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.

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.

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.

CCR5 Δ32 mutation and gene expression to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC phase III trials.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 170-170
Author(s):  
Annika Lenz ◽  
Wu Zhang ◽  
Yi Xiao ◽  
Joshua Millstein ◽  
Shivani Soni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cox Regression ◽  
Phase Iii ◽  
Line Treatment ◽  
Ccr5 Expression ◽  
First Line ◽  
Ccr5 Gene ◽  
Expression Levels ◽  
The Impact ◽  
First Line Treatment

170 Background: Germline polymorphisms in CCR5 have been associated with treatment outcome in pts with mCRC receiving regorafenib and cetuximab-based treatment. CCR5 Δ32, a loss of function deletion, plays a key role in infectious diseases but data in CRC are scarce. We tested whether CCR Δ32 and CCR5 gene expression may be associated with outcome in mCRC pts receiving first-line treatment. Methods: The impact of CCR5 Δ32 was evaluated in 614 pts enrolled in the randomized FIRE-3 trial (FOLFIRI/cetuximab, cet, n = 313; FOLFIRI/bevacizumab, bev, n = 301). Gene expression was evaluated in 102 pts in the FOLFIRI/cet arm from FIRE-3 and 155 pts treated in the MAVERICC trial (FOLFIRI/bev, n = 76; FOLFOX6/bev, n = 79) from tumor tissue by HTG EdgeSeq Oncology Biomarker Panel and NanoString expression panel, respectively. The association between CCR5 Δ32 and clinical outcomes was evaluated using Cox regression and log-rank tests. Gene expression was dichotomized using an optimal cutoff and P-values computed using a permutation-based approach. Results: In FIRE-3, CCR5 Δ32 was significantly associated with worse PFS in patients with right-sided tumors (RT) receiving FOLFIRI/cet (n = 32; median PFS 3.41 vs 7.84 mo; HR 4.39, 95%CI 1.12-17.24; P= .022;). These associations were not observed in left-sided tumors or pts treated with bev. Lower levels of CCR5 expression trended to be associated with shorter PFS and OS in the same subgroup of RT treated in the cet arm ( P= .096 and P= .063 for PFS and OS, respectively). Lower CCR5 expression was associated with longer PFS in pts treated with FOLFIRI/bev in the MAVERICC trial, regardless of tumor side (mPFS 17.91 vs 11.04 mo; P= .03). A significant interaction between the impact of CCR5 expression levels on PFS and chemotherapy backbone was observed ( P= .019). Low CCR5 expression was associated with worse PFS in pts with RT treated with oxaliplatin (11.10 vs 13.80 mo; P= 0.023). Conclusions: Our results provide the first evidence that CCR5 Δ32 and CCR5 gene expression levels may predict outcomes in mCRC pts receiving first-line treatment with a differential effect depending on tumor location, biologic agent and chemotherapy backbone.

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.

scholarly journals Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

2021 ◽  
Vol 9 (4) ◽  
pp. e002421
Author(s):  
Alessio Cortellini ◽  
Massimo Di Maio ◽  
Olga Nigro ◽  
Alessandro Leonetti ◽  
Diego L Cortinovis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Metastatic Nsclc ◽  
The Impact

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

Validation of the decipher genomic classifier (GC) in SAKK 09/10: A phase III randomized trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy (RP).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5010-5010
Author(s):  
Alan Dal Pra ◽  
Pirus Ghadjar ◽  
Stefanie Hayoz ◽  
Daniel Eidelberg Spratt ◽  
Vinnie YT Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Controlled Trial ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Phase Iii ◽  
Clinical Progression ◽  
Clinical Value ◽  
Prognostic Utility ◽  
The Impact

5010 Background: GC has been shown to independently prognosticate outcomes in prostate cancer. Herein, we validate the GC in a European randomized phase III trial of dose escalated SRT after RP. Methods: SAKK 09/10 (NCT01272050) randomized 350 patients with biochemical recurrence after RP to 64Gy vs 70Gy. No patients received androgen deprivation therapy (ADT) or pelvic nodal radiotherapy. A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. RP samples were centrally reviewed for the highest-grade tumor and those passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to obtain the GC score (0 to 1; < 0.45, 0.45-0.6, > 0.6 for low-, intermediate-, and high, respectively). The primary aim of this study was to validate the GC for the prediction of freedom from biochemical progression (FFBP) using Cox multivariable analysis (MVA) adjusting for age, T-category, Gleason score, persistent PSA after RP, PSA at randomization, and randomization arm. The secondary aims were to evaluate the association of GC with clinical progression-free survival (CPFS) and use of salvage ADT. Results: Of 233 patients with tissue available, 226 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 6.3 years (IQR 6.0-7.2). GC score (continuous per 0.1 unit, score 0-1) was independently associated with FFBP (HR 1.14 [95% CI 1.03-1.25], p = 0.009). Higher GC scores were independently associated with CPFS, use of salvage ADT, and rapid biochemical failure ( < 18 months after SRT). High- vs. low/intermediate-GC showed a HR of 2.22 ([95% CI 1.37-3.58], p = 0.001) for FFBP, 2.29 ([95% CI 1.32-3.98], p = 0.003) for CPFS, and 2.99 ([95% CI 1.50-5.95], p = 0.002) for use of salvage ADT. Patients with high-GC had 5-year FFBP of 45% [95% CI 32-59] vs 71% [95% CI 64-78] in low-intermediate GC. Similar estimates for GC risk groups were observed in the 64Gy vs 70Gy in GC high (5-year FFBP of 51% [95% CI 32-70] vs 39% [95% CI 20-59]) and in low-intermediate GC (75% [95% CI 65-84] vs 69% [95% CI 59-78]). Conclusions: This study represents the first contemporary randomized controlled trial in patients with recurrent prostate cancer treated with early SRT without ADT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and radiotherapy dose, patients with a high-GC were more than twice as likely than a lower GC score to experience biochemical and clinical progression and receive salvage ADT. This data confirms the clinical value of Decipher GC for tailoring treatment in the postoperative salvage setting.

Growth in eligibility criteria content and failure to accrue among National Cancer Institute (NCI)-affiliated clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1515-1515
Author(s):  
John Stuart Peterson ◽  
Deborah Plana ◽  
Danielle Sara Bitterman ◽  
Skyler B Johnson ◽  
Benjamin Harris Kann
Keyword(s):  
Multivariable Analysis ◽  
Phase Iii ◽  
Word Count ◽  
Eligibility Criteria ◽  
Support Unit ◽  
National Priority ◽  
Clinical Trial Accrual ◽  
Unique Word ◽  
Cancer Trials ◽  
The Impact

1515 Background: Cancer clinical trial accrual across diverse socioeconomic and demographic groups is a national priority, yet up to 20% of trials fail due to poor accrual. Eligibility criteria content may contribute to poor accrual, but effects are challenging to measure. We sought to evaluate growth of eligibility criteria within NCI-affiliated cancer trials and the impact on trial accrual over the past decade. Methods: We conducted a retrospective study with the Aggregate Analysis of ClinicalTrials.gov (AACT) (abstracted: 02/02/2021). We included NCI-affiliated, interventional Phase II or III trials that initiated between 01/01/2008 and 12/13/2018. We excluded active and recruiting trials that lacked accrual data on the Cancer Trials Support Unit website. Trials whose status was “Withdrawn”, “Terminated”, or “Suspended” due to low accrual, or had less than 50% target accrual after two years active were deemed accrual failures. Eligibility criteria were extracted from inclusion and exclusion criteria and complexity was estimated by the number of unique content words, calculated by removing duplicates and stop words from the word count. Association of unique word count with accrual failure was evaluated by univariable and multivariable logistic regressions, adjusting for other predictors of low accrual identified in earlier research. Results: Of 1197 trials included, 231 (19.3%) failed due to low accrual. Eligibility criteria increased in length from a median of 214 (IQR [23, 282]) unique content words in 2008 to 417 (IQR [289, 514]) in 2018. The rate of trial accrual failure increased with unique word count decile from 11.8% in the first decile (12 to 112 words) to 29.4% in the tenth decile (445 to 750 words) (P = 0.004). On multivariable analysis, unique word count remained independently associated with low accrual (OR: 1.07 per decile, 95%CI [1.01-1.13], P = 0.02), as did Phase III and metastatic disease settings (Table). Conclusions: Eligibility criteria content has increased dramatically in the last decade in NCI-affiliated trials. Increasing eligibility criteria content associates strongly with accrual failure, even after adjusting for multiple known predictors of accrual. These findings underscore the need for efforts to simplify eligibility criteria to improve trial accrual. Further investigation is ongoing to determine specific criteria qualities that portend accrual failure.[Table: see text]

Genetic variants involved in the lipid metabolism pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC trials.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 118-118
Author(s):  
Jingyuan Wang ◽  
Joshua Millstein ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Genetic Variants ◽  
Progression Free Survival ◽  
Snp Markers ◽  
Acid Oxidation ◽  
Metabolism Pathway ◽  
Increased Risk ◽  
In Fire ◽  
The Impact

118 Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches the glucose-dependent metabolism to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer. Previous reports suggested that polymorphisms of the lipid metabolism-related genes are associated with the increased risk of CRC and poor clinical outcome in CRC. Therefore, we hypothesized that genetic variants in the lipid metabolism pathway may predict first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 and MAVERICC, was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 25 selected SNPs in 10 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1, LPCAT2, PPARG, CPT1A, ACSS2, SREBF1, FASN, ACACA) was analyzed. Those treated with FOLFIRI/ bevacizumab (bev) in FIRE-3 (n = 107) and MAVERICC (n = 163) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/ cetuximab (cet) (n = 129) arm was used as the control. Interaction between each SNP and treatment was evaluated in FIRE-3 (FOLFIRI/bev arm vs. FOLFIRI/cet arm). Results: In the discovery (FIRE-3 bev) cohort, pts with FASN rs4485435 any C allele (N = 21) showed significantly shorter progression-free survival (PFS) (8.69 vs 13.48 months) compared to carriers of G/G (N = 62) in both univariate (hazard ratio [HR] = 2.88; 95% confidence interval [CI]: 1.57-5.29; p = 0.00037) and multivariate (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analyses. These data were validated in the MAVERICC bev cohort in multivariate analysis (11.17 vs 14.06 months; HR = 2.07; 95%CI: 1.15-3.74; p = 0.02). Pts carrying any T allele in PPARG rs3856806 (N = 36) showed significantly longer overall survival (OS) (Not reached vs 42 months) than carriers of C/C (n = 93) in the FIRE-3 cet cohort in both univariate (HR = 0.4; 95%CI 0.17-0.92; p = 0.03) and multivariate (HR = 0.37; 95%CI 0.15-0.93; p = 0.02) analyses, but the association was not observed in the bev cohort of MAVERICC and FIRE-3. In the comparison of bev arm vs cet arm in FIRE-3, interactions were shown with FASN rs4485435 (p = 0.017) on PFS and PPARG rs3856806 (p = 0.059) on OS. Conclusions: Our study demonstrates for the first time that FASN polymorphism could predict outcomes of bev-based treatment in mCRC patients; Meanwhile PPARG polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF/EGFR treatment.

scholarly journals Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

2015 ◽  
Vol 33 (25) ◽  
pp. 2735-2744 ◽  
Author(s):  
Thomas Sandmann ◽  
Richard Bourgon ◽  
Josep Garcia ◽  
Congfen Li ◽  
Timothy Cloughesy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Analysis ◽  
Molecular Subtype ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Wild Type ◽  
First Line ◽  
Data Set ◽  
Total N ◽  
Biomarker Analysis

Purpose The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup. Patients and Methods A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype. Results A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only. Conclusion Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set.

Lapatinib plus letrozole compared with letrozole alone as first-line therapy in hormone receptor positive HER2+ metastatic breast cancer (MBC): A quality-of-life (QOL) analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1039-1039 ◽  
Author(s):  
B. N. Sherif ◽  
B. Sherrill ◽  
M. Amonkar ◽  
Y. Wu ◽  
J. Maltzman ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Patient Population ◽  
Metastatic Breast ◽  
Analysis Of Covariance ◽  
Phase Iii ◽  
First Line ◽  
First Line Therapy ◽  
Hormone Receptor Positive ◽  
Line Therapy ◽  
The Impact

1039 Background: A phase III randomized double-blind multicenter trial compared lapatinib plus letrozole (L+Let) with letrozole plus placebo (Let), as first-line therapy for hormone receptor positive (HR+) MBC. Median PFS, the primary endpoint of the study, in patients who were HER2+ was significantly prolonged for L+Let compared with Let (8.2 vs 3 months, Hazard Ratio (95% CI)=0.71(0.53,0.96), p=0.019). This analysis focuses on the impact of treatments on QOL in the HER2+ subgroup. Methods: QOL outcomes included the Functional Assessment of Cancer Therapy-Breast (FACT-B) total, FACT-general (FACT-G), and trial outcome index (TOI) scores assessed at screening, every 12 weeks and at withdrawal. Higher scores indicate better QOL. Changes from baseline were analyzed using analysis of covariance. In a responder analysis, patients achieving minimally important differences in QOL scores (QOL responders) were compared with Fisher's exact test. Results: Among 1,286 patients, 219 were identified as HER2+ (L+Let n=111; Let n=108). Baseline QOL scores were comparable in the two arms. In this population, mean changes in subscale and total QOL scores were generally stable over time in both treatment arms for patients who stayed on study. For example, on the FACT-B, the average change from baseline in both groups was positive at all scheduled visits through Week 48 and the maximum difference between arms was 2.6 points (CI: -5.8, 11). There were no significant differences between the two treatment arms in percentage of QOL responders (Table). Conclusions: The addition of lapatinib to letrozole significantly increases PFS while maintaining QOL when compared with letrozole alone thus confirming the clinical benefit of the combination therapy in the HR+, HER2+ MBC patient population. This combination provides an effective option in this patient population by maintaining QOL and delaying the need for chemotherapy and its accompanying side effects. [Table: see text] [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document