 2 (1–5). Among 51 (59%) KRAS wild-type patients, 12 PRs and 1 CR were observed, for an overall RR of 25% (13/51). AR-IHC was high, low or unconclusive in 27, 22 and 2 cases respectively. AR-low patients reported a significantly worse RR (2/22, 9%) compared with AR-high (10/27, 37%) (p = 0.024) and a trend toward shorter PFS (3.5 vs 5.3 months, HR 0.88 [95%CI: 0.46–1.60], p = 0.628) and OS (8.8 vs 15.1 months, HR 0.60 [95%CI: 0.30–1.10], p = 0.106). Conclusions: These results underline the potential role of endogenous ligands in influencing the activity of anti-EGFR monoclonal antibodies. Absent or low AR expression at IHC may be related to resistance to cetuximab plus irinotecan. Further data regarding the prognostic impact of AR expression are needed. No significant financial relationships to disclose.
VEGF and VEGFR1 gene expression levels and tumor recurrence in adjuvant colon cancer
Authors: Ning Y. , Lurje G. , Danenberg K. , Cooc J. , Yang D. , Pohl A. , Zhang W. , Lenz H. 
Published: August 2020

4040 Background: Tumor recurrence after curative resection is still a major problem in the management of adjuvant colon cancer, with recurrence rate approximately 30–40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. Our group previously showed that angiogenesis gene polymorphisms (VEGF and IL-8) may associated with tumor recurrence in adjuvant colon cancer (Lurje Ann Oncol, 2008). Here we tested the hypothesis whether gene expression levels of angiogenesis pathway (COX-2, EGFR, VEGF, VEGFR1, VEGFR2 and IL-8) could also predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Tissue samples from 140 adjuvant colon cancer patients (69 females and 71 males with a median age of 59 years; range=28–86) were available for gene expression assays. These tissue samples were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) and LAC+USC medical center between 1999 and 2006. Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Results: We found VEGF and VEGFR1 gene expression levels independently significantly associated with time to tumor recurrence in adjuvant colon cancer patients. Patients with lower VEGF gene expression and lower VEGFR1 gene expression levels had significantly longer time to tumor recurrence compared to those with higher VEGF and higher VEGFR1 gene expression levels (p<0.05, log-rank test). Conclusions: VEGF and VEGFR1 gene expression levels may predict tumor recurrence risk in adjuvant colon cancer patients. Our exploratory data warrant future confirmatory trial. [Table: see text]
Use of a prognostic pathway signature for colorectal cancer comprised of EGFR/COX2 and imatinib drug target activation to predict occult metastasis in M0 CRC
Authors: Pierobon M. , Silvestri A. , Calvert V. , Deng J. , Belluco C. , Nitti D. , Colombatti A. , Mammano E. , Liotta L. , Petricoin E. 
Published: August 2020

4042 Background: Development of distant metastasis is the main cause of death among CRC patients. Approximately 30% of CRC patients initially staged M0-N0 die from tumor recurrence. Previously, we determined that members of EGFR/PDGFR/cAbl/cKit pathways were hyperactivated in hepatic synchronous CRC metastasis compared to primary tumor. In order to determine if this signature was a distinguished repertoire of the early stage primary tumor, we analyzed 58 CRC M0 at the moment of the diagnosis that upon 5 yr follow-up had differing disease progressions. Methods: All tissues were immediately snap frozen after surgery. Reverse phase protein microarray (RPMA) was performed using microdissected material to generate multiplexed pathway profiling. For each sample 75 different endpoints were analyzed. Results: Statistical comparison of the 75 endpoints in 8 M0 patients who progressed to M1 and 50 patients who remained M0 regardless of initial staging, revealed a number of signaling proteins whose activation/phosphorylation were elevated and subsumed in a linked pathway. Specifically COX2 and c-Kit/PDGFR/Notch were highly activated in the 8 patients with occult metastasis. A prognostic pathway signature comprised of 13 interlinked molecules was developed. Univariate, ROC and Kaplan-Meier analysis of this signature revealed a statistically significant prognostic signature with an AUC of 0.87 and a 95% confidence interval. Conclusions: A signaling portrait of 13 interlinked proteins provided a strong prognostic indicator for metastasis regardless of stage. This signature was comprised of the phosphorylation/activation of growth factor receptors, including the entire suite of Gleevec targets. A large number of these prognostic signature components were previously found activated in the metastatic lesions themselves which indicates a potential functional role of this linked protein network in metastatic progression and maintenance. If validated in larger study sets, clinical trials to test Gleevec therapy combined with Cox2 /EGFR inhibitors to prevent/delay development of distant metastasis in patients with M0 should be considered. [Table: see text]
Nodal positivity between <12 and >12 lymph nodes harvested in colorectal cancer undergoing SLNM compared with conventional surgery
Authors: Wiese D. , Soni M. , Gayer A. , Korant A. , Sirop S. , Chakravaty B. , Arora S. , Iddings D. , Saha S. 
Published: August 2020

4048 Background: Sentinel Lymph Node Mapping (SLNM) upstages significantly more patients (pts) than conventional surgery (Conv Sx) in Colon Cancer (CCa). According to current guidelines, the examination of 12 or more LNs are required to ensure accurate staging. Our study compares the rates of nodal positivity between differing numbers of total Lymph Nodes (LNs) harvested to see if the nodal positivity of <12 LN harvested by SLNM is equivalent to >12 LN obtained by Conv Sx. Methods: Of 951 pts with CCa, 545 pts underwent SLNM and standard oncological resection; 406 pts received Conv Sx without SLNM. The total number of LNs harvested for each pt as well as number of pts with metastatic LNs were recorded. Pts were grouped according to 2–11 LNs, 12–25 LNs and >25 LNs. Results: Of 951 pts, 81 pts in SLNM group and 6 in Conv Sx group were excluded due to benign disease. Average (avg) total nodes harvested in 2–11 node group for SLNM and Conv Sx was 7.9 vs 6.8 nodes respectively. Overall nodal positivity for SLNM pts and Conv Sx pts in the 2–11 node groups was 48% vs. 33% (p=.02). In the 12–25 node group, avg total number of LNs harvested was 17.23 and 16.32 respectively. In the 12–25 node group, 53% of pts in the SLNM arm had +ve nodes vs 44% (p=0.17) in the Conv Sx group. In pts with >25 nodes harvested avg nodal positivity was 33.78% vs 32.38% for SLNM and Conv Sx. Overall nodal positivity was 55% for SLNM vs 37% for Conv Sx group. When SLNM pts with 2–11 LN harvested were compared to Conv Sx pts with 12–25 LN harvested, nodal positivity was 48% vs 44% (p=0.55). Conclusions: Increased survival has been shown when >12 nodes are harvested in CCa. On avg SLNM identified a higher number of total nodes than conventional surgery. In addition, SLNM pts had higher nodal positivity with <12 LNs harvested compared to the nodal positivity of >12 nodes harvested in the Conv Sx group. A higher number of LN harvested coupled with a greater nodal positivity with less LNs make SLNM a more accurate way to stage CCa. [Table: see text] No significant financial relationships to disclose.