Polymorphisms in the telomerase complex to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE and FIRE-3 phase III trials.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 566-566
Author(s):  
Francesca Battaglin ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Shu Cao ◽  
Alberto Puccini ◽  
...  
Keyword(s):  
Multivariable Analysis ◽  
Phase Iii ◽  
First Line ◽  
Discovery Cohort ◽  
Mutational Status ◽  
Phase Iii Trials ◽  
Telomere Capping ◽  
Predictive And Prognostic Value ◽  
The Impact

566 Background: Telomere/telomerase interplay is involved in the regulation of genomic stability and cellular replicative potential. In CRC, shortening of telomeres promotes early steps of carcinogenesis but the prognostic role of telomere length is debated. High circulating levels of telomerase reverse transcriptase (TERT) appear to be a negative prognostic biomarker and polymorphisms in the telomerase RNA component (TERC) are associated with increased cancer risk. We hypothesized that genetic variants in the telomerase/telomere capping complex may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 21 selected SNPs within 13 genes ( TERT, TERC, CLPTM1L, TERF1/2, POT1, ACD, NOP10, NHP2, GAR1, STN1, CTC1) was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 451 pts enrolled in two independent randomized trials. TRIBE FOLFIRI/bevacizumab (bev) arm (n=215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n=107, mPFS/OS: 11.5/31.4 mo) as validation and FOLFIRI/cetuximab (cet) arm (n=129, mPFS/OS: 12.8/49.8 mo) as control. Results: In the discovery cohort, pts carrying any A allele of TERT rs2075786 showed longer mPFS (11.1 vs 9.3 mo, P= .021) and OS (33.5 vs 25 mo, P= .005) compared to the G/G genotype in multivariable analysis. Same results were observed for pts carrying any T allele of CLPTM1L rs401681 compared to the C/C genotype ( P= .022). Any C allele carriers of TERC rs2293607 also showed longer mOS in multivariable analysis ( P= .041) and the A/A genotype of ACD rs6979 was associated with longer mPFS in both uni- and multivariable analysis. Interestingly, the T/T genotype of CLPTM1L rs401681 was associated with shorter mPFS (7.8 vs 13.5 mo) in the cet cohort in uni- ( P= .003) and multivariable analysis ( P= .041). In subgroup analyses based on RAS mutational status several SNPs in additional genes were associated with PFS and/or OS in different cohorts. Conclusions: Our results suggest that SNPs in core telomerase/telomere capping complex genes may have a predictive and prognostic value in mCRC pts receiving targeted first-line treatments.

Genetic variations within the CD40L immune stimulating gene predict outcome for mCRC patients treated with first-line FOLFIRI/bevacizumab: Data from FIRE-3 and TRIBE.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 558-558
Author(s):  
Martin D. Berger ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Shu Cao ◽  
Yuji Miyamoto ◽  
...  
Keyword(s):  
Data Extraction ◽  
Predictive Marker ◽  
Phase Iii ◽  
First Line ◽  
Angiogenic Therapy ◽  
Cell Mediated Immune Response ◽  
Phase Iii Trials ◽  
Validation Set ◽  
The Impact ◽  
First Time

558 Background: The introduction of immunotherapy has significantly improved outcome in various tumors. Immune stimulating proteins exert an anti-tumor effect mainly through enhancing T-cell mediated immune response. Additionally, preliminary data suggest a major role of immune stimulating proteins in modulating angiogenesis. We therefore hypothesize that variations in genes involved in the immune activation pathway may predict outcome in pts with mCRC treated with first-line FOLFIRI/ bevacizumab (bev). Methods: The impact of 4 functional SNPs within the CD40L, Light, OX40L and ICOS genes on outcome was evaluated in 322 pts with mCRC treated with first-line FOLFIRI/bev in two randomized phase III trials. We used TRIBE as a discovery (n = 215) and FIRE-3 as a validation set (n = 107). One hundred twenty-nine pts treated with FOLFIRI/cetuximab (cet) served as a control cohort (FIRE-3). OncoArray, a custom array manufactured by Illumina was used for data extraction. Genomic DNA was extracted from blood. Results: Baseline characteristics: FOLFIRI/bev, discovery set (TRIBE), median PFS/OS/FU 9.7/26.2/48.9 mo; FOLFIRI/bev, validation set (FIRE-3), PFS/OS/FU 11.5/32.4/71.1 mo; FOLFIRI/cet, control set (FIRE-3) PFS/OS/FU 12.8//23.9/70.7 mo. The CD40L rs1126535 SNP showed significant association with OS. Pts in the discovery cohort harboring any T allele and treated with FOLFIRI/bev had a longer median OS compared to C/C carriers (27.9 vs. 20.0 mo) in both univariate (HR 1.83, 95% CI 1.19-2.81, p = 0.005) and multivariate analyses (HR 1.62, 95% CI 1.03-2.56, p = 0.038). Similarly, any T allele carriers in the validation cohort had a significantly longer median OS than those harboring a C/C genotype (40 vs. 19.0 mo) in the multivariate analysis (HR 2.80, 95% CI 1.05-7.50, p = 0.040). However, this association could not be shown in pts receiving FOLFIRI/cet (HR 0.60, 95% CI, 0.18-1.94, p = 0.38). Conclusions: We show for the first time that the CD40L polymorphism rs1126535 might serve as a predictive marker in pts with mCRC treated with FOLFIRI/bev. Targeting CD40L might be promising to further improve treatment against mCRC and to overcome resistance to anti-angiogenic therapy.

GEMOX as first-line chemotherapy in advanced pancreatic cancer (APC): A monoinstitutional experience

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15179-15179
Author(s):  
M. Di Marco ◽  
E. Nobili ◽  
R. Di Cicilia ◽  
G. Brandi ◽  
S. Bertolini ◽  
...  
Keyword(s):  
Advanced Pancreatic Cancer ◽  
Complete Response ◽  
Median Number ◽  
Phase Iii ◽  
First Line ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Number Of Cycles ◽  
The Impact ◽  
Line Chemotherapy

15179 Background: To date, gemcitabine (GEM) remains the cornerstone of chemotherapy (CHT) for APC. According to GERCOR and GISCAD phase III trials the combination of GEM and oxaliplatin (GEMOX) has proven superior to GEM alone in terms of response rate (RR), time to progression (TTP) and clinical benefit rate (CBR). Methods: We conducted a retrospective analysis on 19 patients (pts) affected with histologically-confirmed APC, in order to determine the impact of GEMOX as first-line chemotherapy in terms of objective responses (OR) and TTP, using the Kaplan-Meier method. Among the 19 pts considered there were 15 males and 4 females (median age at diagnosis of 60.84 yrs; ECOG 0–2). The staging, according to AJCC criteria, was: IIB in 1 case, III in 5 cases and IV in the 13 remaning cases. The only metastatic site was the liver (in 13/19 pts). Ten of the 19 pts underwent surgical treatment prior to CHT: 2 radically resected (R0) subsequently treated with GEMOX after recurrence, 4 with positive margins (R1) and 4 surgically palliated. All pts received GEM 1000 mg/m2/d1 + oxaliplatin 100 mg/m2/d2 every 2 weeks. The median number of cycles was 5.89. Results: Among the 19 pts, 3 had a partial response (PR, 15.69%), 6 had stable disease (SD, 31.57%); no complete response was observed and 10 pts had progressive disease (PD, 52.63%). The overall disease control rate (DCR: PR + SD) was 47.37% while the OR were 15.69%. The median survival observed was 9.03 months (95% C.I. 5.15–12.91) and the median TTP was 6.13 months (95% C.I. 2.81–9.46). The main toxicities were: leucopenia, piastrinopenia, diarrhoea, nausea, fever and peripheral neuropathy; 3 pts discontinued the treatment due to grade 3–4 neurotoxicity. Conclusions: In our experience GEMOX gives an improved control of APC in terms of OR and TTP, with acceptable toxicity. The OS is in accordance to literature as well as the other data. No significant financial relationships to disclose.

Impact of single agent daily prednisone on survival and toxicities in post-docetaxel men with metastatic castration-resistant prostate cancer (mCRPC): An analysis of 2 phase III trials.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 213-213
Author(s):  
Guru Sonpavde ◽  
Gregory Russell Pond ◽  
Arnoud J. Templeton ◽  
Eugene D. Kwon ◽  
Johann S. De Bono
Keyword(s):  
Statistical Significance ◽  
Oral Prednisone ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Grade 3 ◽  
Combination Regimens ◽  
The Impact

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.

Genetic variants in R-Spondin/RNF43 complex and gene expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 190-190
Author(s):  
Francesca Battaglin ◽  
Yi Xiao ◽  
Joshua Millstein ◽  
Andreas Seeber ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Multivariable Analysis ◽  
Colorectal Carcinogenesis ◽  
Phase Iii ◽  
First Line ◽  
Tissue Samples ◽  
Expression Levels ◽  
The Impact ◽  
Gene Expression Levels

190 Background: Wnt signaling deregulation is a primary driver of colorectal carcinogenesis. RNF43 is a key suppressor of Wnt activation while R-Spodin inhibits RNF43 activity. RNF43 mutations are associated with the serrated neoplasia pathway, BRAF mutation and MSI. We hypothesized that genetic variants in the R-Spodin/RNF43 complex and corresponding genes expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 17 functional SNPs within RNF43/ ZNRF3, LGR4/5 and RSPO1/2/3 was analyzed in 129 pts treated with first-line FOLFIRI/cet and 107 pts treated with FOLFIRI/bevacizumab (bev). Gene expression levels were measured from tumor tissue samples from 102 pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. False discovery rate (FDR) for gene expression analysis was computed using the Benjamini-Hochberg approach (significant Q < 0.1). Results: In the cet cohort, pts with the C/C genotype of ZNRF3 rs132531 had significantly shorter overall survival compared to any T allele carriers (mOS: 20.3 vs 52 mo) in both univariable (HR 3.61, 95% CI 1.65-7.88, P < .001) and multivariable analysis (adjusted P = .01). Conversely, RSPO1 rs4652964 any G allele carriers showed increased tumor response (TR) rates compared to the A/A genotype (83 vs 66 %, P = .04). These associations were not observed in bev arm. Lower gene expression levels of RNF43 were associated with shorter PFS in pts with right-sided tumors receiving FOLFIRI/cet ( P = .006, Q < 0.1). RSPO1 expression levels were also associated with TR in the same subgroup (70 vs 10% in high vs low; P = .001, Q < .05). RNF43 expression was associated with TR in pts with left-sided tumors (82% in high vs 58% in low, P = .014, Q = 0.1). Conclusions: Our results provide the first evidence that germline polymorphisms and tumor gene expression levels of RNF43/ ZNRF3 and RSPO1 may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and contribute to modulate anti-EGFRs activity.

Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab (cet) in patients (pts) with metastatic colorectal cancer (mCRC): Data from the FIRE-3 phase III trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 564-564
Author(s):  
Francesca Battaglin ◽  
Alberto Puccini ◽  
Shu Cao ◽  
Joshua Millstein ◽  
Ryuma Tokunaga ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Receptor Complex ◽  
Tlr4 Expression ◽  
First Line ◽  
Expression Levels ◽  
Ras Status ◽  
In Fire ◽  
The Impact

564 Background: Large metagenomic studies associate disrupted gut microbiome signatures, comprising more prevalently gram-negative bacteria, with CRC carcinogenesis. TLR4, the LPS receptor, has been involved in microbiota-mediated tumorigenesis. High TLR4 expression is associated with poor prognosis in CRC and TLR4 can activate EGFR through ligands epiregulin and amphiregulin. Hence, we hypothesized that genetic variants in the LPS receptor complex and TLR4 expression levels may predict cetuximab efficacy in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in the randomized FIRE-3 trial was genotyped through the OncoArray, a custom array manufactured by Illumina. The impact on outcome of 5 functional SNPs within TLR4, MD2 and CD14 was analyzed in 129 pts treated with first-line FOLFIRI/cet (discovery, mPFS/OS: 12.8/49.8 mo) and 107 pts treated with FOLFIRI/bevacizumab (bev) (mPFS/OS: 11.5/31.4 mo). Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the discovery cohort, pts carrying the C/T variant of TLR4 rs4986791 had significantly shorter mPFS and OS compared to the C/C genotype in both uni- and multivariable analysis (PFS: 5.4 vs 13.3 mo, adjusted P[ Padj] = .01; OS: 21.7 vs 40.7 mo, Padj= .03). Conversely, C/C carriers of rs12377632 had a longer mPFS compared to any T in uni- and multivariable analysis (15.8 vs 12.2 mo, Padj< .001). Any A allele carriers of MD2 rs12546552 and any G allele carriers of CD14 rs2569190 showed shorter mPFS in multivariable analyses. These associations were not observed in bev arm. Significant interaction was found between TLR4 rs12377632 and RAS status ( P= .015). High TLR4 expression (log2 > 10.93) was associated with worse mPFS (7.2 vs 11 mo, P= .003) and OS (19.1 vs 29.8 mo, P< .001) in FIRE-3 cet arm. Conclusions: Our results provide the first evidence that polymorphisms in the LPS receptor complex and TLR4 expression levels may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment and, overall, contribute to resistance to anti-EGFRs.

Effect of KRAS and NRAS mutational status on first-line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer (mCRC): New results from the CRYSTAL trial.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. LBA443-LBA443 ◽  
Author(s):  
Fortunato Ciardiello ◽  
Heinz-Josef Lenz ◽  
Claus-Henning Kohne ◽  
Volker Heinemann ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Mutation Detection ◽  
Antibody Therapy ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Exon 2 ◽  
Ras Mutation ◽  
Mutational Status ◽  
The Impact ◽  
Kras Exon

LBA443 Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detection is ongoing using BEAMing (Beads, Emulsions, Amplification, and Magnetics) with a mutation detection cut-off of 0.1%. Tumor genomic DNA samples from 541 randomized patients with KRAS exon 2 wt disease (81% of KRAS wt patient population) and tumor material available are currently being screened. Treatment arms will be compared using two-sided log-rank tests for PFS and OS, and the Cochran–Mantel–Haenszel (CMH) test for response. Results: RAS mutation status is currently available from 192 patients (28.8% ascertainment) with further RAS assessment ongoing. Currently 63.5% of the samples are RAS wt and 36.5% are new RAS mutations. Conclusions: Updated information on the full RAS mutation dataset of up to 400 samples combined with the clinical data will be presented and implications for patient care discussed.

Gene expression and genetic variants in Parkinson's disease (PD) genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3 phase III trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3595-3595
Author(s):  
Francesca Battaglin ◽  
Shu Cao ◽  
Alberto Puccini ◽  
Ryuma Tokunaga ◽  
Madiha Naseem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Methylation Status ◽  
Multivariable Analysis ◽  
Epidemiological Studies ◽  
Tumor Location ◽  
Phase Iii ◽  
First Line ◽  
Age Related ◽  
The Impact

3595 Background: PD is one of the most common age-related neurodegenerative disorders. Large epidemiological studies have consistently reported a reduced risk of CRC in PD patients (pts), but the biology behind this evidence is unclear. The methylation status of SNCA, one of the causal PD genes, has been identified as a tool for CRC screening and early diagnosis when detected in stool samples, and alterations in core PD genes are prevalent across human malignancies including CRC. Methods: The impact on outcome of 13 SNPs within 6 core PD genes ( SNCA, PRKN, UCHL1, PINK1, DJ-1, LRRK2) was analyzed in pts enrolled in the randomized FIRE-3 trial. Genomic DNA from blood samples of pts treated with first-line FOLFIRI-cetuximab (cet, n = 129) and FOLFIRI-bevacizumab (bev, n = 107) was genotyped through the OncoArray, a custom array manufactured by Illumina. Gene expression levels were measured from 102 tumor samples of pts in the cet arm by HTG EdgeSeq Oncology Biomarker Panel. Results: In the cet cohort, pts carrying the G/G variants of SNCA rs356165 and rs2736990 had significantly shorter mOS (30 vs 41.1 mo) compared to any A genotype in both uni- and multivariable analysis (adjusted P[ Padj] = .047 and .042, respectively). LRKK2 rs3761863 T/T allele carriers showed shorter mPFS (9.5 vs 13.3 mo, Padj = .01), while rs11564148 any A carriers had longer mPFS (14.2 vs 10.2 mo, Padj = .01) compared to reference genotypes. LRKK2 rs11564148 any A carriers also showed longer mOS in multivariable analysis (43.7 vs 33.2 mo, Padj = .044). Any C allele carriers of PINK1 rs1043424 showed longer mPFS in uni- and multivariable analysis ( Padj < .001). No significant interaction was found with gender, tumor location and RAS status. These associations were not observed in bev arm. High SNCA expression was associated with worse mPFS (log2 > 7.89, 5.9 vs 11.2 mo) and mOS (log2 > 7.68, 17.9 vs 31.1 mo) in FIRE-3 cet arm ( P < .05). Conclusions: We provide the first evidence that gene expression and genetic variants in PD genes may have a predictive value in mCRC pts receiving first-line cetuximab-based treatment. Our findings open new perspectives on the role of PD genes in CRC biology warranting further investigation.

Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3048-3048
Author(s):  
Francesca Battaglin ◽  
Shu Cao ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Meta Analysis ◽  
Critical Role ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
The Impact

3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( PFDR= 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( PFDR= 0.056), and between SLC6A3 rs6347 and OS ( PFDR= 0.041) and SLC6A3 rs6876890 and TR ( PFDR= 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.

Polymorphisms in beta-defensin pathways and clinical outcomes in metastatic colorectal cancer patients treated with FOLFIRI-bevacizumab in two randomized phase III trials.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 662-662
Author(s):  
Madiha Naseem ◽  
Martin D Berger ◽  
Alberto Puccini ◽  
Ryuma Tokunaga ◽  
FRANCESCA BATTAGLIN ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcomes ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Negative Control ◽  
Snp Markers ◽  
Phase Iii ◽  
Wild Type ◽  
Phase Iii Trials ◽  
The Impact

662 Background: Beta defensin 1 (DEFB1) and 2 (DEFB4A) are antimicrobial peptides secreted from colonic epithelial cells in response to inflammation. DEFB1 has been shown to serve as a tumor suppressor, whereas high concentrations of DEFB4A are linked with angiogenesis. This study examines the impact of single nucleotide polymorphisms (SNPs) in beta-defensin pathways in two independent phase III trials: FIRE-3 and TRIBE. Methods: The OncoArray database containing 530K SNP markers provided by Illumina was used to find associations between clinical outcomes and 10 functional SNPs from DEFB1, DEFB4A, PPARG, NFKB1, MUC2, and TLR4 genes. Patients treated with first-line FOLFIRI/bevacizumab (bev) in the randomized phase III FIRE-3 trial (n = 107) and TRIBE trial (n = 215) served as discovery and validation cohorts respectively. The FIRE-3 FOLFIRI and cetuximab (cet) arm served as a negative control (n = 129). Results: A total of 451 patients were included. The NFKB1 rs3821958 SNP showed significant association with OS and PFS in overall pts and those with left-sided CRC. Compared to pts carrying the mutant A allele, those with the wild-type G/G genotype had a shorter median OS (19 vs 40 mts) and PFS (9.2 vs 11.7 mts) in both univariate ((OS: HR = 2.32, 95%CI 1.21-4.42, p = 0.006) (PFS: HR = 1.93, 95%CI: 1.11-3.37, p = 0.014)) and multivariable analysis ((OS: HR = 2.90, 95%CI 1.47-5.70, p = 0.002) (PFS: HR = 2.08, 95%CI:1.18-3.67, p = 0.012)). This finding was validated in TRIBE, where carriers of G allele had shorter PFS in univariate analysis (HR = 1.44, p = 0.019). Opposite results were observed in pts receiving cet, where G/G carriers had improved OS in univariate analysis (HR = 0.46, p = 0.048). Pts with left-sided CRC who carried the wild-type allele had poorer OS and PFS in both trials. Conclusions: NFKB1 rs3821958 SNP is known to activate DEFB1 and is downstream of EGFR. Harboring a mutant allele in this SNP confers a mortality benefit in left-sided and overall pts treated with bev, and worsens OS in pts receiving cet. Hence, NFKB1 could serve as an important predictive biomarker. Future studies are warranted to further elucidate its role in colorectal cancer.

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