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

Stephanie Smith, Dan Su, Irene A. Rigault de la Longrais, Peter Schwartz, Manuela Puopolo, Thomas J. Rutherford, Gil Mor, Herbert Yu, Dionyssios Katsaros

From the Departments of Epidemiology and Public Health and Obstetrics and Gynecology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT; Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China; and the Department of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy

Address reprint requests to Herbert Yu, MD, PhD, Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St, New Haven, CT 06520-8034; e-mail: herbert.yu{at}yale.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 
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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 
Excision repair cross-complementation group 1 (ERCC1) is a DNA repair gene in the nucleotide excision repair (NER) pathway that is activated when platinum-based chemotherapeutic agents, such as cisplatin and carboplatin, form DNA adducts.^1,2 Although platinum is widely used to treat ovarian cancer, approximately 20% of patients fail to respond to treatment, and initial responders remain at risk for disease progression.^3,4 Genetic variations that affect cellular repair of drug-induced DNA damage may influence patient response to chemotherapy. Understanding these variations may improve patient care by allowing physicians to optimize treatment based on each patient's genetic and molecular background.

Prior research has linked DNA repair capability and platinum-based chemotherapy resistance to ERCC1 expression. Increased NER capacity and high ERCC1 mRNA expression have been seen in cisplatin-resistant ovarian cancer cell lines.⁵ High ERCC1 expression in ovarian cancer has also been associated with resistance to platinum-based treatment.^6,7 In one study, inhibition of ERCC1 expression by antisense RNA increased the sensitivity of cisplatin-resistant ovarian cancer cell lines to the drug. Mice transplanted with these ERCC1-deficient cell lines survived longer than controls after treatment with cisplatin, suggesting that ERCC1 may be involved in patient response to cisplatin treatment.⁸

A single nucleotide polymorphism (SNP) in codon 118 of the ERCC1 gene features a C to T transition that may have functional relevance as a marker of ERCC1 expression. The polymorphic codon encodes the same amino acid, asparagine, but has been associated with a 50% reduction in codon AAT transcription compared with codon AAC.⁹ In an ovarian cancer cell line, the T substitution has been linked to decreased levels of ERCC1 mRNA, indicating reduced DNA repair capability.¹⁰ Consistent with greater transcription activity of the AAC codon, a recent study in ovarian cancer patients reported an association between the C/C genotype and increased resistance to platinum-based chemotherapy.¹¹ To further investigate the effect of ERCC1 on ovarian cancer treatment and survival, we analyzed ERCC1 SNP 118 genotype and ERCC1 mRNA expression in tumors from ovarian cancer patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 
Study Design
This study analyzed tumor samples from women who underwent surgery for primary epithelial ovarian cancer between October 1991 and February 2000 in the Gynecologic Oncology Unit at University of Turin in Italy. An ethical review committee at the university approved the study and patients provided consent. Tumor samples were snap-frozen in liquid nitrogen after surgical removal and were stored at –80°C until analysis. Investigators who analyzed the ERCC1 SNP in codon 118 and mRNA expression were blinded to patient information on clinicopathologic characteristics, treatment response, and survival outcomes. For analysis, an initial cohort of 212 patients was restricted to the 178 patients treated with platinum-based chemotherapy, after excluding one patient who received nonplatinum chemotherapy and 33 patients (15.6%) who did not have chemotherapy. For the 178 platinum-treated patients, age at diagnosis ranged from 26 to 82 years, with a mean of 57.4 years (standard deviation, 11.2). Among these patients, 33 had stage I (18.5%), 12 had stage II (6.7%), 120 had stage III (67.4%), and 13 had stage IV (7.3%) disease, according to the International Federation of Gynecology and Obstetrics criteria.¹² Using the WHO guidelines for tumor grade and histology,¹³ there were 23 patients with grade 1 (12.9%), 34 with grade 2 (19.1%), and 121 with grade 3 (68.0%) tumors. There were 77 patients with serous tumors (43.3%) and 101 patients with nonserous tumors (56.7%), including 34 with undifferentiated (19.1%), 32 with endometrioid (18.0%), 13 with clear cell (7.3%), 12 with mucinous (6.7%), and 10 with Mullerian (5.6%). Surgical cytoreduction (debulking) was optimal in 48.9% of patients (n = 87), and suboptimal (residual lesions > 1 cm) in the remaining 51.1% of patients (n = 91).

After surgery, all platinum-treated patients received carboplatin or cisplatin; among them, 75 were also given paclitaxel (42.1%) while 103 received no paclitaxel (57.9%). Other drugs prescribed with platinum and/or paclitaxel included cyclophosphamide (n = 51), adriamycin (n = 8), and epirubicin (n = 22). Patient response to chemotherapy was complete if disease resolved for at least 1 month, as evaluated by clinical examination, imaging, and serum CA125, 1 month after the last cycle of chemotherapy. Pathologic evaluation by second-look laparotomy was performed for some patients according to the institutional protocols at the time. Partial response required at least a 50% reduction in the size of observable lesions, where size was the product of the lesions' maximum and minimum diameters, provided there were no new lesions for at least 1 month. Disease was stable if lesions decreased in size by less than 50% or increased by less than 25%, or progressive if lesions increased by 25% or more, or if new lesions developed. Excluding two patients without treatment response information, response was complete for 128 patients (72.7%) and poor for 48 patients (27.3%), including 36 with partial response, four with stable disease, and eight with progressive disease. For all platinum-treated patients, the median progression-free survival was 19.8 months (range, 0.6 to 108.8) and median overall survival was 37.5 months (range, 0.6 to 114.1). During follow-up, 92 patients (51.7%) experienced disease progression; among them, 67 died and 25 survived throughout the study. Of the 86 patients (48.3%) without disease progression, 18 died without remission and 68 survived throughout the study.

SNP Genotyping
Genomic DNA was extracted from tumor samples after manual pulverization. The SNP at ERCC1 codon 118 [rs11615] was genotyped using the TaqMan SNP assay (Applied Biosystems, Foster City, CA) and SDS software, version 1.3.1 (Applied Biosystems). The polymerase chain reaction (PCR) solution included 2.5 µL 2X TaqMan Universal PCR Master Mix No AmpErase UNG, 0.25 µL ERCC1 probes, 1.75 µL nuclease-free water, and 0.5 µL DNA sample. After baseline fluorescence measurements at 60°C, PCR included a 10-minute incubation at 95°C, 40 cycles of denaturing at 92°C for 15 seconds and annealing and extending at 60°C for 1 minute, and a final measurement of fluorescence at 60°C.

ERCC1 mRNA Expression
Total RNA was extracted from tumors using RNeasy Mini Kits (Qiagen, Valencia, CA; #74104). The SuperScript First-Strand Synthesis System for reverse transcriptase (RT) PCR (Invitrogen; Carlsbad, CA; #18080-051) was used for RT and resultant cDNA served as a PCR template. Quantitative real-time PCR was performed to determine ERCC1 mRNA expression, using glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) as an endogenous control to calibrate each sample's initial level of template. Cloned ERCC1 and GAPDH segments were used as PCR standards, and were prepared as follows. Inserted ERCC1 and GAPDH segments were PCR amplified from sample cDNA, and PCR products were isolated with gel electrophoresis and purified using a gel extraction kit (Qiagen; #28004). Purified PCR products (3 µL) were ligated to the pGEM-T Easy Vector (Promega, Madison, WI; #1360) and incubated at 4°C overnight. Ligation products (5 mL) were transfected into 50 µL of Subcloning Efficiency DH5 alpha Competent E coli Cells (Invitrogen; #18265-017). After overnight incubation at 37°C, plasmid DNA was purified (Qiagen; #27104) and digested by EcoR1 to confirm the size of inserted DNA. After measuring the concentration of purified DNA, copy number was calculated as [(concentration x volume)/(size of DNA insert x 660)] x (6.02 x 10²³). ERCC1 and GAPDH plasmid DNA were serially diluted to copy numbers between 1.0 x 10⁸ and 1.0 x 10¹². Quantitative real-time PCR was carried out in 25 µL solution, with 12.5 µL Power SYBR Green PCR Master Mix (Applied Biosystems), 0.5 µL each of 10 µmol/L forward and reverse primers, 1 µL of 5 ng/µL cDNA, and 10.5 µL H₂O. PCR included a 10-minute denature at 95°C and 40 cycles of annealing at 60°C for 1 minute and denaturing at 95°C for 15 seconds. Samples, negative controls, and PCR standards were run in duplicate. Each run must achieve amplification efficiency more than 80% and a correlation coefficient of at least 0.99. SDS software calculated standard curves and ERCC1 expression levels after adjusting for GAPDH.

Statistical Analysis
Genotypes were analyzed separately and as combined C/C versus C/T + T/T groups. ERCC1 mRNA expression was analyzed as a continuous variable and as a categoric variable after grouping expression by tertile. When ERCC1 genotype and phenotype data were combined, expression was categorized by the median. Associations between categoric variables were analyzed using ² tests. Survival analysis was performed for progression-free and overall survival using Kaplan-Meier curves and Cox proportional hazards regression. Analysis was conducted with SAS, version 9.1 (SAS Institute, Cary, NC), with a significance level of = .05.

	RESULTS

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ERCC1 Genotype
Of the 178 patients treated with platinum-based chemotherapy, 35 were C/C (19.7%), 61 were T/T (34.3%), and 82 were C/T (46.1%). Genotype was not associated with clinicopathologic variables (Table 1). Patients who received platinum chemotherapy were not clinicopathologically different from the initial cohort of 212 patients (Appendix Table A1, online only). Among patients treated with platinum without paclitaxel, but not among those given platinum with paclitaxel, a lower percentage of C/C patients, compared with C/T and T/T patients, had complete response to treatment (P = .062; Table 2). As presented in Table 3, the C/C genotype was associated with two-fold increases in risk of disease progression (hazard ratio [HR], 1.95; P = .051) and death (HR, 2.01; P = .033) over the C/T and T/T genotypes for patients given platinum without paclitaxel, but not for patients given platinum plus paclitaxel. Kaplan-Meier survival curves also show different associations of genotype with overall survival between patients receiving platinum with and without paclitaxel (Fig 1). Among those receiving platinum without paclitaxel, the median overall survival time was 25.7 months (interquartile range [IQR], 17.8 to 52.0) for C/C genotypes and 50.4 months (IQR, 23.4 to 85.9) for C/T and T/T genotypes.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier estimates of overall survival by ERCC1 genotype in patients treated with platinum (A) without paclitaxel and (B) with paclitaxel indicated a different effect of genotype on survival by treatment group.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of (A, B) diease progression-free survival and (C, D) overall survival by ERCC1 mRNA expression in patients treated with platinum (A, C) without paclitaxel and (B, D) with paclitaxel indicate a different effect of ERCC1 mRNA expression on survival by treatment group.

	DISCUSSION

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Consistent with prior findings linking the C/C genotype to poor treatment response,¹¹ we found that patients with C/C genotypes were less likely to have complete response to chemotherapy and were at higher risk for disease progression and death compared with those with C/T or T/T genotypes. Patients with elevated ERCC1 mRNA expression had greater risk of disease progression compared with those with low expression. Moreover, ERCC1 genotype and mRNA expression tended to have a joint effect on survival, as patients with C/C genotypes and high ERCC1 expression had significantly shorter progression-free survival and substantially shorter, though not statistically significant, overall survival than those without these features. Interestingly, these associations were seen only in patients treated with platinum-based therapy without paclitaxel. For patients treated with platinum and paclitaxel, treatment response, disease progression, and survival did not vary among those with different ERCC1 mRNA levels or genotypes at codon 118. This distinction suggests that patients with the C/C genotype or high ERCC1 expression may need paclitaxel with platinum, whereas patients with C/T or T/T genotypes or low ERCC1 expression may respond well to platinum regimens with or without paclitaxel.

Research suggests that paclitaxel interferes with ERCC1 expression, offering a biologically plausible explanation for the differences between patients treated with and without paclitaxel. An in vitro experiment has shown that radiation activates ERCC1 expression in gastrointestinal cancer cell lines, but not in the same cell lines treated with paclitaxel before radiation, suggesting that paclitaxel may suppress ERCC1, impairing DNA repair and cellular resistance to drug-induced DNA damage.¹⁴ If paclitaxel blocks ERCC1 expression in ovarian cells, then paclitaxel treatment may inhibit ERCC1-related DNA repair activity, offsetting patient resistance to platinum treatment. Our findings support this possibility, as survival of patients with high ERCC1 mRNA levels and/or C/C genotype differed from that of patients with low ERCC1 and/or non-C/C genotype only when paclitaxel was not combined with platinum. If the SNP at ERCC1 codon 118 and ERCC1 expression level are really indicative of patient response to platinum treatment, then combined platinum and paclitaxel therapy may be recommended for those with high risk.

High ERCC1 expression has not just been linked to poor survival in ovarian cancer, but in other cancers as well. High levels of ERCC1 mRNA have predicted poor survival for colorectal cancer patients, and low ERCC1 expression has been linked to improved survival for advanced bladder cancer patients.^15,16 Low or no ERCC1 mRNA in non–small-cell lung cancer (NSCLC) has been associated with better response to cisplatin and longer survival, while ERCC1 overexpression has been linked to shorter overall survival.^17-20 NSCLC patients whose tumors stained negative for ERCC1 protein had better 5-year survival than those with ERCC1-positive tumors.²¹ Improved treatment response and survival were also seen in gastric cancer patients with ERCC1-negative tumors.²² Our results support this link between low ERCC1 mRNA levels and favorable survival, but our inability to detect a dose-response relationship suggests that absolute expression may be less important once ERCC1 mRNA level passes a certain threshold.

Although our results did not link genotype at codon 118 to ERCC1 mRNA levels, prior studies have suggested that this SNP may influence expression, offering a plausible explanation for the association we observed between codon 118 genotype and ovarian cancer survival. A comparison of two platinum-resistant ovarian cancer cell lines differing only at codon 118 has documented lower peak levels of ERCC1 mRNA and reduced DNA repair capability in cells with the less frequently used AAT codon, compared with those with AAC.^9,10 Synonymous polymorphic codons like this have been shown to affect translation kinetics, with infrequently used codons having slower protein translation.²³ In this way, codon changes may alter protein-ribosome interactions and cotranslational protein folding.^24,25 Functional relevance of synonymous SNPs has been documented in a recent study of multidrug resistance 1 (MDR1) gene, in which less frequently used codons were linked to a functionally and structurally different protein.²⁶ We speculate that the ERCC1 SNP at codon 118 may in a similar way influence ERCC1 function beyond the level of mRNA expression.

The association that we have observed between codon 118 genotype and survival after platinum treatment has been corroborated in some but not all cancers, indicative of a complex system of interactions. For colorectal cancer patients, the T allele was linked to better treatment response in one study, but to treatment resistance and poor survival in another.^27,28 The C allele has been associated with better treatment response and survival in NSCLC, but no relationship has been seen between genotype and treatment response in gastric cancer.^29-33 Such inconsistencies suggest that ERCC1 regulation and DNA repair function may differ by cell and tissue type, indicating the need for further investigation.

Our results are consistent with a role for paclitaxel in the inhibition of ERCC1 expression, but the biologic interaction between paclitaxel and ERCC1 needs to be further examined in ovarian cancer cell lines and in vivo experiments. A large clinical study would help to verify the relationship between this SNP, ERCC1 mRNA expression, protein function, and treatment response. Although our study did not randomly assign patients to platinum treatment groups with or without paclitaxel, we have detected no obvious biases between the treatment groups. Due to changes in treatment standards over time, most patients who entered the study between 1991 and 1996 received cisplatin with cyclophosphamide (no paclitaxel), and between 1996 and 2000 received cisplatin or carboplatin with paclitaxel.^34,35 Since there were no major changes in diagnosis or prognosis of ovarian cancer during the study period, the distribution of patients treated with or without paclitaxel should not differ substantially, as observed. A greater proportion of those treated with paclitaxel versus without had tumors of late stage, high grade, and serous histology (Appendix Table A2, online only). These are risk factors for worse survival, and could explain why survival tended to be shorter for patients receiving platinum plus paclitaxel. However, there is no reason to believe that these prognostic differences between treatment groups would invalidate our results, since the distribution of ERCC1 genotypes and mRNA expression did not differ by paclitaxel status. Further, Kaplan-Meier survival estimates did not differ greatly from the Cox proportional hazards estimates that controlled for clinical features.

Our findings may have important clinical implications. While standard ovarian cancer treatment currently consists of platinum therapy with paclitaxel, optimizing treatment based on patient genetics and tumor characteristics could be beneficial where combined platinum and paclitaxel therapy may be withheld due to expense or toxicity. A recent report has suggested that elderly ovarian cancer patients are less likely to receive paclitaxel with platinum therapy due to the aggressiveness of the drug.³⁶ While our results are preliminary, they suggest that ERCC1 may be a good candidate for identifying patients for whom paclitaxel may be particularly beneficial but not routinely prescribed, as patients in our study with the C/C genotype at ERCC1 codon 118 and high ERCC1 mRNA expression seemed to require paclitaxel treatment in addition to platinum to achieve comparable survival with patients with C/T or T/T genotypes and low ERCC1 expression.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 
Conception and design: Dan Su, Herbert Yu, Dionyssios Katsaros

Financial support: Herbert Yu, Dionyssios Katsaros

Administrative support: Herbert Yu

Provision of study materials or patients: Irene A. Rigault de la Longrais, Manuela Puopolo, Herbert Yu, Dionyssios Katsaros

Collection and assembly of data: Stephanie Smith, Dan Su, Irene A. Rigault de la Longrais, Manuela Puopolo, Thomas J. Rutherford, Gil Mor, Herbert Yu, Dionyssios Katsaros

Data analysis and interpretation: Stephanie Smith, Dan Su, Peter Schwartz, Thomas J. Rutherford, Gil Mor, Herbert Yu

Manuscript writing: Stephanie Smith, Dan Su, Peter Schwartz, Herbert Yu, Dionyssios Katsaros

Final approval of manuscript: Stephanie Smith, Dan Su, Irene A. Rigault de la Longrais, Peter Schwartz, Manuela Puopolo, Thomas J. Rutherford, Gil Mor, Herbert Yu, Dionyssios Katsaros

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

 

	GLOSSARY

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix GLOSSARY REFERENCES

ERCC1:

Excision repair cross-complementing gene. Encodes a nucleotide excision repair protein that repairs a range of lesions, including UV-induced thymine dimers and other photoproducts, and also lesions caused by a variety of chemical agents.

SNP (single nucleotide polymorphism):

Genetic polymorphisms are natural variations in the genomic DNA sequence present in greater than 1% of the population, with SNP representing DNA variations in a single nucleotide. SNPs are being widely used to better understand disease processes, thereby paving the way for genetic-based diagnostics and therapeutics.

NER (nucleotide excision repair):

NER is a major DNA repair pathway that repairs primarily bulky DNA adducts caused by environmental mutagens, such as pyrimidine dimers induced by ultraviolet radiation, benzo[a]pyrene-guanine adducts caused by smoking, and guanine-cisplatinum adducts formed during chemotherapy. In NER, a small region of the strand surrounding the damage is removed from the DNA helix as an oligonucleotide.

Quantitative RT-PCR (real-time polymerase chain reaction):

Quantitative RT-PCR consists of detecting PCR products as they accumulate. It can be applied to gene expression quantification by reverse transcription of RNA into cDNA, thus receiving the name of quantitative reverse transcriptase polymerase chain reaction. In spite of its name, quantitative, results are usually normalized to an endogenous reference. Current devices allow the simultaneous assessment of many RNA sequences.

Cox proportional hazards regression model:

The Cox proportional hazards regression model is a statistical model for regression analysis of censored survival data. It examines the relationship of censored survival distribution to one or more covariates. It produces a baseline survival curve, covariate coefficient estimates with their standard errors, risk ratios, 95% CIs, and significance levels.

	NOTES

 
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 22, 2007; accepted August 8, 2007.

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