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Association between polymorphisms of ERCC1 and survival in epithelial ovarian cancer patients with chemotherapy. Epithelial ovarian cancer (EOC) is the.
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Association between polymorphisms of ERCC1 and survival in epithelial ovarian cancer patients with chemotherapy Aim: We evaluated whether the ERCC1 polymorphisms had an effect on survival in epithelial ovarian cancer (EOC) patients with platinum-based chemotherapy. Materials & methods: Clinical data of 209 EOC patients between 2002 and 2008 were reviewed. The genotypes of 19007T/C and 8092C/A polymorphisms were assessed in all patients using PCR–RFLP. Results: The 19007T/C polymorphism was significantly associated with response to treatment. Compared with the patients carrying C/C genotype, the patients with the T/T genotype have a significantly decreased response to platinum-based chemotherapy (odds ratio: 32.26; 95% CI: 3.66–250.00). Cox’s multivariate ana­lysis suggested that EOC patients with the T/T genotype had an increased risk of disease progression (hazard ratio: 3.34; 95% CI: 1.77–6.29) and death (hazard ratio: 2.87; 95% CI: 1.38–5.96) compared with those carrying the C/C genotype. Conclusion: The 19007T/C polymorphism may be a useful prognostic marker in patients with EOC treated with platinum-based chemotherapy in Chinese women. Original submitted 26 October 2011; Revision submitted 5 December 2011 KEYWORDS: 19007T/C SNP n 8092C/A SNP n epithelial ovarian cancer n ERCC1 n platinum chemotherapy n SNP

Epithelial ovarian cancer (EOC) is the leading cause of death in females with pelvic malignancies. It is estimated that five new cases per 100,000 are diagnosed yearly in China [1] . The lack of effective screening strategies and absence of symptoms in the early stages of the disease, caused more than 70% of patients to be at an advanced stage in their first diagnostic. Platinum-based chemotherapy is the first-line chemotherapy following cytoreductive surgery for advanced EOC [2] ; however, approximately 20% of patients fail to respond to treatment, and up to 75% of patients in initial responders eventually relapse [3,4] . Platinum-resistance is the most common cause of decreased progressionfree survival (PFS) and overall survival (OS). Thus, identification of patients who are platinum resistant could lead to a better selection of therapy and could potentially improve survival rates. One of the mechanisms by which tumor cells develop resistance to platinum agents is enhanced by DNA repair to remove platinum– DNA adducts [5] . Thus, powerful DNA repair capacity may predict a resistance to platinumbased chemotherapy and may be a prognostic factor for decreased survival in advanced ovarian cancer. ERCC1,an essential member in the nucleotide excision repair (NER) pathway, has been reported to play a major role in the response to platinum-based chemotherapies, such as cisplatin and oxaliplatin. ERCC1 forms

a heterodimer with xeroderma pigmentum F and executes a 5´ incision into the damaged DNA strand, which is the last of several steps to remove the platinum-damaged DNA lesion [5–7] . A number of studies have suggested that ERCC1 mRNA levels and protein expression are significantly correlated with cisplatin resistance in various human cancers in vitro and in vivo [8–10] . The polymorphisms of ERCC1, 19007C/T (codon 118, rs11615) and 8092C /A (rs3212986), have been reported to affect the ERCC1 mRNA and protein levels [11,12] . Codon 118C/T polymorphism (AAT, AAC) encodes the same amino acid, asparagine, but codon AAT has been associated with a 50% transcription reduction compared with codon AAC [11] . The second polymorphism, 8092C/A, located in the 3´ untranslated region, has been shown to change ERCC1 mRNA stability and mRNA levels [12] . The association between these two polymorphisms and an altered outcome in platinum-based chemotherapy in multiple malignancies, including ovarian cancer, has been extensively studied, but results are still inconclusive [13–16] . In this study, we further assessed whether 19007C/T and 8092C/A polymorphisms had an effect on pharmacy response or survival time in EOC Chinese female patients treated with platinum-based chemotherapy.

10.2217/PGS.11.181 © 2012 Future Medicine Ltd

Pharmacogenomics (2012) 13(4), 419–427

Li Yan1, Yang Shu-Ying1, Kang Shan1, Benjamin HK Yip2, Zhou Rong-Miao1, Wang Na1 & Sun Hai-Yan*1 Hebei Medical University, Fourth Hospital, Shijiazhuang, 050011, China 2 Department of Psychiatry, University of Hong Kong, Hong Kong *Author for correspondence: Tel.: +86 311 86095337 Fax: +86 311 86077634 [email protected] 1

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ISSN 1462-2416

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Materials & methods „„ Study population Two hundred and nine Han female patients treated for ovarian neoplasms at the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China, were recruited for this study between 2002 and 2008. Eligibility criteria for this cohort included newly diagnosed, histologically confirmed primary EOC in women of any age and of Han Chinese nationality. The patients were excluded from this study if they had either neoadjuvant chemotherapy, chemotherapy before surgical staging, concurrent primary neoplasms, and benign ovarian disease. The selective characteristics of EOC patients are shown in Ta ble  1. The study was approved by the Ethics Committee of Hebei Cancer Institute Shijiazhuang, China and informed consent was obtained from all recruited subjects. The study adhered to the Helsinki declaration. „„ Chemotherapy All patients received platinum-based chemo­ therapy 1–2 weeks after cytoreductive surgery. The chemotherapeutic regimen consisted of cisplatin (75  mg/m 2 ) or carboplatin (area under the curve 5, Calvert’s formula) and cyclophosphamide (700 mg/m 2 ) or paclitaxel (175 mg/m 2 ). Patients with early-stage EOC Table 1. Clinical characteristics of epithelial ovarian cancer patients. Characteristics

All patients (%)

FIGO stage I–II III–IV

67 (32.1) 142 (68.9)

Grade High grade Intermediate grade Low grade

20 (9.6) 73 (34.9) 116 (55.5)

Tumor residual size 0 cm ≤1 cm >1 cm

23 (11.0) 52 (24.9) 134 (64.1)

Pathology Serous Mucinous Endometrioid Others

117 (56.0) 21 (10.0) 44 (21.1) 27 (12.9)

Surgery Complete resection Optimal debulking Suboptimal debulking

44 (21.1) 131 (62.7) 34 (16.3)

FIGO: International Federation of Gynecology and Obstetrics.

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(International Federation of Gynecology and Obstetrics [FIGO] stage IB–IIC) received three to five cycles of chemotherapy, while the others with advanced-stage EOC (FIGO stage IIIA–IV) did six to eight cycles. „„ Survival defintion All clinical data were assessed without knowledge of the genotype status. Response to chemotherapy was evaluated retrospectively according to the WHO response evaluation criteria [17] . The evaluation was based on data from medical records describing the patient’s clinical condition and the CA125 levels in the 3–4  week intervals. PFS was defined as the time from study entry until disease recurrence or death. Disease recurrence was defined as a biopsy-verified appearance of a new lesion, reappearance of any lesion that had disappeared or development of tumor-related symptoms. OS was defined as the time from study entry until death regardless of cause or date of last contact [18] . Responders (platinum-sensitive) were defined as an ovarian cancer patient who had a treatmentfree interval greater than 6 months from the last date of the initial six cycles of platinum-based combination chemotherapy [19] . A nonresponder (platinum-resistance) was defined as an ovarian cancer patient who had a treatment-free interval less than 6  months from the last date of the initial six cycles of platinum-based combination chemotherapy, including disease that had progressed during chemotherapy. „„ DNA extraction Venous blood (5  ml) from each subject was collected into Vacutainer ® tubes containing ethylenediamine tetraacetic acid and stored at 4°C. After sampling, genomic DNA was extracted within 1 week through digestion with proteinase K (Merck, Darmstadt, Germany) followed by a salting-out procedure [20] . DNA examination was conducted with informed patient consent. „„ Genotyping Genotypes were determined by the PCR–RFLP method. Briefly, the PCR was performed in 20  µl volume containing 100  ng DNA template, 2.0  µl 10× PCR buffer for 19007C/T and 1.6 µl 10× PCR buffer for 8092C/A, 2.5 U of Taq DNA polymerase (Tiangen Bjotech Co., Ltd, Beijing, China), 0.4  µl 10  mmol/l deoxynucleotide triphosphates and 200  nM of each primer. The PCR cycling conditions were 5 min at 94°C followed by 35 cycles of future science group

Association between polymorphisms of ERCC1 & survival in EOC

Research Article

Table 2. Clinical characteristics of ovarian cancer patients stratified by genotype of 19007T/C and 8092C/A. Characteristics

19007T/C

8092C/A

p-value*

C/C (n %)

C/T (n %)

T/T (n %)

28 (40.0) 70 (50.4)

38 (54.3) 60 (43.2)

4 (5.7) 9 (6.4)

36 (53.7) 62 (43.7)

27 (40.3) 71 (50.0)

8 (40.0) 33 (45.2) 57 (49.1)

p-value*

C/C (n %)

C/A (n %)

A/A (n %)

0.331

47 (67.1) 70 (50.4)

22 (31.4) 55 (39.6)

1 (1.5) 14 (10.0)

0.015

4 (6.0) 9 (6.3)

0.372

37 (55.2) 80 (56.3)

26 (38.8) 51 (35.9)

4 (6.0) 11 (7.8)

0.868

11 (55.0) 36 (49.3) 51 (44.0)

1 (5.0) 4 (5.5) 8 (6.9)

0.550

11 (55.0) 36 (49.4) 70 (60.3)

8 (40.0) 32 (43.8) 37 (31.9)

1 (5.0) 5 (6.8) 9 (7.8)

0.627

13 (59.1) 23 (43.4) 62 (46.3)

8 (36.4) 27 (50.9) 63 (47.0)

1 (4.5) 3 (5.7) 9 (6.7)

0.682

12 (52.2) 30 (57.7) 75 (56.0)

9 (39.1) 19 (36.5) 49 (36.5)

2 (8.7) 3 (5.8) 10 (7.5)

0.986

58 (54.7) 6 (31.6) 14 (29.8) 20 (54.1)

42 (39.6) 12 (63.2) 31 (66.0) 13 (35.1)

6 (5.7) 1 (5.2) 2 (4.2) 4 (10.8)

0.020

55 (51.9) 14 (73.7) 27 (57.4) 21 (56.8)

44 (41.5) 3 (15.8) 16 (34.1) 14 (37.8)

7 (6.6) 2 (10.5) 4 (8.5) 2 (5.4)

0.475

Age (years) 1 cm Pathology Serous Mucinous Endometrioid Others

p-value was obtained using Fisher’s exact test. FIGO: International Federation of Gynecology and Obstetrics. *

45 s at 94°C for 19007C/T, 30 s at 94°C for 8092C/A, and 45 s at 60.5°C for 19007C/T, 30 s at 65.2°C for 8092C/A, and 45 s at 72°C for 19007C/T, 30  s at 72°C for 8092C/A, with a final step at 72°C for 7  min to allow for the complete extension of all PCR fragments. Accordingly, a 199-bp PCR amplification fragment was generated using the primers 5´-GCAGAGCTCA­C C­TGAGGA AC-3´ (forward) and 5´-GAGGT­G CAA­­GAAGAG­ GTGGA-3´ (reverse) for 19007C/T, and a 329-bp PCR amplification fragment using the primers 5´-CCGG AGGC TGT T T­ GATGTC-3´ (forward) and 5´-CCCCAAGA­ GGAGATGCCAG-3´ (reverse) for the 8092C/A. The PCR product was digested by TaiI (Fermentas China Co., Ltd) for 19007C/T or MboII (Fermentas China Co., Ltd, Shenzhen, China). „„ Statistical ana­lysis Statistical ana­l ysis was performed using the SPSS 13.0 software package (SPSS, Chicago, IL, USA). Fisher’s exact test was used to compare the genotypes and clinical pathological variables of patients. The odds ratio and 95% CI were calculated using logistic regression. Survival analyses were performed using the Kaplan–Meier ana­lysis with log-rank future science group

test. The association of each SNP with the risk of recurrence and death was analyzed by the Cox proportional hazard model adjusting for age, histology, stage, tumor residual size and histology. A probability level of 5% was considered significant.

Results „„ Genotype frequency Among the 209  patients with EOC, the genotype frequency of 19007T/C was 46.9% with C/C, 46.9% with C/T, and 6.2% with T/T, and the genotype frequency of 8092C/A was 56.0% with C/C, 36.8% with C/A, and 7.2% with A/A. Both genotypes were in Hardy–Weinberg equilibrium. Ta ble  2 shows patients’ clinical characteristics stratified by the two genotypes. The Fisher exact test results showed that the distribution of genotype frequency in the 8092C/A polymorphism might be associated with the age of patients, while the 19007T/C polymorphism associated with the histology in patients with ovarian cancer. „„ Drug response A total of 138 (66.0%) patients responded to the first-line therapy and 71 (34.0%) of all patients did not respond to the therapy. Allele www.futuremedicine.com

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frequencies of the 19007C/T polymorphism were significantly different between responders and nonresponders. Compared with the C/C genotype, the T/T genotype significantly decreased the response to platinum-based chemotherapy in patients with EOC; the odds ratio adjusted for age, stage, grade, tumor residual size and histology is 32.2 (95%  CI:  3.66– 250.00). By contrast, responders did not have a significant difference in allele frequencies of 8092C/A, compared with nonresponders. „„ Survival The median PFS of patients carrying the C/C, C/T and T/T genotype of 19007C/T were 20, 18 and 5  months, respectively; and the mean OS of those patients were 36, 32 and 19, respectively. Survival ana­lysis showed that the 19007C/T polymorphism was associated

Proportion of recurrence

1.0 0.8 0.6 0.4 0.2 0.0 10

0

20 Months

30

40

with survival prognosis of EOC patients (F igur e  1  &  Ta ble  3) . Compared with the C/C genotype, patients carrying the T/T genotype had a shorter median PFS and median OS time. Kaplan–Meier plots illustrate the differences in PFS ( Figure 1A ; p  0.05). Compared with the C/C genotype, the C/A or A/A genotypes were not associated with disease progression or death (F igure 2 & Table 3) . „„ Combined genotypes of 19007T/C & 8092C/A The results of the haplotype analysis revealed that 19007 C/T and 8092 C/A polymorphisms were in linkage disequilibrium (D’  =  0.80, p  ≤  0.001). The patients with the 19007TT/8092CC combined genotype had a shorter survival time than those with the 19007CC/8092CC combined genotype (Table 4) .

Proportion of survival

1.0 0.8 0.6 0.4 0.2 0.0 0

19007T/C C/C

10

T/C

T/T

20 Months

T/C-censored

30

40

C/C-censored

T/T-censored

Figure 1. Kaplan–Meier estimates of clinical outcome by ERCC1 19007T/C polymorphism in patients. (A) Progression-free survival. (B) Overall survival.

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Discussion The effect of the ERCC1 19007C/T and 8092C /A polymorphisms on treatment response and survival of EOC patients with platinum-based chemotherapy have been studied, but the results were not consistent (Table 5) . In this paper, we further assessed the association between these two polymorphisms and treatment response, PFS and OS in EOC patients with platinum-based chemotherapy. The results suggested that the T/T genotype of the 19007C/T polymorphism decreased platinum-based chemotherapy response, thus worsening PFS and OS of EOC patients. On the other hand, the 8092C/A polymorphisms seems to have no effect on treatment response or patients’ survival rate. The A sn118A sn (190 07C /T ) silent mutation in exon 4 of the ERCC1 gene was future science group

Association between polymorphisms of ERCC1 & survival in EOC

Research Article

Table 3. The association ana­lysis results between ERCC1 and clinical outcomes of epithelial ovarian cancer patients treated with chemotherapy. Genotype

Recurrence No (n %)

Yes (n %)

Hazard ratio

36 (48.6) 38 (51.4) 0 (0)

62 (46.0) 60 (44.4) 13 (9.6)

1.00 1.05 3.34‡

39 (52.7) 32 (43.2) 3 (4.1)

78 (57.8) 45 (33.3) 12 (8.9)

1.00 0.76 1.14

95% CI†

Survival Yes (n %)

No (n %)

Hazard ratio

95% CI†

0.72–1.53 1.77–6.29‡

68 (51.9) 60 (45.8) 3 (2.3)

30 (38.5) 38 (48.7) 10 (12.8)

1.00 1.41 2.87‡

0.85–2.33 1.38–5.96‡

0.52–1.11 0.61–2.13

72 (55.0) 48 (36.6) 11 (8.4)

45 (57.7) 29 (37.2) 4 (5.1)

1.00 1.05 1.70

0.65–1.71 0.60–4.81

19007T/C C/C T/C T/T 8092C/A C/C C/A A/A

Cox proportional hazard regression for progression or death, adjusted for age, stage, grade, tumor residual and histology. Values are significant.

† ‡

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this polymorphism is unclear [11] . Recently, Gao et  al. reported that Asn118Asn itself is not related to the phenotypic differences in

Proportion of recurrence

1.0 0.8 0.6 0.4 0.2 0.0 0

10

20 Months

30

40

0

10

20 Months

30

40

A/A-censored

C/C-censored

1.0

Proportion of survival

first described in cell lines and tumor tissue specimens of ovarian cancer. This mutation was a conversion of the common codon AAC, to an infrequently used codon AAT. Compared with codon AAC, codon AAT had a 50% reduction in transcription  [11] . In multiple cancer studies, the Asn118Asn SNP was shown to be associated with an altered outcome in cancer patients with platinum-based chemotherapy, but the results vary in different types of malignancies. For example, in non-small-cell lung cancer, most studies suggest that the C allele signifies a better response to platinumbased chemotherapy  [13,21] . However, in metastatic colorectal cancer, both the C and T alleles were found to be associated with either an improved or impaired outcome  [22,23] . For ovarian cancer, several studies reported that the patients with the T allele or T/T genotype may have a better response to chemotherapy when compared with those with the C/C genotype  [24–26] . Interestingly, similar to non-small-cell lung cancer, our study results showed the carriers of the T/T genotype had a significantly lower response rate and shorter PFS and OS in EOC patients. This discrepancy may be due to the following: first, the genetic background of the different ethnicities may partly explain these conflicting findings. The allele and genotype frequency distributions of the Asn118Asn polymorphism were different among races; the genotype frequencies of C/C, C/T and T/T were 8.8, 54.0 and 37.2% in the European population, while they were 62.8, 27.9 and 9.3% in the Chinese population [101] . Second, although previous studies have suggested that the conversion of the common codon A AC to an infrequently used codon A AT could affect protein translation rate and response to cisplatin, the function of

0.8 0.6 0.4 0.2 0.0

8092C/A A/A

C/A

C/C

C/A-censored

Figure 2. Kaplan–Meier estimates of clinical outcome by ERCC1 8092C/A polymorphism in patients. (A) Progression-free survival. (B) Overall survival.

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Table 4. The combined genotype of 19007T/C, 8092C/A and survival of epithelial ovarian cancer patients treated with chemotherapy. Genotype

8092CC Relative risk

19007C/C 19007C/T 19007T/T



8092CA

Survival and dead patients (n)

1.0 30, 15 1.08 (0.48–2.44) 39, 21 6.00 (1.41–25.48) 3, 9

Relative risk

8092AA

Survival and dead patients (n)

0.76 (0.30–1.92) 29, 11 1.79 (0.73–4.41) 19, 17 0, 1

Relative risk

Survival and dead patients (n)

0.89 (0.24–3.36) 9, 4 2, 0

Relative risk (95% CI) adjusted for age, stage, grade, tumor residual and histology.



ERCC1 expression or function, but rather that this polymorphism may be linked to other causative variants or haplotypes [27] . The linkage disequilibrium plot shows that the Asn118Asn SNP is linked in a haplotype block of 18 kb within ERCC1 and the adjacent genomic region in the European (Tuscans in Italy and Utah residents with Northern and Western European ancestry from the Centre de’Etude du Polymorphism Humain collection) population. But this is not true for African (Yoruban in Ibadan, Nigeria) or Asian (Han Chinese in Beijing, China, and Japanese in Tokyo, Japan) populations  [28] . Thus, the causative SNP linked with Asn118Asn SNP might be different, which also probably contributes to the discrepancy among races.

Furthermore, future genetic association studies should be expanded to include other polymorphisms linked to ERCC1 N118N, especially those in the regulatory regions of this gene. Third, small sample size and different genotyping methods in a series of studies may also be an explanation for this discrepancy. The 8092C/A polymorphism is located in the 3´-untranslated region of ERCC1 gene, which was found to be involved in translational repression of ERCC1 mRNA. To date, the association between this polymorphism and platinum-based chemotherapy of cancer patients has not been studied as extensively as the Asn118Asn variant. For ovarian cancer patients, two studies showed that the carriers

Table 5. Previous pharmacogenetics studies on ERCC1 19007T/C and 8092C/A polymorphisms in epithelial ovarian cancer. SNP

Therapy

Patients (n) Location Association

Hazard ratio (95% CI)

19007T/C

Cisplatin plus cyclophosphamide

104

Russia

2.51 (1.09–5.57)

[29]

Taxanes and platinum compounds Platinum-based chemotherapy

118 60

Korea Korea

0.17 (0.04–0.74)

[24]

Platinum-based chemotherapy

159

Denmark

1.61 (0.83–3.14)

[25]

Cisplatin and paclitaxel Carboplatin Platinum-based chemotherapy

233 914 178

USA UK USA

1.00 (0.66–1.54)

[15]

3.73 (1.56–8.89)

[26]

Carboplatin- and paclitaxel-based chemotherapy Cisplatin plus cyclophosphamide Taxanes and platinum compounds

280

USA

0.48 (0.49–0.95)

[33]

104 118

Russia Korea

3.29 (1.40–7.73) 1.94 (1.07–3.51)

[29]

Cisplatin and paclitaxel

233

USA

1.44 (1.06–1.94)

[15]

Carboplatin Carboplatin- and paclitaxel-based chemotherapy

914 280

UK USA

1.29 (0.97–1.72)

[33]

8092C/A

424

T/C genotype: a higher risk of nephrotoxicity No association T allele: a reduced risk of platinum resistance TT genotype: signaled a better response to chemotherapy No association No association C/C genotypes: significantly shorter progression-free survival, and substantially shorter overall survival T allele: an independent predictor for better survival C/A genotype: renal dysfunction A allele: an increased risk of disease progression and death A allele: an increased risk of disease progression No association No association

Pharmacogenomics (2012) 13(4)

Ref.

[32]

[16]

[32]

[16]

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Association between polymorphisms of ERCC1 & survival in EOC

with C/A or A/A genotypes had a significantly shorter PFS and OS [15,29] . Khrunin et  al. reported that the genotypes of the 8092C/A polymorphism are not associated with PFS and OS in EOC patients treated with platinum-based chemotherapy, but those with the C/A genotype had a higher risk of nephrotoxicity  [29] . Similar to the study of Marsh et  al. [16] , our results suggested that the 8092C/A polymorphism might not be associated with the response to platinumbased chemotherapy and PFS and OS in patients with EOC. The genotype frequencies of the 8092C/A polymorphism were similar in several studies, but with inconsistent results. This could be attributable, at least in part, to differences in the stage of disease, study design and sample size between the published studies. It is worth noting that 67  cases (32.1%) with IC–II stage were included in the present study. Although prognosis of ovarian cancer patients with early-stage disease is better than those with advanced-stage disease, up to 50% of women with higher-risk stage I or stage II EOC will relapse, and their survival is just as poor as those with recurrent advancedstage disease  [30] . According to the National Comprehensive Cancer Network guidelines [31] , those patients with higher-risk stage I or stage II EOC should receive platinum-based chemotherapy after cytoreductive surgery; therefore, the aforementioned 67  patients were recruited in this study. However, the results were unaffected when the patients with early-stage disease were excluded (data not shown). Our study has several limitations. First, it is limited by the length of follow-up, only 3-year survival rates are calculated for those cases resected between the years of 2007 and 2008; second, a relatively small number of enrolled patients limits the statistical power compared with previous large-scale studies [16] . Third, performance status, which is a very strong predictor of outcome, was not included in our study. However, despite these limitations, the data of our study contribute significant information on the prognostic and predictive value of ERCC1 polymorphisms and may prove to be useful tools towards individualizing EOC treatment strategies.

Conclusion In this study, we further evaluated the associations between ERCC1 polymorphisms and clinical outcomes in EOC patients treated future science group

Research Article

with platinum-based chemotherapy. To our knowledge, this is the first report demonstrating that the ERCC1 19007C/T polymorphism is associated with PFS and OS in EOC patients treated with platinum-based chemotherapy in the Chinese population; in other words, the T/T genotype of the ERCC1 19007C/T polymorphism may be a useful marker for predicting worse survival in EOC patients.

Future perspective The NER pathway plays a central role in the response to platinum-based chemotherapy in various cancers including ovarian cancer. ERCC1, one of the NER proteins, is measured to assess its functional status of the NER pathway. The accumulated evidence indicated that the genetic polymorphisms in the ERCC1 gene may be involved in an individual’s responsive ability to platinum-based chemotherapy. Therefore, identification of extreme drug resistance profiles associated with polymorphisms in the ERCC1 gene and the other genes in the NER pathway may better predict response to platinum-based therapy. Acknowledgements The authors greatly acknowledge several doctors in the Department of Obstetrics and Gynecology, the Fourth Affiliated Hospital of Hebei Medical University, China, for their assistance in recruiting study subjects. Additionally, the authors would like to thank BHK Yip, Department of Psychiatry, University of Hong Kong, Hong Kong, for critical reading of the manuscript.

Financial & competing interests disclosure The project was supported, in part, by funds for the Construction of Potentially Distinguished Scientific Projects in the program of Hebei Universities and The Scientific Technique Program of the Research and Development in Hebei Province (08276101D-41). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research The authors state that they have obtained appropriate insti­tutional review board approval or have followed the princi­ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investi­g ations involving human subjects, informed consent has been obtained from the participants involved. www.futuremedicine.com

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Executive summary ERCC1 polymorphisms & platinum-based chemotherapy ƒƒ 19007C/T (codon 118, rs11615) and 8092C/A (rs3212986) polymorphisms in ERCC1 may be a useful prognostic marker in various cancer patients who accept platinum-based chemotherapy. ƒƒ There was a discrepancy among the effects of these two polymorphisms on survival of ovarian cancer patients treated with platinum-based chemotherapy in different studies. ƒƒ To date there is no report about the relationship of rs11615 and rs3212986 with the clinical outcome of ovarian cancer in the Chinese population. For first time, we have evaluated whether these two polymorphisms had an influence on the survival of ovarian cancer patients. Results ƒƒ Patients that carried the T/T genotype of the 19007C/T polymorphism had a significantly decreased response to platinum-based chemotherapy; the adjusted odds ratio was 32.26 (95% CI: 3.66–250.00). ƒƒ The patients with the T/T genotype of the 19007C/T polymorphism had an increased risk of disease progression (hazard ratio: 3.34; 95% CI: 1.77–6.29) and death (hazard ratio: 2.87; 95% CI: 1.38–5.96). ƒƒ The 8092C/A polymorphism was not associated with ovarian cancer patient survival in the Chinese population. Discussion ƒƒ The ovarian cancer patients carrying the T/T genotype of the 19007T/C polymorphism may have a poor prognosis in the Chinese population. ƒƒ Further studies are needed to assess our outcome in the Chinese population. complementation group 1 gene is associated with poor outcome of platinum-based doublet chemotherapy of advanced nonsmall cell lung cancer patients. Cancer Invest. 28, 1078–1083 (2010).

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Reviews the nucleotide excision repair pathway and platinum-based anticancer chemotherapy. Reed E. ERCC1 and clinical resistance to platinum-based therapy. Clin. Cancer. Res. 11, 6100–6102 (2005). Enzlin JH, Scharer OD. The active site of the DNA repair endonuclease XPF-ERCC1 forms a highly conserved nuclease motif. EMBO J. 21, 2045–2053 (2002).

8

Li Q, Yu JJ, Mu C et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res. 20, 645–652 (2000).

9

Ren S, Zhou S, Zhang L et al. High-level mRNA of excision repair cross-

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polymorphisms, disease progression, and survival in the Gynecologic Oncology Group Phase III trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian cancer. J. Clin. Oncol. 26, 3598–3606 (2008). n

16

Demonstrates that the 19007C/T polymorphism could affect protein translation rate and response to cisplatin. n

Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol. Biomarkers Prev. 9, 843–847 (2000). nn

Demonstrates that the 8092C/A polymorphism may be involved in translational repression of ERCC1 mRNA.

13 Park SY, Hong YC, Kim JH et al. Effect of

15

Gandara DR, Kawaguchi T, Crowley J et al. Japanese–US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J. Clin. Oncol. 27, 3540–3546 (2009). Krivak TC, Darcy KM, Tian C et al. Relationship between ERCC1

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17

Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 47, 207–214 (1981).

18

Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).

19

Markman M. Decision-making in the management of recurrent epithelial ovarian cancer. In: Gynecologic cancer: Controversies in Management. Gershenson DM (Ed.). Churchill Livingstone, London, UK, 447–454 (2004).

ERCC1 polymorphisms and the modification by smoking on the survival of nonsmall cell lung cancer patients. Med. Oncol. 23, 489–498 (2006). 14

Showed that the ovarian cancer patients with the A allele of the 8092 C/A polymorphism had a significantly shorter progression-free survival and overall survival in the USA.

future science group

Association between polymorphisms of ERCC1 & survival in EOC

20 Miller SA, Dybes DD, Polesky HF. A simple

salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988). 21

Isla D, Sarries C, Rosell R et al. Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced nonsmall-cell lung cancer. Ann. Oncol. 15, 1194–1203 (2004).

polymorphism in ovarian cancer. Int. J. Gynecol. Cancer 18, 702–710 (2008). n

ERCC1 genotype and phenotype in epithelial ovarian cancer identify patients likely to benefit from paclitaxel treatment in addition to platinum-based therapy. J. Clin. Oncol. 25, 5172–5179 (2007).

24 Kang S, Ju W, Kim JW et al. Association

between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp. Mol. Med. 38, 320–324 (2006). 25 Steffensen KD, Waldstrøm M, Jeppesen U,

Brandslund I, Jakobsen A. Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1

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recurrence in early-stage high-risk epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol. Oncol. 116, 307–311 (2010). 31

DK, Figg WD. The ERCC1 N118N polymorphism does not change cellular ERCC1 protein expression or platinum sensitivity. Mutat. Res. 708, 21–27 (2011). nn

Demonstrates that the 19007C/T polymorphism is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes.

28 Barrett JC, Fry B, Maller J, Daly MJ.

Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005). 29 Khrunin AV, Moisseev A, Gorbunova V,

Limborska S. Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. Pharmacogenomics J. 10, 54–61 (2010).

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32 Kim HS, Kim MK, Chung HH et al. Genetic

polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: a Korean population-based study. Gynecol. Oncol. 113, 264–269 (2009).

27 Gao R, Reece K, Sissung T, Reed E, Price

23 Stoehlmacher J, Park DJ, Zhang W et al.

A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br. J. Cancer 91, 344–354 (2004).

30 Chan JK, Tian C, Teoh D et al. Survival after

26 Smith S, Su D, Rigault de la Longrais IA et al.

22 Viguier J, Boige V, Miquel C et al. ERCC1

codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin. Cancer Res. 11, 6212–6217 (2005).

Demonstrates that the TT genotype of the 19007C/T polymorphism may be favorable toward a better response to platinum-based chemotherapy in Denmark.

Research Article

n

Suggested that patients with the A allele of the 8092 C/A polymorphism have an increased risk of disease progression and death.

33 Krivak TC, Darcy KM, Tian C et al. Single

nucleotide polypmorphisms in ERCC1 are associated with disease progression, and survival in patients with advanced stage ovarian and primary peritoneal carcinoma; a Gynecologic Oncology Group study. Gynecol. Oncol. 122, 121–126 (2011).

„„ Website 101 NCBI. dbSNP.

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