TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) central nervous system (CNS) metastases (mets).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 515-515 ◽  
Author(s):  
Carey K. Anders ◽  
Allison Mary Deal ◽  
Vandana Gupta Abramson ◽  
Minetta C. Liu ◽  
Anna Maria Storniolo ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Topoisomerase I ◽  
Molecular Subtype ◽  
Brain Mri ◽  
Predictive Biomarkers ◽  
Volumetric Analysis ◽  
Repair Gene ◽  
Kaplan Meier ◽  
Dna Repair Gene ◽  
Cancer Agent

515 Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (> 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7–4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR + PR + SD ≥ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.

RAD51Bme as predictive biomarker for PD-1 blockade response in non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15235-e15235
Author(s):  
Inês Maria Guerreiro ◽  
Daniela Barros-Silva ◽  
Paula Lopes ◽  
Ana Luísa Cunha ◽  
João Lobo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Dna Repair Gene

e15235 Background: Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with likelihood of response to specific checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B, a DNA-repair gene, as candidate predictive biomarker for efficacy of anti-PD-1 therapy in patients with non-small cell lung cancer (NSCLC), correlating with patients’ outcome. Methods: PD-L1 immunoexpression and RAD51Bme levels were analysed in samples of NSCLC obtained from patients not treated with anti-PD-1 blockade (testing cohort) and patients treated with anti-PD-1 (validation cohort). Results: Of a total of 127 patients assessed, 58.3% depicted positivity for PD-L1 (PD-L1+). RAD51Bme levels significantly associated with PD-L1 immunoexpression. Patients with clinical benefit from immunotherapy disclosed higher RAD51Bme levels (p = 0.04) and significantly higher median progression free survival (PFS) (p = 0.02). PD-L1+ was also associated with longer overall survival (p = 0.03). Conclusions: We demonstrated that RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

A germline microRNA-based biomarker signature of immune-associated toxicity to anti-PD1/PDL1 therapy.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 96-96
Author(s):  
Joanne B. Weidhaas ◽  
Aaron Wolfe Scheffler ◽  
David Salzman ◽  
Anusha Kalbasi ◽  
Kirk Wilenius ◽  
...  
Keyword(s):  
Predictive Value ◽  
Germ Line ◽  
Immune Therapy ◽  
Predictive Biomarkers ◽  
Training Data ◽  
Cancer Type ◽  
Repair Gene ◽  
Validation Data ◽  
Dna Repair Gene ◽  
Biomarker Signature

96 Background: Treatment with anti-PD1/anti-PDL1 agents is associated with toxicity termed immune related adverse events (iRAEs). While the prevalence of Grade 2 and higher iRAEs is approximately 25-30%, biomarkers have not been previously identified. We tested the hypothesis that functional, germ-line mutations would predict iRAEs. Methods: Four classifiers were trained on a set of 61 melanoma patients evaluated for toxicity and response. Subjects were classified as experiencing high toxicity (≥ Grade 2) vs low toxicity (< Grade 2). Performance of the classifiers was tested on a validation set of 89 cancer patients with a variety of cancer types, with the most common being GU and NSCLC. Classifiers were built for each treatment of marker data including classification trees, LASSO-regularized logistic regression, boosted trees (BT), and random forests. The final performance measures, accuracy, specificity, sensitivity, negative predictive value, positive predictive value, area under the curve (AUC), and F1 score, were reported on the categorical treatment of the training data using leave-one-out cross validation on the validation data. We also evaluated the association between our most significant toxicity biomarker and response to anti-PD1/PDL1 therapy. Results: Within the melanoma training sample, we found a biomarker signature where toxicity is predicted with 79.0% accuracy (F1 = .714, AUC = .827) using BT. The same biomarker panel also accurately predicted toxicity in the validation cohort with 85.6% accuracy (F1 = .760, AUC = .883). Of the most predictive biomarkers, three were in microRNA binding sites in RAC1, CD274, and KRAS, two in immune related genes IL2RA and FCGR2A, and one in the DNA repair gene ATM. Our most significant biomarker in RAC1 did not predict response to anti-PD1/PDL1 treatment (p=0.91). Conclusions: We have identified a germ-line biomarker signature which predicts Grade 2 or higher iRAEs for patients treated with anti-PD1/anti-PDL1 therapy, regardless of cancer type, and does not predict an increased likelihood of response to these therapies. These findings are an important step in defining how to better safely personalize immune therapy, whose use is growing rapidly.

scholarly journals A 15-DNA Repair Gene Prognostic Signature for Immunotherapy in Gastric Cancer

2021 ◽  
Author(s):  
Binbin Yuan ◽  
Chengfei Jiang ◽  
Lingyan Chen ◽  
Jinlong Cui ◽  
Min Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Repair ◽  
Scoring System ◽  
Predictive Biomarkers ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Integrated Analysis ◽  
Repair Gene ◽  
Therapeutic Outcomes ◽  
Dna Repair Gene

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P &lt; 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.

DNA-repair gene (DRG) single nucleotide polymorphisms (SNPs) influence on response and survival in stage IV SCCHN patients treated with CDDP-based therapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5505-5505
Author(s):  
M. Quintela-Fandino ◽  
R. Hitt ◽  
P. P. Medina ◽  
S. Gamarra ◽  
M. Amador ◽  
...  
Keyword(s):  
Stage Iv ◽  
Nucleotide Polymorphisms ◽  
Multinomial Regression ◽  
Repair Gene ◽  
Kaplan Meier ◽  
Treatment Type ◽  
Dna Repair Gene ◽  
Response To Chemotherapy ◽  
Cox's Model ◽  
The Impact

5505 Background: CDDP kills tumor cells by DNA cross-linking. SNPS at DRG may influence the ability of patients to respond to CDDP. We studied the role of the SNPs XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A and XRCC1-Arg399Gln to influence the response to CDDP-based therapy and to predict survival in SCCHN patients Methods: SNPs were genotyped in DNA from peripheral lymphocytes using PCR-restriction fragment length polymorphism in 103 stage IV (0% M1) SCCHN patients followed prospectively. Treatment schedules were concurrent CDDP/RT (n = 28), CDDP + fluoropyrimidine (FP)→ CDDP/RT (33) or CDDP + FP + taxane→CDDP/RT (42). Endpoints: to assess the impact of the SNPs in OS (Kaplan Meier and Cox’s model) and in response to chemotherapy (multivariate multinomial regression). The covariables gender, age, treatment type, number of polymorphic (poly.) variants (0–8), smoking and alcohol consumption and amount (mg) of CDDP were included in the multivariate analysis Results: Median age 60 yrs (39–94); 97 (94%) male. After 78 months of follow-up, 24% had died, 22% had relapsed and 51% were free of disease. The allele frequencies for the homozygous common allele, heterozygous and homozygous poly. variant were: ERCC1: 53, 40 and 7%; XPD312: 50, 42 and 8%; XPD751: 35, 57 and 8%; XRCC1: 35, 51 and 13%. Overall, 9%, 16%, 22%, 20%, 24%, 6%, 1% and 1% of the patients harbored 0, 1, 2, 3, 4, 5, 6 and 7 poly. variants simultaneously. Table shows OS according to genotype. Patients with only common alleles had a median OS of 5.1 months (4.3–6.0) vs not reached for patients with ≥1 variant (p = 0.0000)(mean 6.2 (4–8.4) vs 61.3 (53–59.8). Each variant allele decreases the probability of dying 2.1 fold (p = 0.0000) on the Cox’s analysis (7 variants = 175 fold protection) and increases 2.94 fold (multinom. reg.)the probability of achieving a CR vs PD (p = 0.041) Conclusions: In our series the poly. variants at DRG are the strongest prognosis factors and accurately predict clinical response among SCCHN patients. [Table: see text] No significant financial relationships to disclose.

scholarly journals Transcriptional Pausing and Activation at Exons-1 and -2, Respectively, Mediate the MGMT Gene Expression in Human Glioblastoma Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 888
Author(s):  
Mohammed A. Ibrahim Al-Obaide ◽  
Kalkunte S. Srivenugopal
Keyword(s):  
Dna Methyltransferase ◽  
Glioblastoma Cells ◽  
Rt Pcr ◽  
Repair Gene ◽  
Exon 2 ◽  
Mgmt Gene ◽  
Dna Repair Gene ◽  
Exon 1 ◽  
Transcriptional Pausing ◽  
Transcription Assays

Background: The therapeutically important DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is silenced by promoter methylation in human brain cancers. The co-players/regulators associated with this process and the subsequent progression of MGMT gene transcription beyond the non-coding exon 1 are unknown. As a follow-up to our recent finding of a predicted second promoter mapped proximal to the exon 2 [Int. J. Mol. Sci.2021, 22(5), 2492], we addressed its significance in MGMT transcription. Methods: RT-PCR, RT q-PCR, and nuclear run-on transcription assays were performed to compare and contrast the transcription rates of exon 1 and exon 2 of the MGMT gene in glioblastoma cells. Results: Bioinformatic characterization of the predicted MGMT exon 2 promoter showed several consensus TATA box and INR motifs and the absence of CpG islands in contrast to the established TATA-less, CpG-rich, and GAF-bindable exon 1 promoter. RT-PCR showed very weak MGMT-E1 expression in MGMT-proficient SF188 and T98G GBM cells, compared to active transcription of MGMT-E2. In the MGMT-deficient SNB-19 cells, the expression of both exons remained weak. The RT q-PCR revealed that MGMT-E2 and MGMT-E5 expression was about 80- to 175-fold higher than that of E1 in SF188 and T98G cells. Nuclear run-on transcription assays using bromo-uridine immunocapture followed by RT q-PCR confirmed the exceptionally lower and higher transcription rates for MGMT-E1 and MGMT-E2, respectively. Conclusions: The results provide the first evidence for transcriptional pausing at the promoter 1- and non-coding exon 1 junction of the human MGMT gene and its activation/elongation through the protein-coding exons 2 through 5, possibly mediated by a second promoter. The findings offer novel insight into the regulation of MGMT transcription in glioma and other cancer types.

scholarly journals DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture

2015 ◽  
Vol 2015 ◽  
pp. 1-6
Author(s):  
Aysel Kalayci Yigin ◽  
Mehmet Bulent Vatan ◽  
Ramazan Akdemir ◽  
Muhammed Necati Murat Aksoy ◽  
Mehmet Akif Cakar ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fragment Length Polymorphism ◽  
Control Group ◽  
Chordae Tendineae ◽  
Repair Gene ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Polymerase Chain

Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. The aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR). Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP). The frequencies of the heterozygote genotype (Lys/Gln-AC) and homozygote genotype (Gln/Gln-CC) were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%,p=0.049; 38.15% versus 16.2%,p=0.018). Homozygote variant (Gln/Gln) genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097–3.863;p=0.018). Heterozygote variant (Lys/Gln) genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041–2.129;p=0.049). The variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101–1.992;p=0.011). This study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR.

scholarly journals DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population

2021 ◽  
Vol 28 (3) ◽  
pp. 1879-1885
Author(s):  
Maria Samara ◽  
Maria Papathanassiou ◽  
Lampros Mitrakas ◽  
George Koukoulis ◽  
Panagiotis J. Vlachostergios ◽  
...  
Keyword(s):  
Dna Repair ◽  
Urothelial Carcinoma ◽  
European Population ◽  
Nucleotide Polymorphisms ◽  
Environmental Carcinogens ◽  
Repair Gene ◽  
High Exposure ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Xrcc3 Thr241met

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/−, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14–4; p = 0.01). The −/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07–0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16–0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT −/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT −/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.

Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

2014 ◽  
Vol 41 (3) ◽  
pp. 458-465 ◽  
Author(s):  
Gustavo Martelli Palomino ◽  
Carmen L. Bassi ◽  
Isabela J. Wastowski ◽  
Danilo J. Xavier ◽  
Yara M. Lucisano-Valim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Systemic Sclerosis ◽  
Blood Cells ◽  
Gene Polymorphisms ◽  
Peripheral Blood Cells ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

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