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4051
Background: Preop therapy for resectable pancreatic cancer (PC) maximizes access to multimodality therapy and increases the R0 resection rate. Based on our phase I chemoradiation ...(chemoRT) trial in PC patients, we hypothesized that the addition of bev to gem-based chemoRT in pts with resectable PC may allow more pts to undergo pancreaticoduodenectomy (PD), improve the rate of R0 resections, and prolong overall survival. Methods: Pts with biopsy proven, stage I/II adenocarcinoma of the pancreatic head or uncinate process received 6 weekly infusions of gem (400 mg/m
2
) and 3 infusions of bev (10 mg/kg, every 2 wks) with concomitant RT, 50.4 Gy at 1.8 Gy/fr. Pts were restaged 4-6 wks after the last dose of radiation. Those without disease progression and with good PS underwent surgery. Pts with adequate recovery received bev (10 mg/kg) every 2 weeks for 3 mo starting ~ 6 wks after surgery. Results: This study enrolled 11 of a planned 31 pts but was terminated early due to unforeseen postop complications. Median age is 64 yrs; all pts had ECOG-PS 0-1. Median CA19-9 was 52. Median follow-up from surgery was 41 mths. All completed chemoRT; 10 underwent restaging and 1 pt died from cardiac arrest before restaging. 9 pts (90 %) went to surgery and underwent a successful R0 PD. Pathologic PR rate (>50 % tumor kill) was 56 %. As we have previously reported, preop grade 3-4 toxicities were infrequent and major postop complications occurred in 5 of the 9 pts (56%) who underwent PD. Median overall survival (OS) was 30.1 mths (range: 2.6 - 63.9) for the entire cohort. Of the 9 resected pts, median OS was 45.5 mths with 5 of 11 pts (45%) achieving survival longer than best historical control (median 58.2 mths). Conclusions: The addition of bev to our prior backbone of gem-based preoperative chemoRT led to a higher resection rate (90%) than our previous protocols. Updated survival results of this study are promising. Taken together, these results may prompt further investigation of this regimen with modifications in the timing of bev delivery.
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4054
Background: IGF-1 up-regulates PC proliferation and invasiveness through activation of PI3K/Akt signaling pathway and down-regulates PTEN. We investigated IGF-1 expression in ...tissue and blood as potential predictive markers in phase II study of IGF1R-directed monoclonal antibody, MK-0646 in APC. Prior phase I established the MTD of MK0646 at 5 mg/kg with gemcitabine (G) and erlotinib (E) and 10 mg/kg with G alone. Methods: Patients (pts) with stage IV, previously untreated APC, ECOG PS 0-1, adequate hematologic and organ function were enrolled. Arm A: G 1,000 mg/m
2
over 100 min, weekly x 3, MK-0646 weekly x 4; Arm B: G 1000 mg/m
2
and MK-0646 + E 100 mg daily. Arm C (control) was G 1,000 mg/m
2
+ E 100 mg. Cycles were repeated every 4 weeks. Pts were equally randomized in the 3 arms. Primary study objective was progression-free survival (PFS). Pre-treatment peripheral blood samples were measured for IGF-1 level by ELISA; archival core biopsies were analyzed for IGF-1 mRNA expression. RNA extraction from FFPE samples used Roche Transcriptor First Strand cDNA Synthesis Kit. TaqMan
PreAmp technique was used to amplify target cDNA prior to TaqMan
RT-PCR analysis. Cox proportional hazards model for PFS analyzed the interaction between tissue IGF-1 expression and treatment. Results: 50 pts were enrolled (A=15, B=16,C=16 pts, 3 ineligible). Median PFS of arms A, B and C were 5.5 months (95% CI: 3.9 – NA), 3.0 months (95% CI:1.8 – 5.6) and 2.0 months (95% CI: 1.8 – NA), respectively (log-rank test; p = 0.17). Median OS of A was 11.3 months (95% CI: 8.9 – NA), B 8.9 months (95% CI: 5.3 – NA) and C 5.7 months (95% CI: 2.0 – NA) (log-rank test; p = 0.44). 35 archival core biopsies were analyzed, 21 had adequate tissue for analysis. Using a Multivariable Cox proportional hazards model for PFS, where IGF-1 was dichotomized at the median, there was a 76% reduction in the risk of disease progression or death in arm A as compared with the control (arm C) at high IGF-1 level (p = 0.16). When IGF-1 was fitted as a continuous variable, this reduction was 96% (p = 0.08). There was no correlation between tissue and serum IGF-1. Conclusions: Tissue expression of IGF-1 level may represent a promising predictive biomarker for IGF1R-directed therapy in APC.
Abstract
Background: PP4 has been reported to be overexpressed in breast and lung cancers. While previous studies have identified the role of PP4 in activating NFκB and JNK signaling pathway, the ...expression and functions of PP4 in pancreatic cancer has not been studied in detail. Methods: We examined the expression of PP4 protein in 133 patient samples of stage II pancreatic ductal adenocarcinoma (PDA) samples by immunohistochemistry (IHC). To confirm our IHC results, we measured the expression levels of PP4 mRNA in 15 PDA samples and 15 benign pancreatic tissue sample by real time RT-PCR. We also measured PP4 protein levels in in 9 fresh frozen PDA samples and their paired benign pancreatic tissues by Western blot. Using univariate and multivariate analysis, we correlated PP4 expression with survival and other clinicopathologic features. Results: PP4 was overexpressed in 75 of 133 (56%) stage II PDA samples by immunohistochemistry. Compared to benign pancreatic tissue, PP4 protein levels were higher in 9 of 9 PDA samples by Western blot analysis. PP4 mRNA expression levels in PDA samples were significantly higher than benign pancreatic tissue, suggesting that overexpression of PP4 in PDA is due to increase mRNA expression. PP4 overexpression was associated with higher frequencies of distant metastasis (p=0.02) and poor overall and recurrence-free survivals (p = 0.002 and 0.005) independent of tumor size, margin status, and lymph node status (stage) in patients with stage II PDAs. Conclusions: Our study shows that PP4 is frequently overexpressed in PDA samples and is associated with poor prognosis in patients with stage II PDA. Therefore, targeting PP4 signaling pathway may represent a new approach for the treatment of PDA.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5527. doi:1538-7445.AM2012-5527
Abstract
Background: TGFβ acts both as a tumor suppressor or tumor promoter depending upon cellular context and stage of tumor progression. TGFβ exerts its effects through the TGFβR1/ R2 receptors ...and the SMAD transcription regulators. We investigated the prognostic value of TGFβ signaling biomarkers in pancreatic cancer. Methods: We measured plasma TGFβ1 level using Meso Scale Discovery Multi-array® Human TGFβ1 Assay in 643 pancreatic cancer patients. TGFβR2 (Novus) and SMAD4 (Proteintech) protein expression were measured in 86 biopsies using immunohistochemisty (IHC). IHC intensity was scored 0-3. Percentage IHC-positive cancer cells were 0-3 (0: 0%+, 1: 1-10%+, 2: 10-25%+, 3: >25%+). Final IHC score was measured as intensity × percentage. We also genotyped 3 SNPs of TGFB1 gene using the Taqman assay. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) by TGFβ1 level. Multivariate Cox proportional hazards models with relevant clinical covariates were used to assess the relationship between IHC score and OS. Results: In patients with locally advanced and metastatic disease (n = 355), there was a significant association of plasma TGFβ1 with OS. OS of the top quartile of TGFβ1 levels (>19.05 ng/mL) vs. those with low level was 27.7 weeks vs. 40 weeks, respectively log-rank p = 0.0125, adjusted for baseline CA 19-9 and performance status (PS). No significant association between plasma TGFβ1 and OS was noted in surgical patients (n = 288). In the multivariate Cox model, after adjusting for baseline stage, CA 19-9, PS, age and TGFβR2 expression, complete loss of SMAD4 expression (IHC score 0) was significantly associated with lower OS HR (95% CI): 1.85 (1.06-3.23), p = 0.03. Progressive disease on gemcitabine-based therapy was more likely in SMAD4 IHC 0 group as compared with higher score (46.5% vs. 38.1% progressed; chi square p = 0.069). TGFB1 –1346T>C CT/TT genotype correlated with shorter OS HR (95% CI): 1.21 (1.02-1.45), p = 0.03 after adjusting for clinical variables. Conclusions: This large retrospective study suggests an important stage-dependant role of the TGFβ pathway in pancreatic cancer. Targeting this pathway in advanced pancreatic cancer may have therapeutic relevance.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4491. doi:1538-7445.AM2012-4491
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4043
Background: Currently, no definitive epigenetic markers exist to predict recurrence and overall survival (OS) of colorectal cancer patients after surgical resection. Promoter ...hypermethylation of the ID4 (inhibitor of DNA binding), RECK (reversion-inducing cysteine rich protein with Kazal motifs), and CHFR (checkpoint with forkhead-associated and RING finger domains) genes have been associated with reduced mRNA and protein expression in colorectal cancer. The purpose of this study was to determine the association of methylation of these genes and also MINT1 (methylated in tumor loci) with recurrence-free survival (RFS) and OS in colon cancer patients. Methods: DNA methylation was quantitatively evaluated using pyrosequencing in tissue samples from 64 patients with AJCC stage II and III colon cancer without HNPCC seen at M.D. Anderson during 1999–2007. Survival outcomes were determined by retrospective chart review and evaluated by Kaplan-Meier plot and log-rank test for univariate analysis and Cox's proportional hazard model for multivariate analysis. Mean methylation rate of multiple CpG sites in the promoter region was used. For this analysis, we defined <15%, 15%-30%, and >30% as methylation-negative, -low, and -high, respectively. Results: There were 19 stage II (30%) and 45 stage III (70%) patients. The median age was 62.1 years (range: 31–86). Adjuvant chemotherapy was completed in 49 patients (77%). After a median follow-up of 54.9 months, 12 (19%) patients developed recurrence and 7 (11%) have died. Methylation of MINT1, ID4, and RECK did not correlate with RFS and OS. The CHFR methylation-high (42%) group had low RFS (P=.04) and OS (P=.03) when compared with the CHFR methylation- negative (38%) and -low (20%) group. CHFR methylation-high was associated with N
2
disease (P=.04) and right-sided tumors (P=.002). Multivariate analysis indicated T
4
disease P=.004, HR=8.42 (95% CI: 1.98–35.8) and CHFR methylation-high P=.04, HR = 3.79 (95% CI: 1.04–13.8), were poor prognostic factors for recurrence. Conclusions: The presence of high CHFR promoter methylation correlates with advanced lymph node metastasis and shortened RFS and OS. Methylation of the CHFR promoter is a potential epigenetic marker for colon cancer recurrence and overall survival.
No significant financial relationships to disclose.
Abstract
Background: Cetuximab, the chimeric monoclonal antibody (mAb) directed against the human epidermal growth factor receptor (EGFR) is widely used for the treatment of colorectal cancer and is ...also effective in pancreatic cancer preclinical models. Acquired resistance to cetuximab is common and the IGF-1R signaling pathway is critically involved in this process. We hypothesized that the combined activation of EGFR and IGF1-R is responsible for the constitutive activation of the transcriptional factor STAT-3 which in turn results in acquired resistance to cetuximab in colorectal and pancreatic tumors. Targeting this activation of EGFR and IGF1-R using the combination of cetuximab and R1507 could potentially reverse this resistance.
Methods: A model of pancreatic cancer (PC) cell line resistant in vivo to cetuximab was established by injecting orthotopically, luciferase- and GFP- expressing AsPC-1 human PC cells into nude mice. Once established these tumors in vivo, the mice were treated with cetuximab 500 µg ip bi-weekly until the 34th week, when tumor growth occurred despite cetuximab due to acquired resistance. The tumors were rapidly excised and the GFP- positive cells were selected to establish the cetuximab- resistant clone AsPC-1-CR. Two models of colon cancer (CRC) cell line with acquired resistance in vivo to cetuximab, SW480-CR and GEO-CR, were established as previously described (Bianco et al. Clin Cancer Res. 2008 14(16):5069-80). MTT assay was used to assess the antitumor activity of cetuximab, R1507, and the combination in vitro. Synergy was assessed according the combination-index method of Chou and Talalay. The expression of IGF1-R was studied by Western blot. STAT-3 activation was analyzed by EMSA. Inhibition of directional cell migration was studied in an in vitro wound-healing model.
Results: The cetuximab- resistant PC and CRC cell lines, showed a significantly lower in vitro sensitivity to cetuximab when compared to the respective control cell lines. AsPC-1-CR and SW480-CR cells demonstrated a higher expression of IGF1-R. STAT-3 DNA binding activity was significantly increased in all of the cetuximab- resistant cells as compared with control cell lines. The addition of R1507 did not improve the antitumor activity of cetuximab in the control cell lines. However, the combination of cetuximab + R1507 reversed the resistance to cetuximab in the AsPC-1-CR and SW480-CR cell lines, thereby demonstrating synergistic antitumor activity in the setting of acquired resistance. R1507+cetuximab also significantly inhibited the migration of cetuximab- resistant CRC cells.
Conclusion: IGF-1R inhibition using R1507 is a promising approach to restore the sensitivity to cetuximab in PC and CRC cells that have developed acquired resistance.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 616.
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