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Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3259-3267 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.3902
Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway
From the Ottawa Hospital, Division of Gynaecologic Oncology, Centre for Cancer Therapeutics, Ottawa Health Research Institute; and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada Corresponding author: Johanne I. Weberpals, MD, MSc, FRCSC, The Ottawa Hospital, General Campus, Division of Gynaecologic Oncology, Room 8130, 501 Smyth Rd, Ottawa, Ontario, K1H 8LG, Canada; e-mail: jweberpals{at}ottawahospital.on.ca
Among the most promising pathways for molecular targets in sporadic epithelial ovarian cancer (SEOC) are those involving the BRCA1 protein. Because somatic mutations in BRCA1 are rare in SEOC, it was originally postulated that BRCA1 plays a limited role in the pathogenesis of this disease. However, inactivation of BRCA1 through various mechanisms is a relatively frequent event in ovarian cancer. This is important because BRCA1 is involved in the cellular response to DNA damage and repair and has an essential role in the maintenance of genomic stability. The BRCA1 tumor suppressor protein is known to interact with genes and proteins known collectively as the BRCA1 pathway, and defects in this pathway are believed to be a driving force for cancer progression. As a result, there is compelling evidence to suggest that the dysfunction of BRCA1 may be a central mechanism in all ovarian carcinogenesis, and this has clinical and molecular significance beyond the management of patients with hereditary ovarian cancer. The aim of this review is to evaluate the evidence for BRCA1 dysfunction in SEOC and to link this dysfunction to a defective DNA repair pathway and ultimately the promotion of genomic instability and tumorigenesis. Furthermore, we advocate the continued need to study BRCA1 and its pathway by prospectively correlating clinicopathologic data with molecular aberrations. This will determine whether BRCA1 has relevance as a predictive and prognostic marker in SEOC and whether aberrations in the BRCA1 pathway warrant further study as potential therapeutic targets.
Approximately 90% of epithelial ovarian cancers are considered to be sporadic events, without evidence of an autosomal dominant hereditary predisposition. The remaining 5% to 10% are primarily associated with germline mutations of Breast Cancer 1 (BRCA1; 17q12-21) and BRCA2 (13q12-13) genes and account for 95% of hereditary ovarian carcinomas.1,2 Carriers of such germline mutations have a lifetime risk of 55% to 85% for breast cancer and 15% to 60% for ovarian cancer.3 The specific mechanism of BRCA1-related tumorigenesis is not well defined, but the BRCA1 gene has been shown to bind to numerous proteins4 and seems to be implicated in several cellular processes including homologous recombination,5 chromatin remodeling,6 regulation of the cell cycle,7,8 transcription,9,10 and cell growth and differentiation.11,12 In familial BRCA1 and BRCA2 heterozygotes, somatic inactivation of the wild-type allele with retention of the inherited disease-predisposing allele in ovarian tumor cells conforms to Knudson's two-hit model for a tumor suppressor gene13,14 and supports the concept that a BRCA mutation acts recessively at the cellular level.15-17 Women with a strong family history of breast/ovarian cancer or a positive BRCA mutation may be offered contraceptive agents or prophylactic oophorectomy to diminish cancer risk. However, there is no accepted clinical benefit to knowing BRCA1 status in ovarian cancer screening or in the management of patients who have the disease.18 This review addresses the role of BRCA1 in DNA repair, the mechanisms of its inactivation in sporadic epithelial ovarian cancer (SEOC), and the potential implications of BRCA1 deficiency on the management of patients with ovarian cancer.
DNA Damage Response The BRCA1 gene encodes a 220-kd nuclear phosphoprotein that has a highly conserved amino-terminal RING finger domain and an acidic C-terminal transcription activation domain (Fig 1).19,20 The two C-terminal motifs are postulated to play a role in cell cycle checkpoint control in response to DNA damage. BRCA1 plays an integral role in responding to cellular stress, localizing to sites of damaged DNA22,23 and activating specific repair processes (Fig 2).
Under genotoxic stress, DNA double-strand breaks (DSBs) activate protein kinases including ATR and ATM,24 and phosphorylated BRCA1 is believed to regulate downstream mechanisms of cellular response.25 BRCA1 has been shown to operate as a scaffolding protein26 and, rather than forming a large multiprotein complex,27 is now believed to colocalize with independent complexes at sites of DNA damage.28 Proteins that constitutively interact with BRCA1, such as BARD1, BACH1, BRCA2, and RAD51, and damage-inducible BRCA1-associated proteins, such as MRE11/RAD50/NBS1 and TopBP1, are recruited to damaged DNA sites in a BRCA1-dependent and BRCA1-independent manner, respectively. These interactions are believed to have a role in checkpoint activation and the coordination of DNA repair.
Checkpoint Mechanisms in Response to DNA Damage BRCA1's ability to activate cell cycle checkpoints in response to cellular stress has relevance to mechanisms of sensitivity to the first-line chemotherapy drugs in ovarian cancer cisplatin and paclitaxel. Because BRCA1 is required for CHK1 activation after stalled replication, it is believed that the cytotoxic effects of DNA-damaging agents can be rescued by BRCA1. Indeed, overexpression of BRCA1 in ovarian cancer cells in vivo leads to resistance to cisplatin, etoposide, and doxorubicin.35 BRCA1 has also been implicated in the spindle assembly checkpoint, such that downregulation of BRCA1 causes disruption of the mitotic spindle.36-38 This may account for resistance to the microtubule-interfering agent paclitaxel in cells with inhibited endogenous BRCA1 expression.36,39,40
BRCA1 Regulation and DNA Repair
BRCA1 associates with protein complexes that are involved in the repair of DNA DSBs, stalled replication forks, and DNA cross-links, usually through the error-free mechanism of HR. HR predominates during the S and G2 phases of the cell cycle when undamaged homologous strands are available as a template for the repair of damaged DNA. Cells that lack BRCA1 have a deficiency in the repair of DSB by the conservative mechanism of HR.43 Cells without normal BRCA1 activity, which are reduced to using error-prone pathways, accumulate genetic alterations as a result of failure to arrest and repair DNA damage or self-destruct, thereby leading to genomic instability and neoplastic progression. Alternative compensation mechanisms in DNA DSB repair such as nonhomologous end-joining and single-strand annealing44 are nonconservative and can generate mutations in the form of insertions and/or deletions. There is also evidence that BRCA1 is implicated in the nucleotide excision repair pathway because it has be shown in a breast cancer model that silencing of BRCA1 may lead to additional mutations, particularly in the nontranscribed strand of TP53, resulting in genetic alterations leading to tumorigenesis.45
The maintenance of genomic integrity is essential to prevent the accumulation of DNA damage, which leads to dysregulated growth and a transformed cellular phenotype.46,47 DNA ploidy has emerged as one of the most important prognostic factors in SEOC. The analysis of 284 patients with stage I ovarian carcinoma by high-resolution image cytometry revealed that DNA ploidy was a stronger predictor of survival than histologic grade and stage.48 Patients with diploid and tetraploid tumors had 10-year relapse-free survival rates of 95% and 89%, respectively, compared with 70% and 29% for polyploid and aneuploid tumors, respectively. Cells that lack BRCA1 or BRCA2 accumulate chromosomal abnormalities including chromosomal breaks, severe aneuploidy, and centrosome amplification.49 Xu et al30 examined the chromosomal defects of BRCA1 mutant cells that were deleted for exon 11 of the BRCA1 gene. Mutant mouse embryonic fibroblasts, which have a defective G2-M checkpoint in response to gamma irradiation, had multiple copies of centrosomes and formed abnormal mitotic spindles, leading to the nonclonal accumulation of chromosome aberrations. The same group also found that murine cells that harbor truncated BRCA2 (BRCA2Tr/Tr) spontaneously incur gross chromosomal rearrangements and genomic DNA breaks during division that may cause loss of heterozygosity (LOH) at functionally important loci.50 BRCA2Tr/Tr exhibited hypersensitivity to DNA damage by interstrand cross-linkers such as mitomycin, resulting in aberrant genetic exchange between nonhomologous chromosomes as detected by spectral karyotyping analysis. Therefore, loss of the BRCA1/BRCA2 genes is believed to promote chromosomal instability and trigger additional genetic changes necessary for neoplastic transformation.
Ovarian cancer cell lines carrying BRCA1 mutations have been used to investigate the ability of BRCA1 to mediate resistance to chemotherapy51 and response to DNA damage.52 However, model systems in which BRCA1 expression is suppressed using antisense or RNA interference techniques may be more relevant to BRCA1-deficient SEOC because expression is reduced but not eliminated. Studies using these approaches in ovarian cancer cells are limited, but two studies have shown that reduction in BRCA1 expression using antisense inhibition or retrovirus-mediated small interfering RNA increases sensitivity to cisplatin.53,54 Much of our current knowledge of the mechanisms of BRCA1-related tumorigenesis has been revealed by BRCA1-deficient mouse models.55 Although BRCA1 knockout mice die during embryogenesis, restricting BRCA1 deficiency to specific tissues has shown the importance of this gene to both mammary and ovarian epithelial morphology and in defining the ability of BRCA1 deficiency to sensitize ovarian epithelium to transformation.56 Inactivation of BRCA1 in mouse ovarian surface epithelium leads to preneoplastic changes including hyperplasia, epithelial invaginations, and inclusions cysts, which arise earlier and in greater frequency than in control ovaries.57 Similar alterations in epithelial morphology have been reported at higher frequency in prophylactic oophorectomy specimens in women with a family history of ovarian cancer and/or carrying BRCA1 mutations.58 Excision of exon 11 of BRCA1 in mouse mammary epithelial cells caused increased apoptosis, abnormal ductal development, and tumorigenesis, and tumors associated with increased genetic instability were characterized by aneuploidy, chromosomal rearrangements, or alteration of p53 transcription.59 These observations, as well as reports showing that BRCA1-deficient mouse ovarian epithelial cells have increased sensitivity to platinum,56,57 demonstrate that animal model systems have value in the preclinical evaluation of the impact of BRCA1 pathways on prognosis and treatment. In women with a BRCA1 mutation, it is unknown whether breast and ovarian tissues are more susceptible to somatic mutation or are more dependent on a functional BRCA1 or whether the combination of BRCA1-deficiency plus hormone sensitivity plays a role. Recent mouse models, which correlate BRCA1 inactivation with upregulation of aromatase expression60 and reduced progesterone receptor degradation,61 strongly suggest that BRCA1 influence on steroid hormone production or signaling may contribute to its tumor-suppressive activity. In particular, the demonstration that transient knockdown of BRCA1 expression using small interfering RNA enhances aromatase expression and thereby estrogen production in ovarian granulosa cells and primary preadipocytes47 offers the intriguing possibility that the combined effect of aberrant estrogen biosynthesis and compromised DNA repair may account for the tissue specificity of BRCA1-associated cancers.
There is accumulating evidence that silencing of BRCA1 or misregulation of related genes in the BRCA1 pathway may be important in the pathogenesis of a significant proportion of sporadic tumors.62 Unlike familial cancers that harbor a germline mutation, in SEOC, there is reduced expression of the normal BRCA1 gene. Different from other tumor suppressor genes, somatic BRCA1 mutations are uncommon in SEOC, representing only approximately 9% of cases.16,63 However, gene mutation may be only one of several mechanisms responsible for the BRCA1 dysfunction in ovarian cancer.
Loss of Heterozygosity
Tong et al67 found a correlation between LOH of P53 and LOH of BRCA1 and BRCA2 in various epithelial tumors, including ovary, breast, endometrial, and head and neck cancers, suggesting that the relationship between P53 and BRCA1/BRCA2 may be universal to epithelial tumors. Specifically, the inactivation of P53 was most significantly associated with LOH of BRCA1 in 51 ovarian tumors. In a unique LOH study in an ovarian carcinoma in situ, it was reported that LOH for microsatellites for P53 and for a specific BRCA1-linked marker was apparent, implying that the inactivation of these genes occurs as an early event in ovarian carcinogenesis.78 Indeed, concomitant inactivation of BRCA1 and P53 in mouse ovarian surface epithelial cells resulted in increased proliferation not seen when either is inactivated alone.57 Studies in conditional knockout mice suggest that loss of BRCA1 in mammary cells leads to tumors at relatively low frequency; however, with the addition of a heterozygous mutation in P53, there were many more mammary tumors.59 BRCA1 and P53 have been shown to have a functional interaction,79 and tumorigenesis may result when BRCA1 inhibition and mutated P53 act synergistically to incite chromosomal instability.80
Hypermethylation
Haploinsufficiency
The concept of BRCAness was coined to describe the silencing or dysfunction of genes in BRCA1-related pathways, rather than mutations inherent to BRCA1 itself, that may account for the pathogenesis of SEOC.62 This implies a shared phenotype between familial and sporadic cancers that has been attributed to a common underlying DNA repair defect. Complementary DNA microarrays were used to examine the role of BRCA mutations in ovarian carcinogenesis by comparing gene expression in cancers with germline mutations of BRCA1 and BRCA2 and in SEOC.88 The gene expression profiles of SEOC share features of BRCA1- or BRCA2-associated cancers, as illustrated by the differential expression of 110 genes, which could segregate the sporadic samples into BRCA1-like and BRCA2-like. This study not only supported a role for BRCA1 in SEOC, but also correlated the dysregulation of the BRCA genes to a particular pattern of gene expression. In a study of 92 tumors from women with ovarian cancer, 82% contained alterations in BRCA1, BRCA2, or both, consisting of mutations, absent mRNA, or isolated LOH.71 An immunohistochemistry study of BRCA1 in SEOC revealed a significant reduction in the BRCA1 protein (immunoreactivity in 75% of benign cystadenomas, 100% of borderline epithelial ovarian tumors, and 34% of SEOC).72 There was also a sharp decline in BRCA1 expression with increasing grade of SEOC. Russell et al73 demonstrated reduced or absent protein expression in 90% of 57 SEOCs, with a 44% incidence of LOH at the BRCA1 locus. However, there was no significant correlation between LOH status and levels of RNA and protein expression. This group also reported that 80% of BRCA1-positive tumors were stage I or II compared with 21% and 38% of tumors classified as having intermediate or low levels of BRCA1 staining, respectively, implying that BRCA1 loss is a late event in tumor progression. The largest study of BRCA1 expression in SEOC, which was a correlative study of the Gynecologic Oncology Group89 and a landmark study demonstrating increased survival with the use of intraperitoneal chemotherapy, examined 230 ovarian tumors and found a statistically significant decrease in BRCA1 protein expression with advancing stage.69 Immunohistochemical staining was observed in all stage I and stage II tumors, whereas 65% of stage III tumors had little to no staining. However, there was no statistically significant relationship between tumor grade and BRCA1 expression. Survival data on 152 patients revealed that minimal BRCA1 expression was protective for survival. BRCA1 expression has also been found to be reduced in sporadic breast cancer,90-92 favoring the hypothesis that, although BRCA1 is ubiquitously expressed in all tissues, it may have a similar propensity for inactivation in breast and ovarian epithelium. BRCA1 expression has been correlated with prognostic variables such as tumor grade, metastatic potential, and survival,90,93,94 and it has consistently been found that reduced BRCA1 expression is correlated with poor prognostic factors such as high histologic grade and distant metastases.93 However, when BRCA1 levels were adjusted for tumor grade, patients with decreased BRCA1 had a significantly longer disease-free survival,94 in keeping with the suggestion that BRCA1 deficiency is correlated with a better prognosis. Stage for stage, patients with BRCA1 deficiency, either as a result of a hereditary mutation or a decreased expression, are believed to do better as a result of increased sensitivity to treatment. Interestingly, there has also been a correlation with BRCA1 expression levels and prognosis in lung cancer. BRCA1 mRNA expression was measured in 55 non–small-cell lung cancer patients who received neoadjuvant chemotherapy with gemcitabine and cisplatin. Median survival times for patients in the middle and top quartiles for BRCA1 expression were 37.8 and 12.7 months, respectively, whereas for patients in the bottom quartile, median survival was not reached.95 These reports, which comprise histopathologic and limited gene expression studies, illustrate that BRCA1 inactivation is consistently observed in SEOC as well as other malignancies. However, there is a lack of prospective clinical data and mechanistic analyses in the study of BRCA1 dysfunction in ovarian cancer.
Among patients with advanced-stage ovarian cancer, those with hereditary mutations in BRCA1 and BRCA2 have been shown to have a survival advantage over patients with sporadic disease.96,97 This observation has been attributed mainly to BRCA-deficient tumors exhibiting increased sensitivity to DNA-damaging agents as a result of the induction of irreparable DNA DSBs. Although preclinical studies on BRCA1-related chemotherapy sensitivity in ovarian cancer are relatively few, an earlier report on resistant variants of the breast and ovarian cell lines MCF-7/R and SKOV-3/R to cisplatin demonstrated increased sensitivity to cisplatin with antisense inhibition of BRCA1.53 Since then, it has been suggested in breast cancer that BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis in the presence of a range of cytotoxic agents. Quinn et al39 concluded that BRCA1 abrogates the sensitivity to apoptosis in the presence of DNA-damaging agents including cisplatin and etoposide and, in contrast, BRCA1 induces sensitivity to the antimicrotubule agents paclitaxel and vinorelbine. This is in agreement with data that correlate the inhibition of BRCA1 with increased sensitivity to cisplatin and resistance to paclitaxel that is associated with transcriptional modifications of the c-Jun NH(2)-terminal kinase (JNK) pathway.98 Small interfering RNA screens were used to identify genes that affect drug response, and there was enhanced cisplatin cytotoxicity in tumor cells having both BRCA network and P53 disruptions.99 Preclinical studies of BRCA1 as a predictive marker in breast cancer have been validated by retrospective clinical studies indicating that BRCA1 mutation carriers have a greater response to DNA-damaging chemotherapy than their sporadic counterparts.100-102 A complete response to anthracycline- and cyclophosphamide-based chemotherapy was observed in 10 of 11 patients with a BRCA1 or BRCA2 mutation compared with only two of 11 nonmutation carriers, suggesting that patients with a BRCA mutation are more sensitive to chemotherapy.100 The study by Goffin et al102 of 278 women, including 30 patients with a BRCA1 mutation, showed that BRCA1 mutation status is a negative prognostic factor, especially in lymph node–negative women. Carriers of a BRCA1 mutation did worse than noncarriers who did not receive adjuvant treatment, suggesting that patients with a BRCA1 mutation may derive a greater benefit from chemotherapy as a result of increased sensitivity to doxorubicin and cisplatin.102 Further evidence exists that BRCA1 confers resistance to apoptosis through the DNA damage pathway in that BRCA1-deficient cells expressing reconstituted BRCA1 demonstrate resistance on exposure to DNA damage–inducing ionizing radiation. In the BRCA1-null human ovarian cancer cell line UWB1.289, there was greater radiation sensitivity, reflected by decreased clonogenic survival with increasing doses of radiation. However, in reconstituted UWB1-289 + BRCA1 cells, there was a corresponding dose-related increase in clonogenic survival as a result of restoration of the ability to repair damaged DNA.52 Although prospective studies examining the role of BRCA1 as a predictive marker in ovarian cancer are lacking, the current literature suggests several interesting concepts. The first is the possibility that a positive BRCA1 mutation status may lend itself to specific tailoring of treatment either with radiation or chemotherapy. The natural deduction from this is that relative levels of BRCA1 expression may also have therapeutic significance for managing patients with sporadic disease. Finally, the role of BRCA1 in the DNA damage and repair in ovarian cancer is of great interest from a clinical standpoint, and further studies concerning potentially novel therapeutics aimed at this pathway are needed.
A future role seems promising for BRCA1 as a clinically useful prognostic marker and possibly as an indicator for differential response to chemotherapy, but targeting BRCA1-related interactions to prevent tumor proliferation and metastases is challenging as a result of the complexity of BRCA1 signaling and its participation in diverse processes within the cell (Fig 4). Conceptually, the simplest approach would be to rescue the tumor-suppressive actions of BRCA1 by restoring its expression in cancer cells. The frequent and significant association of P53 inactivation with LOH of BRCA1 and the accumulation of chromosomal abnormalities in cells that lack BRCA1 render it questionable whether restoration of BRCA1 function alone would be sufficient or effective as a therapeutic strategy in the face of the continuing presence of P53 mutations and other genotypic changes. However, it has been shown that retroviral transfer of wild-type BRCA1 into BRCA1-deficient breast and ovarian cancer cell lines inhibits their growth in vitro and in vivo, resulting in significantly increased survival in nude mice.103 Furthermore, the potential for BRCA1 rescue as a therapeutic approach was shown when mice with established tumors survived longer when administered intraperitoneal retrovirus expressing wild-type BRCA1 compared with nonexposed mice. A phase I clinical trial of intraperitoneal retroviral BRCA1 gene therapy in 12 patients with recurrent or persistent metastatic ovarian cancer showed promise in terms of vector stability, minimal antibody response, and disease stabilization.104 Unfortunately, these benefits were not born out in subsequent phase I and II trials.105
With the recent discovery of hypermethylated genes in malignancy, the use of DNA demethylating agents as molecular therapies has gained considerable interest. Therapies that address the hypermethylation status of the BRCA1 promoter may thus be effective for restoring BRCA1 expression in a subset of SEOC patients. Reduction of DNA methyltransferase activity through pharmacologic agents such as decitabine may relieve the block in BRCA1-induced transcriptional activity. Initial trials with such agents in leukemia patients have had modest success.106,107 The consequences of restoring BRCA1 expression on the DNA repair mechanisms in malignant cells must also be considered. It is conceivable that more efficient damage repair evoked by BRCA1 may reduce the rate of tumor progression by inhibiting further genomic instability. However, restoring the cellular capacity for repairing DNA damage may also impair the effectiveness of any subsequent DNA damage-inducing insult (radiation or chemotherapy) that might otherwise have proven lethal to malignant cells. Mamon et al108 have shown that expression of wild-type BRCA1 in a BRCA1-mutated tumor cell line increased radiotherapy resistance, restored repair of potentially lethal damage, and markedly reduced radiation-induced chromosomal aberrations. Because inhibition of BRCA1 is associated with increased sensitivity to DNA cross-linking agents such as cisplatin, any therapeutic strategy to rescue BRCA1 expression may impact on chemotherapy sensitivity. The loss of BRCA1 function is associated with multiple cellular defects including failure to activate the CHK1 signaling cascade, inability to undergo G2-M arrest, and inefficient repair of DNA damage. Therefore, strategies for therapeutic intervention would, in theory, need to target key proteins involved in multiple pathways. Alternatively, attention to pathways that could specifically rescue the proapoptotic function of BRCA1 may put forward potential targets. For example, P53-independent induction of the DNA damage-response gene GADD45 by BRCA1 with resultant activation of JNK/SAPK-dependent cell death suggests a mechanism for BRCA1-induced apoptosis.109 Accordingly, it has been proposed that JNK/SAPK pathway activation may be a means of therapeutic intervention in breast cancer.110 Perhaps the most appealing therapeutic strategy is not to repair the deficiencies caused by loss of BRCA1 but to take advantage of the Achilles heel that arises as a consequence of this loss. Cells that lack BRCA1 have an impaired capacity to repair DNA damage with high fidelity using HR.43 This weakness could be exploited by targeting BRCA1-deficient cancer cells with drugs that cause DNA damage normally reliant on BRCA1 for repair. It has been proposed that poly(ADP-ribose) polymerase 1 (PARP1), an enzyme critical for base excision repair, may be a potential target because BRCA1 dysfunction sensitizes cells to inhibition of this enzyme.111,112 Impairment of expression or activity of PARP1 in BRCA1-defective cells leads to severe toxicity as a result of chromosomal instability, cell cycle arrest, and subsequent apoptosis. Therefore, inhibition of PARP1 activity may be a promising strategy for the treatment for BRCA1-deficient tumors. Currently, there are a number of PARP1 inhibitors in phase I and II trials with a particular emphasis on potential activity in breast cancer.113
The clinical impact of germline mutations in BRCA1 is unequivocal. However, there may be a distinct and larger subset of patients with ovarian cancer for whom the inhibition of BRCA1 may have key prognostic and therapeutic implications. Further study is indicated to clearly define the group of patients with BRCA1 dysfunction to obtain corresponding clinical data and to better understand aberrations in the BRCA1 pathway with promise for the application of novel molecular therapeutics.
The author(s) indicated no potential conflicts of interest.
Conception and design: Johanne I. Weberpals, Katherine V. Clark-Knowles, Barbara C. Vanderhyden Manuscript writing: Johanne I. Weberpals, Katherine V. Clark-Knowles, Barbara C. Vanderhyden Final approval of manuscript: Barbara C. Vanderhyden
Supported by a Gynecological Cancer Research Award from the Mitchell Family Fund, National Ovarian Cancer Association and Cancer Care Ontario (J.I.W.), and a grant from the Canadian Institutes of Health Research (B.C.V.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
