Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5568-5568
Author(s):  
K. D. Steffensen ◽  
M. Waldstrøm ◽  
U. Jeppesen ◽  
I. Brandslund ◽  
A. Jakobsen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Epithelial Ovarian Cancer ◽  
Dna Adducts ◽  
Excision Repair ◽  
Snp Genotyping ◽  
Repair Capacity ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy ◽  
Ercc1 Expression

5568 Background: The response of tumor cells to platinum-based drugs involves DNA repair mechanisms. Platinum-DNA adducts are repaired by nucleotide excision repair (NER) enzymes that recognize the DNA damage and excise the platinum-DNA adducts from the injured DNA strand. Excision repair cross-complementation group 1 (ERCC1) is one of the genes that encode the proteins of the NER complex and several studies have linked ERCC1 to platinum resistance in cell lines and in human cancers. Cells with a high repair capacity, e.g. high level of ERCC1 expression may therefore be resistant to platinum-based chemotherapy, and conversely, polymorphisms within encoding DNA repair enzymes or low repair capacity may confer sensitivity. A common single nucleotide polymorphism (SNP) of ERCC1 at codon 118 have been proposed to impair ERCC1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum based chemotherapy. The aim of this study was to evaluate ERCC1 expression and ERCC1 118 polymorphism in epithelial ovarian cancer and the potential association with response to platinum-based chemotherapy. Methods: Formalin-fixed, paraffin-embedded tissue sections from 159 patients with epithelial ovarian cancer, FIGO stage IIb-IV, were used for immunohistochemistry (monoclonal mouse antibody, clone 8F1, Neomarkers). ERCC1 codon 118 SNP genotyping was performed by real time PCR, Taqman SNP genotyping assay. Results: ERCC1 protein overexpression was found in 37.7 % of the tumors. The response rate (normalization of CA125 during platinum-based chemotherapy) was 63.6 % (35/55) in patients with ERCC1-negative tumors compared to only 35.6 % (16/45) in patients with ERCC1-positive tumors. (p = 0.0052, χ2). Furthermore increasing immunohistochemical score (H-score) was associated with poorer response to chemotherapy. (p = 0.0006, Spearman`s). The T/T genotype (44 %) showed better response to chemotherapy than C/C + C/T (15 % + 41 %) variants (p=0.042). Conclusions: Patients with ERCC1-negative tumors appear to have significantly better response to platinumbased chemotherapy compared to patients with ERCC1-positive tumors. In addition the TT genotype seems to be favorable towards better response to platinum-based chemotherapy. No significant financial relationships to disclose.

ERCC1 Genotype and Phenotype in Epithelial Ovarian Cancer Identify Patients Likely to Benefit From Paclitaxel Treatment in Addition to Platinum-Based Therapy

2007 ◽  
Vol 25 (33) ◽  
pp. 5172-5179 ◽  
Author(s):  
Stephanie Smith ◽  
Dan Su ◽  
Irene A. Rigault de la Longrais ◽  
Peter Schwartz ◽  
Manuela Puopolo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Disease Progression ◽  
Treatment Response ◽  
Cancer Patients ◽  
Excision Repair ◽  
Platinum Resistance ◽  
Platinum Based Chemotherapy ◽  
Risk Of Disease ◽  
Ercc1 Expression

Purpose To investigate the effect of excision repair cross-complementation group 1 (ERCC1) on treatment response and survival of patients treated with platinum chemotherapy with or without paclitaxel. Patients and Methods Tumor samples from epithelial ovarian cancer patients were evaluated for ERCC1 mRNA expression and a single nucleotide polymorphism at codon 118 (C>T). Of 178 patients treated with postoperative platinum-based chemotherapy, 75 were also given paclitaxel. For all of these patients, ERCC1 expression and genotype were analyzed for associations with treatment response and survival. Results Among the 103 patients treated with platinum without paclitaxel, the C/C genotype, compared with C/T and T/T, was associated with greater risk of disease progression and death (hazard ratio [HR], 1.95, P = .051; HR, 2.01, P = .033, respectively); high levels of ERCC1 mRNA, compared with low levels, were associated with greater risk of disease progression (HR, 2.41; P = .014). Similarly, when the ERCC1 data were combined, patients with the C/C genotype and high ERCC1 expression had greater risk for disease progression (HR, 3.73; P = .003) compared with those with low expression and non-C/C genotype. However, for the 75 patients treated with platinum plus paclitaxel, the C/C genotype and high ERCC1 expression were not associated with poor prognosis, suggesting that paclitaxel may help to alleviate ERCC1-related platinum resistance. Conclusion Ovarian cancer patients with high ERCC1 expression or the C/C genotype at codon 118 may benefit from the combination of platinum and paclitaxel, while those with low ERCC1 expression or the C/T or T/T genotype may respond well to platinum without paclitaxel.

scholarly journals Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway

2018 ◽  
Vol 46 (5) ◽  
pp. 1971-1984 ◽  
Author(s):  
Yong-Bin Liu ◽  
Ying Mei ◽  
Zheng-Wen Tian ◽  
Jing Long ◽  
Chen-Hui Luo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Online Databases ◽  
Platinum Based Chemotherapy ◽  
Nucleotide Excision ◽  
Induced Apoptosis ◽  
Platinum Chemotherapy

Background/Aims: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. Methods: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients’ responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. Results: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. Conclusions: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients’ response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients.

scholarly journals Intracellular Optical Doppler Phenotypes of Chemosensitivity in Human Epithelial Ovarian Cancer

2020 ◽  
Author(s):  
Zhe Li ◽  
Ran An ◽  
Wendy M. Swetzig ◽  
Margaux Kanis ◽  
Nkechiyere Nwani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Outcomes ◽  
Metastatic Tumor ◽  
Tissue Response ◽  
Infrared Light ◽  
Tumor Biopsy ◽  
Tumor Tissues ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

AbstractDevelopment of an assay to predict response to chemotherapy has remained an elusive goal in cancer research. We report a phenotypic chemosensitivity assay for epithelial ovarian cancer based on Doppler spectroscopy of infrared light scattered from intracellular motions in living three-dimensional tumor biopsy tissue measured in vitro. The study analyzed biospecimens from 20 human patients with epithelial ovarian cancer. Matched primary and metastatic tumor tissues were collected for 3 patients, and an additional 3 patients provided only metastatic tissues. Doppler fluctuation spectra were obtained using full-field optical coherence tomography through off-axis digital holography. Frequencies in the range from 10 mHz to 10 Hz are sensitive to changes in intracellular dynamics caused by platinum-based chemotherapy. Metastatic tumor tissues were found to display a biodynamic phenotype that was similar to primary tissue from patients who had poor clinical outcomes. The biodynamic phenotypic profile correctly classified 90% [88% to 91% c.i.] of the patients when the metastatic samples were characterized as having a chemoresistant phenotype. This work suggests that Doppler profiling of tissue response to chemotherapy has the potential to predict patient clinical outcomes based on primary, but not metastatic, tumor tissue.

Prediction of survival in patients with epithelial ovarian cancer based on the timing and rate of normalization of CA125 levels during primary chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5585-5585
Author(s):  
K. S. Matthews ◽  
R. P. Rocconi ◽  
M. Kemper ◽  
K. E. Hoskins ◽  
W. K. Huh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Eligible Patient ◽  
Primary Chemotherapy ◽  
Rank Test ◽  
Primary Therapy ◽  
Linear Regression Models ◽  
Platinum Sensitivity ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

5585 Objective: CA125 is the tumor marker used to evaluate response to chemotherapy in patients with epithelial ovarian cancer (EOC). The aim of this study was to determine if the timing of normalization or percent decrease in CA125 levels during primary chemotherapy could predict survival. Methods: Patients treated at our institution for EOC with primary taxane/platinum-based chemotherapy for 6 cycles between 1996 and 2005 were eligible. Patient demographics, chemotherapy administration, CA125 levels, and survival outcomes were abstracted. Progression-free- survival (PFS), overall survival (OS), and platinum sensitivity (> 6 months from chemotherapy completion) were compared to CA125 levels during primary therapy. Baseline levels, change over time, and timing of CA125 normalization were calculated. Analyses were performed using Kaplan-Meier method and compared using the log-rank test, Chi-square test and Fischer’s exact test. Results: 269 patients with EOC were identified. When stratified by which cycle of chemotherapy achieved normalization, PFS ranged from 25 months at 1st cycle to 4 months at 6th cycle (p< 0.001). OS showed a similar benefit from 74 months at 1st cycle to 22 months at 6th cycle (p<0.001). Platinum sensitivity improved from 23% (normal CA125 after 6th cycle) to 72% (normal CA125 after 1st cycle) (p=0.003). Patients with normalization after the 3rd cycle or sooner compared to patients with normalization after the 4th cycle demonstrated improved PFS (19 vs. 6 months; p<0.001), OS (48 vs. 27 months; p=0.001) and platinum sensitivity (78 vs. 22%; p<0.001). Linear regression models of the slope of the decline of CA125 levels correlated with PFS (p=0.03); however, the models failed to predict an OS advantage. Conclusion: Earlier normalization of CA125 levels during primary chemotherapy for EOC predicts improvement in platinum sensitivity, PFS, and OS. This data provides prognostic information that may influence future decisions regarding chemotherapy. No significant financial relationships to disclose.

scholarly journals Intracellular optical doppler phenotypes of chemosensitivity in human epithelial ovarian cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhe Li ◽  
Ran An ◽  
Wendy M. Swetzig ◽  
Margaux Kanis ◽  
Nkechiyere Nwani ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Outcomes ◽  
Metastatic Tumor ◽  
Tissue Response ◽  
Infrared Light ◽  
Tumor Biopsy ◽  
Tumor Tissues ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

Abstract Development of an assay to predict response to chemotherapy has remained an elusive goal in cancer research. We report a phenotypic chemosensitivity assay for epithelial ovarian cancer based on Doppler spectroscopy of infrared light scattered from intracellular motions in living three-dimensional tumor biopsy tissue measured in vitro. The study analyzed biospecimens from 20 human patients with epithelial ovarian cancer. Matched primary and metastatic tumor tissues were collected for 3 patients, and an additional 3 patients provided only metastatic tissues. Doppler fluctuation spectra were obtained using full-field optical coherence tomography through off-axis digital holography. Frequencies in the range from 10 mHz to 10 Hz are sensitive to changes in intracellular dynamics caused by platinum-based chemotherapy. Metastatic tumor tissues were found to display a biodynamic phenotype that was similar to primary tissue from patients who had poor clinical outcomes. The biodynamic phenotypic profile correctly classified 90% [88–91% c.i.] of the patients when the metastatic samples were characterized as having a chemoresistant phenotype. This work suggests that Doppler profiling of tissue response to chemotherapy has the potential to predict patient clinical outcomes based on primary, but not metastatic, tumor tissue.

scholarly journals Excision Repair Cross-Complementation Group 1 Enzyme as a Molecular Determinant of Responsiveness to Platinum-Based Chemotherapy for non Small-Cell Lung Cancer

2008 ◽  
Vol 3 ◽  
pp. BMI.S485 ◽  
Author(s):  
Giannis Mountzios ◽  
Meletios-Athanasios Dimopoulos ◽  
Christos Papadimitriou
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Adducts ◽  
Excision Repair ◽  
Complementation Group ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Ercc1 Expression ◽  
Group 1

Although platinum-based chemotherapy remains the “standard” in advanced non small-cell lung cancer, not all patients derive clinical benefit from such a treatment. Hence, the development of predictive biomarkers able to identify lung cancer patients who are most likely to benefit from cisplatin-based chemotherapy has become a scientific priority. Among the molecular pathways involved in DNA damage control after chemotherapy, the nucleotide excision repair (NER) is a critical process for the repair of DNA damage caused by cisplatin-induced DNA adducts. Many reports have explored the role of the excision repair cross-complementation group 1 enzyme (ERCC1) expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells. Using immunohistochemistry in resected tumors from patients included in the International Adjuvant Lung Cancer Trial, the study of important biomarkers showed that high ERCC1 protein expression was associated with improved survival in chemo-naïve patients. On the contrary, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. In a prospective cohort studying mRNA expression in tumor biopsies from patients receiving customized therapy with cisplatin and gemcitabine depending on the molecular profile of the tumour, results showed that patients with low ERCC1 mRNA expression had a longer median survival compared to those with high expression. These data suggest the potent use of ERCC1 as a molecular predictor of clinical resistance to platinum-based chemotherapy in the adjuvant setting of NSCLC. Nevertheless, optimization of methodology, including standardization of technical procedures, as well as validation of ERCC1 protein expression in large prospective cohorts, seem necessary before any routine immunohistochemical validation of ERCC1 can be implemented in daily practice.

XPD DNA Nucleotide Excision Repair (NER) Gene Polymorphisms Associated with DNA Repair Deficiency May Predict Better Treatment Outcomes in Secondary Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 168-168 ◽  
Author(s):  
Nataliya Kuptsova-Clarkson ◽  
Christine Ambrosone ◽  
Joli Weiss ◽  
Maria R. Baer ◽  
Lara Sucheston ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Treatment Outcomes ◽  
De Novo ◽  
Excision Repair ◽  
Variant Allele ◽  
Repair Capacity ◽  
Strand Breaks ◽  
Secondary Aml ◽  
Response To Chemotherapy

Abstract Abstract 168 The X-ray cross-complementing group 1 (XRCC1) protein plays an important role in excision and ligation of oxidized DNA bases and strand breaks, in cooperation with other enzymes in the base excision repair (BER) pathway, while XPD helicases unwind DNA prior to repair. Polymorphisms of these DNA repair genes are associated with decreased DNA repair rates and increased genotoxic damage, measured by single-strand breaks and chromosomal aberrations. Compromised repair activity may lead to accumulation of DNA damage and predispose to secondary cancers and increased treatment-related toxicity to normal tissues. It may, however, also result in decreased repair of DNA damage in malignant cells exposed to chemotherapy, facilitating their apoptosis, and therefore decreasing resistance to chemotherapy and improving treatment outcome. Functional DNA repair capacity has been found to be significantly deficient in XRCC1 399Gln and XPD 312Asn, 751Gln variant allele carriers, and NER polymorphisms, particularly ERCC2 (XPD) Lys751Gln SNP, appeared as strong determinants of in vitro toxicity to most anti-cancer agents in the NCI-60 panel of tumor cell lines. Pharmacogenetic studies of DNA repair pathways have consistently demonstrated associations between the XRCC1 Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes and cancer treatment outcomes, including treatment-related toxicities. Notably, the XRCC1 399Gln homozygous variant genotype has been found to decrease risk of developing both de novo and therapy-related AML, and has been associated with worse survival outcomes for other cancers. The variant glutamine allele of XPD Lys751Gln SNP has been associated with shorter disease-free survival (DFS) and overall survival (OS) for AML patients, as well as increased risk of therapy-related AML (t-AML). In this study we evaluated the role of these polymorphisms, as well as XPD haplotypes, in response to chemotherapy, OS, and toxicities in adult de novo (n=214) and secondary (n=79, including 47 with antecedent hematologic disorders and 32 with t-AML) AML patients treated with cytarabine and anthracycline-based chemotherapy regimens at Roswell Park Cancer Institute. Genotyping was performed by MALDI-TOF mass spectrometry, and logistic and proportional hazards regression models were used to evaluate relationships. Significant differential chemotherapy responses were observed in secondary, but not de novo, AML patients with variant XPD 312, XPD 751 and XPD haplotypes. In particular, among secondary AML patients, the XPD 312Asn/Asn XPD 751Gln/Gln variant was associated with eleven-fold higher odds of achieving complete remission (CR) (OR= 11.23; 95% CI, 2.23-56.63), and the odds were also increased among patients with XPD 751Gln/Gln genotypes (OR= 7.07; 95% CI, 1.42–35.18). Patients with the ‘BB/DA' (751Gln/312Asn-751Gln/312Asn/751Gln/Asp312-Lys751-Asp312) diplotype were more likely to achieve CR [OR=31.10; 95% CI: 3.98–242.88] compared to those with the AA/AC/DB diplotype in the secondary AML onset category. Additionally, in this subgroup, the XPD 751 CC, 312GA, 312AA variant genotypes and the XPD ‘BB/DA' haplotype group, which are likely to confer decreased repair function, were significantly associated with longer OS. In the whole patient population there was an association between XPD genotypes/haplotypes and chemotherapy-related toxicities, including a significantly reduced risk of nausea/vomiting (OR= 0.35, 95% CI, 0.13–0.90 for ‘BB/DA' diplotype group) and an increased incidence of infectious complications after induction chemotherapy. Overall, these findings suggest that XPD codon 312 and codon 751 variant genotypes and haplotypes containing at least one variant allele are associated with suboptimal DNA repair and may serve as predictors of more favorable AML treatment responses and diffential toxicities. With validation of results in larger samples, these findings could lead to optimizing chemotherapy AML options by treatment stratification, especially in patients with secondary AML. Disclosures: No relevant conflicts of interest to declare.

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