- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Article Processing Charges ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Recently Accepted Articles ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
Journal of Oncology
Volume 2010 (2010), Article ID 314326, 9 pages
Targeted Therapies in Epithelial Ovarian Cancer
1Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
2Gynecologic Oncology Division, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
3Gynecologic Oncology Unit, Department of Obstetrics & Gynecology, Hospital Sótero del Río, Santiago, Chile
Received 9 May 2009; Revised 13 October 2009; Accepted 22 October 2009
Academic Editor: Charles F. Levenback
Copyright © 2010 Nicanor I. Barrena Medel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Epithelial ovarian cancer remains a major women's health problem due to its high lethality. Despite great efforts to develop effective prevention and early detection strategies, most patients are still diagnosed at advanced stages of disease. This pattern of late presentation has resulted in significant challenges in terms of designing effective therapies to achieve long-term cure. One potential promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. This review examines three of the most provocative targeted therapies with current or future applicability in epithelial ovarian cancer.
Ovarian cancer represents the sixth most common malignancy as well as the seventh leading cause of cancer-related death in women worldwide [1, 2]. In the USA, this neoplasm ranks second among gynecologic cancers, yet it is by far the most lethal one, accounting for more than 15,000 deaths annually . One of the major reasons underlying this dismal prognosis is the fact that nearly 75% of cases are diagnosed at an advanced stage (i.e., tumor already spread beyond the ovary) [4, 5], despite great efforts to develop reliable screening and prevention strategies.
To date, advanced ovarian cancer management has predominantly consisted of surgery followed by chemotherapy consisting of a combination of platinums and taxanes. More recently, neoadjuvant chemotherapy, a therapeutic alternative traditionally reserved for those patients considered poor candidates for upfront surgery, has emerged as a potential first-line option . Even though up to 80% of these patients will respond to initial treatment, most of them will subsequently recur . Chemotherapy success rates after relapse range from 10% to 50%, depending on whether the tumor is platinum sensitive or resistant (i.e., a progression-free interval (PFI) following platinum-based first-line therapy of more or less than 6 months, resp.). Unfortunately, almost all responses are invariably transient. Thus, the 5-year overall survival (OS) for late-stage disease is approximately 45% .
Since “nonspecific” therapies, namely, surgery, radiation, and conventional chemotherapy, have largely failed to achieve cure in the majority of patients affected by epithelial ovarian cancer, investigators have focused on developing novel treatment approaches. Many of these new strategies are based upon an understanding of the critical molecules and pathways specifically involved in tumorigenesis and metastasis. This has led to the development of “targeted” oncologic therapies that might be ultimately more effective and less toxic.
Although significant overlap occurs, targeted therapies can be broadly divided into two categories:(i)those focused on cellular mechanisms that are disregulated in carcinogenesis,(ii)those directed against the neoplasm’s microenvironment, a tumor component lately recognized as highly relevant in both cancer growth and dissemination.
The present article addresses targeted therapies currently being employed or tested in epithelial ovarian cancer (EOC). Since their number has become as numerous as the myriad of critical pathways involved in ovarian neoplastic transformation, this review will focus on three of the most promising and/or well-studied targeted weapons in ovarian cancer therapeutics to date, namely,(i)antiangiogenesis compounds,(ii)epidermal growth factor receptor (EGFR) antagonists,(iii)poly (ADP) ribose polymerase (PARP) inhibitors.
2. Materials and Methods
A comprehensive literature search was conducted using the following key terms: “ovarian cancer”, “targeted therapies”, “antiangiogenesis”, “epidermal growth factor receptor (EGFR) inhibitors”, and “poly (ADP) ribose polymerase (PARP) inhibitors”. For this purpose, primary sources used were PubMed and Cochrane Databases. Articles’ selection was limited to those written in English, without restriction to year of publication. The main analysis was focused on those studies providing clinical evidence, although preclinical data were included either when background information was required or when clinical assays were absent. Highly valuable references cited by primarily collected studies as well as pivotal abstracts presented at prominent oncologic meetings, such as the Society of Gynecologic Oncologists (SGO), the American Society of Clinical Oncology (ASCO), the European Society of Gynaecological Oncology (ESGO), and the International Gynecologic Cancer Society (IGCS), were also assessed and their data incorporated whenever pertinent.
Angiogenesis (i.e., the formation of new blood vessels) plays a critical role in cancer expansion and propagation. While many tumors start as avascular nodules, early data demonstrated that growth is impaired beyond 2 mm3 unless effective neovascularization is established . Hence, this phenomenon appears to be a rate-limiting step in tumor progression. Antiangiogenic therapies have been shown to inhibit new blood vessels development, induce endothelial cells apoptosis, and normalize vasculature .
Many components interact in this process, such as proangiogenic factors, metalloproteinases, and endothelial precursor cells. Among angiogenesis-promoting molecules, the vascular endothelial growth factor (VEGF) is the most sensitive and potent one, as well as the best characterized . It is overexpressed in many human tumors, including ovarian cancer. In ovarian malignancies, high levels of VEGF have been associated with poor prognostic features, such as advanced stage, carcinomatosis, distant metastasis, as well as a decreased survival . Thus, the VEGF pathway has become one of the most attractive research areas in EOC therapeutics. Preclinical data from animal models showed that VEGF blockade was associated with inhibition of ascites formation and tumor growth .
Bevacizumab, a recombinant humanized monoclonal antibody directed against VEGF-A, was the first of these agents to be evaluated in EOC. Case reports and small series constituted the initial clinical evidence supporting its therapeutic value, mainly in recurrent, heavily pretreated patients [12, 13]. Based on these findings, two phase II trials using single-agent bevacizumab in recurrent ovarian cancer, predominantly platinum-resistant disease, were subsequently conducted (Table 1) [14, 15]. Their results demonstrated the following.
This drug has been and continues to be tested in combination with chemotherapy, as a part of the first line treatment in newly diagnosed EOC and recurrent disease. Table 1 both summarizes the most relevant past and ongoing trials conducted in this setting.
Other anti-VEGF as well as non-VEGF mediated Antiangiogenic drugs are currently in clinical development. Table 2 illustrates some of these initiatives.
In conclusion, to date antiangiogenesis appears as one of the most promising targeted strategies explored in EOC. Given the encouraging initial results, bevacizumab has entered phase III trial evaluation. Meanwhile, it is considered a viable option in the recurrent setting. Appropiate bevacizumab dose (7.5 versus 15 mg/kg) and the ability to combine with other biologics require further study as well. Safety issues must be considered when using this compound. Adequate patient selection may potentially reduce the incidence of serious adverse events by excluding those at a highest risk for gastrointestinal perforation or a thromboembolic event. Major risk factors for these two complications have been described (Table 3), yet it should be noted that they still require further validation.
4. Epidermal Growth Factor (EGF) Receptors Antagonists
The family of EGF receptors (EGFRs) is composed of 4 structurally similar receptors which exert a tyrosine kinase function: ErbB1 (commonly referred to as epidermal growth factor receptor), ErbB2 (Her2/neu), ErbB3 (Her3), and ErbB4 (Her4). Their activation triggers a cascade of events ultimately resulting in cell proliferation and survival. Like VEGF, EGFRs are frequently overexpressed and/or dysregulated in solid tumors. Ovarian cancer is not an exception, with up to 70% of cases exhibiting this aberrant phenotype, which has been linked to poor oncologic features and outcomes [5, 7, 29].
These observations have suggested that EGFRs might represent a viable target for novel therapies in EOC. While blockade of these receptors can be achieved by several mechanisms, two of these have been most extensively explored: (a) small molecules capable of inhibiting the tyrosine kinase domain and (b) monoclonal antibodies directed against the extracellular region.
Preliminary preclinical data demonstrated antitumoral activity and a reversion of the chemoresistant phenotype secondary to EGFR inhibition . Nonetheless, and in contrast with the promising results obtained with anti-VEGF therapies, to date clinical trials with EGFR inhibitors alone have produced disappointing results.
4.1. Tyrosine Kinase Inhibitors (TKIs)
Gefitinib and erlotinib are two of the main compounds in this category. Both are orally administrated and relatively well tolerated , which would represent a significant advantage in terms of patients’ quality of life. Core findings from the most relevant trials conducted on these agents can be summarized as follows [32–38].(a)An RR in recurrent ovarian cancer is of less than 10% along with stable disease in up to 44% of patients when used as single agents.(b)These results were improved either when gefitinib was combined with standard chemotherapy or when erlotinib was combined with bevacizumab. The combination gefitinib-tamoxifen did not appear to add any clinical benefit.(c)As a part of the first-line treatment in conjunction with a platinum and a taxane, either upfront or as consolidation therapy, TKIs have yet to confirm a demonstrable survival advantage. The EORTC has just finalized the recruitment of a phase III trial exploring erlotinib as maintenance therapy in both high-risk early-stage and advanced diseases. (d)In terms of side effects, the most frequently observed were diarrhea (up to 30%, being the dose-limiting toxicity), nauseas and vomiting (nearly 10%), and an acne-like cutaneous rash (5%–15%), which interestingly correlated positively with tumor response. As expected, increased toxicity was seen when a cytotoxic agent was coadministrated.
As noted above, the initial experience with these agents has not revealed a definitive role in the treatment of unselected EOC population, either in the first-line or the relapsed setting. However, a subgroup of patients showing an increased likelihood to respond to these compounds has been identified. In Schilder’s trial, published in 2005, clinical outcomes correlated with EGFR status, with a significantly longer progression-free survival (PFS) as well as a trend in improved overall survival (OS) among those who were EGFR (+). Specifically, an enhanced response to gefitinib was linked to the presence of an infrequent mutation affecting the catalytic domain of this receptor . This relationship closely resembles what previously has been described in lung cancer [39, 40]. Thus, it has been suggested that prescreening patients for specific active EGFR mutations could define the population most likely to benefit from this therapy. Further investigation to validate this finding in EOC is warranted.
Novel EGFR inhibitors in development for EOC include lapatinib, canertinib, PKI-166, and EKB-569. Until better evidence supporting a relevant therapeutic value becomes available, the role of TKIs in this neoplasm remains predominately confined to clinical trials.
4.2. Monoclonal Antibodies
Various humanized antibodies against the extracellular region of EGFR have been thought to be potentially effective in EOC. Nonetheless, similar to what has occurred with TKIs, the theory has not been confirmed clinically. Probably the most emblematic example illustrating this unfulfilled potential has been trastuzumab. Multiple initial studies confirmed that Her-2/neu overexpression was associated with an adverse prognosis of patients with epithelial ovarian cancer [41, 42]. Trastuzumab, a selective Her-2/neu inhibitor approved for the treatment of ErbB 2 (+) metastatic breast cancer, was proposed to have antitumoral activity comensurate with that observed in breast cancer. Further clinical evidence in a large GOG trial, however, demonstrated a response rate of only 7%, with disease stabilization in other 39% of ErbB 2(+) recurrent ovarian cancer patients .
Results obtained with other monoclonal antibodies, alone or in combination with standard chemotherapy, are outlined in Table 4.
5. PARP Inhibitors
Approximately 10% of ovarian cancers are considered hereditary. Germline mutations affecting two genes, BRCA1 and BRCA2, account for the vast majority of these cases. The lifetime risk of developing an epithelial ovarian carcinoma among women who carry these genetic defects has been estimated to be up to 60% . The proteins encoded by these tumor suppressor genes participate in multiple cellular processes, including transcription, cell cycle regulation, and repair of DNA double-strand breaks . When inactived, chromosome instability occurs, an event potentially facilitating carcinogenesis.
Many other DNA-repair mechanisms are generally available within the normal cell. The base-excision repair (BER) complex constitutes one of them. The enzyme poly (ADP) ribose polymerase (PARP) is a key component of this pathway. Its scope is restricted to single-strand defects. Accordingly, its malfunction theoretically should not affect double-strand repair; however, a persistent single-strand defect may ultimately result in DNA replication interruption or a double-strand break . When this occurs in a cell that is already unable to repair DNA damage , as the case for BRCA-defective cells, cell cycle arrest or death occurs. This observation, known as synthetic lethality , supports the contention that PARP blockade would be therapeutically effective in hereditary EOC. This premise was initially confirmed in preclinical studies demonstrating a highly increased sensitivity to PARP inhibition among BRCA-deficient cells, with a subsequent decreased cell survival, compared to those heterozygous or BRCA wild-type cells [53, 54].
Clinical studies exploiting this approach have been recently conducted in multiple human solid tumors. Initial trials used these agents primarily as chemosensitizers, mainly in association with methylating compounds . However, with the demonstration of BRCA specific sensitivity, single-agent inhibitors were assessed. Recently, final results of the first phase I trial evaluating Olaparib, an orally administrated PARP inhibitor, in BRCA-defective malignancies, including ovarian cancer, showed a low toxicity along with a response or disease stabilization rate of 63% . Multiple PARP inhibitors are currently being examined in phase II trials. Of interest, Audeh et al. lately reported the interim analysis of a phase II study employing Olaparib in BRCA-deficient advanced ovarian cancer . Overall 57% of patients demonstrated response to PARP inhibition, using either RECIST or CA-125 criteria. Potential use of PARP inhibitors as chemoprophylactics in BRCA mutation carriers  and for treating sporadic ovarian cancers  has been proposed, as well.
A potential barrier to PARP inhibitors use has been the recently described emergence of resistance by reversal of the BRCA-deficient phenotype . The clinical implications of this phenomenon require further clarification.
6. Conclusions and Future Overview
Women with epithelial ovarian cancer are living for longer periods of time than ever before. Development of novel chemotherapeutics has in part contributed to this improved outcome. However, a significant proportion of affected patients still succumbs to this difficult disease. Thus, progress is still needed. To this end, targeted therapies appear to be a promising platform for clinical development.
Many cellular pathways have been implicated in ovarian carcinogenesis, and exploitation of these perturbations critical in forming or maintaining the malignant phenotype has yielded a number of promising compounds. However, to date only Antiangiogenic agents have reached clinical relevance in EOC management. New therapeutic tools showing promising results, such as PARP inhibitors that exploit the abnormality responsible for the initial neoplastic transformation, have demonstrated encouraging clinical potential.
Some relevant lessons learned in targeted therapy development thus far include  the following.(i)The mere presence of a particular molecule or pathway dysregulated in a particular tumor does not guarantee that its inactivation will have therapeutic benefit.(ii)Response does not always translate into prolonged survival, symptom relief, or other valuable clinical endpoints. Conversely, there may be significant improvements in time-to-event endpoints such as time-to-progression or PFS, and yet objective responses may be rare. Thus different clinical parameters may be neccesary for efficacy assessment of targeted agents. (iii)Given the multiplicity and redundancy of aberrant pathways involved in ovarian cancer, it is unlikely that inhibition of a single cascade will be highly effective. Thus agents that act upon multiple levels or interconnected pathways simultaneously appear potentially more promising.
The future of cancer therapeutics will likely include tailored, individualized treatments, designed on the basis of an even deeper understanding of the critical alterations in ovarian carcinogenesis. Gene expression profiles have established that this neoplasia is far from being a uniform disease . Thus, genotype-directed and pharmacogenomic therapies emerge as the next frontier for fruitful exploration and novel drug development.
Conflict of Interest Statement
Nicanor I. Barrena Medel and Jason D. Wright both have no conflicts of interest to declare. Thomas J. Herzog received Honoraria from Educational Programs: GSK, J&J, Lilly, Merck, and Genentech.
- P. Boyle and B. Levin, Eds., “World cancer report 2008,” IARC/WHO.
- J. Permuth-Wey and T. A. Sellers, “Epidemiology of ovarian cancer,” Methods in Molecular Biology, vol. 472, pp. 413–437, 2009.
- A. Jemal, R. Siegel, E. Ward, et al., “Cancer statistics, 2008,” CA: Cancer Journal for Clinicians, vol. 58, no. 2, pp. 71–96, 2008.
- P. Dinh, P. Harnett, M. J. Piccart-Gebhart, and A. Awada, “New therapies for ovarian cancer: cytotoxics and molecularly targeted agents,” Critical Reviews in Oncology/Hematology, vol. 67, no. 2, pp. 103–112, 2008.
- T. A. Yap, C. P. Carden, and S. B. Kaye, “Beyond chemotherapy: targeted therapies inovarian cancer,” Nature Reviews Cancer, vol. 14, pp. 3159–3167, 2009.
- I. Vergote, C. G. Trope, F. Amant, et al., “EORTC-GCG/NCIC-CTG randomized trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC-IV ovarian, fallopian tube or peritoneal cancer (OVCA),” in Proceedings of the 12th Biennial Meeting of the International Gynecologic Cancer Society (IGCS '08), Bangkok, Thailand, October 2008, abstract no. 2008_1767.
- M. Markman, “The promise and perils of ‘targeted therapy’ of advanced ovarian cancer,” Oncology, vol. 74, no. 1-2, pp. 1–6, 2008.
- J. Folkman, “Tumor angiogenesis: therapeutic implications,” The New England Journal of Medicine, vol. 285, no. 21, pp. 1182–1186, 1971.
- W. W. Ma and A. A. Adjei, “Novel agents on the horizon for cancer therapy,” CA: Cancer Journal for Clinicians, vol. 59, no. 2, pp. 111–137, 2009.
- R. A. Burger, “Experience with bevacizumab in the management of epithelial ovarian cancer,” Journal of Clinical Oncology, vol. 25, no. 20, pp. 2902–2908, 2007.
- A. T. Byrne, L. Ross, J. Holash, et al., “Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model,” Clinical Cancer Research, vol. 9, no. 15, pp. 5721–5728, 2003.
- B. J. Monk, D. C. Choi, G. Pugmire, and R. A. Burger, “Activity of bevacizumab (rhuMAB VEGF) in advanced refractory epithelial ovarian cancer,” Gynecologic Oncology, vol. 96, no. 3, pp. 902–905, 2005.
- B. J. Monk, E. Han, C. A. Josephs-Cowan, G. Pugmire, and R. A. Burger, “Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer,” Gynecologic Oncology, vol. 102, no. 2, pp. 140–144, 2006.
- R. A. Burger, M. W. Sill, B. J. Monk, B. E. Greer, and J. I. Sorosky, “Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study,” Journal of Clinical Oncology, vol. 25, no. 33, pp. 5165–5171, 2007.
- S. A. Cannistra, U. A. Matulonis, R. T. Penson, et al., “Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer,” Journal of Clinical Oncology, vol. 25, no. 33, pp. 5180–5186, 2007.
- J. P. Micha, B. H. Goldstein, M. A. Rettenmaier, et al., “A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer,” International Journal of Gynecological Cancer, vol. 17, no. 4, pp. 771–776, 2007.
- A. A. Garcia, H. Hirte, G. Fleming, et al., “Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia,” Journal of Clinical Oncology, vol. 26, no. 1, pp. 76–82, 2008.
- W. P. Tew, N. Colombo, I. Ray-Coquard, et al., “VEGF-Trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC). Preliminary results of a randomized, phase II study,” Journal of Clinical Oncology, vol. 25, no. 18S, 2007, (ASCO Meeting Abstratcs), abstract 5508.
- U. A. Matulonis, S. T. Berlin, C. N. Krasner, et al., “Cediranib (AZD2171) is an active agent in recurrent epithelial ovarian cancer,” Journal of Clinical Oncology, vol. 26, no. 20S, 2008, (ASCO Meeting Abstracts), abstract 5501.
- M. W. Hirte, L. Vidal, G. F. Fleming, et al., “A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial,” Journal of Clinical Oncology, vol. 26, no. 20S, 2008, (ASCO Meeting Abstracts), abstract 5521.
- M. Beeram, A. Patnaik, and E. K. Rowinsky, “Raf: a strategic target for therapeutic development against cancer,” Journal of Clinical Oncology, vol. 23, no. 27, pp. 6771–6790, 2005.
- S. Welch, H. Hirte, R. J. Schilder, et al., “Phase II study of sorafenib (BAY 43-9006) in combination with gemcitabine in recurrent epithelial ovarian cancer: a PMH phase II consortium trial,” Journal of Clinical Oncology, vol. 24, no. 18S, 2006, (ASCO Meeting Abstracts), abstract 5084.
- M. Friedlander, K. C. Hancock, B. Benigno, et al., “Pazopanib (GW786034) is active in women with advanced epithelial ovarian, fallopian tube or peritoneal cancers: initial results of a phase II study,” Journal of Clinical Oncology, vol. 25, no. 18S, 2007, (ASCO Meeting Abstracts), abstract 5561.
- D. W. Siemann, E. Mercer, S. Lepler, and A. M. Rojiani, “Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy,” International Journal of Cancer, vol. 99, no. 1, pp. 1–6, 2002.
- M. Zweifel, G. Jayson, R. Reed, et al., “Combretastin A-4 phosphate (CA4P) carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer: final phase II trial results,” Journal of Clinical Oncology, vol. 27, no. 15S, 2009, (ASCO Meeting Abstracts), abstract 5502.
- F. A. Scappaticci, J. R. Skillings, S. N. Holden, et al., “Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab,” Journal of the National Cancer Institute, vol. 99, no. 16, pp. 1232–1239, 2007.
- J. D. Wright, A. A. Secord, T. M. Numnum, et al., “A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer,” International Journal of Gynecological Cancer, vol. 18, no. 3, pp. 400–406, 2008.
- F. Simpkins, J. L. Belinson, and P. G. Rose, “Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening,” Gynecologic Oncology, vol. 107, no. 1, pp. 118–123, 2007.
- M. J. Palayekar and T. J. Herzog, “The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer,” International Journal of Gynecological Cancer, vol. 18, no. 5, pp. 879–890, 2008.
- F. Ciardello and G. Totora, “Anti-epidermal growth factor receptor in cancer therapy,” Expert Opinion on Investigational Drugs, vol. 11, pp. 755–768, 2002.
- J. Baselga, D. Rischin, M. Ranson, et al., “Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types,” Journal of Clinical Oncology, vol. 20, no. 21, pp. 4292–4302, 2002.
- R. J. Schilder, M. W. Sill, X. Chen, et al., “Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group study,” Clinical Cancer Research, vol. 11, no. 15, pp. 5539–5548, 2005.
- E. M. Posadas, M. S. Liel, V. Kwitkowski, et al., “A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer,” Cancer, vol. 109, no. 7, pp. 1323–1330, 2007.
- A. N. Gordon, N. Finkler, R. P. Edwards, et al., “Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study,” International Journal of Gynecological Cancer, vol. 15, no. 5, pp. 785–792, 2005.
- D. Mavroudis, E. Efstathiou, A. Polyzos, et al., “A phase I-II trial of gefitinib in combination with vinorelbine and oxaliplatin as salvage therapy in women with advanced ovarian cancer (AOC),” Journal of Clinical Oncology, vol. 22, no. 14S, 2004, (ASCO Meeting Abstracts), abstract 5020.
- H. S. Nimeiri, A. M. Oza, R. J. Morgan, et al., “Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II consortia,” Gynecologic Oncology, vol. 110, no. 1, pp. 49–55, 2008.
- U. Wagner, A. du Bois, J. Pfisterer, et al., “Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum-taxane based therapy—a phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6),” Gynecologic Oncology, vol. 105, no. 1, pp. 132–137, 2007.
- P. A. Vasey, M. Gore, R. Wilson, et al., “A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers,” British Journal of Cancer, vol. 98, no. 11, pp. 1774–1780, 2008.
- T. J. Lynch, D. W. Bell, R. Sordella, et al., “Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib,” The New England Journal of Medicine, vol. 350, no. 21, pp. 2129–2139, 2004.
- J. G. Paez, P. A. Jänne, J. C. Lee, et al., “EGFR mutations in lung, cancer: correlation with clinical response to gefitinib therapy,” Science, vol. 304, no. 5676, pp. 1497–1500, 2004.
- E. Felip, J. M. Del Campo, D. Rubio, M. T. Vidal, R. Colomer, and B. Bermejo, “Overexpression of c-erbB-2 in epithelial ovarian cancer: prognostic value and relationship with response to chemotherapy,” Cancer, vol. 75, no. 8, pp. 2147–2152, 1995.
- S. Camilleri-Broët, A. C. Hardy-Bessard, and A. Le Tourneau, “HER-2 overexpression in an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group,” Annals of Oncology, vol. 15, pp. 104–112, 2004.
- M. A. Bookman, K. M. Darcy, D. Clarke-Pearson, R. A. Boothby, and I. R. Horowitz, “Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group,” Journal of Clinical Oncology, vol. 21, no. 2, pp. 283–290, 2003.
- A. A. Secord, J. A. Blessing, D. K. Armstrong, et al., “Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study,” Gynecologic Oncology, vol. 108, pp. 493–499, 2008.
- J. Konner, R. J. Schilder, F. A. DeRosa, et al., “A phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-stage ovarian, primary peritoneal, or fallopian tube cancer,” Gynecologic Oncology, vol. 110, no. 2, pp. 140–145, 2008.
- R. J. Schilder, H. B. Pathak, A. E. Lokshin, et al., “Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash,” Gynecologic Oncology, vol. 113, no. 1, pp. 21–27, 2009.
- M. V. Seiden, H. A. Burris, U. Matulonis, et al., “A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies,” Gynecologic Oncology, vol. 104, no. 3, pp. 727–731, 2007.
- M. S. Gordon, D. Matei, C. Aghajanian, et al., “Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status,” Journal of Clinical Oncology, vol. 24, no. 26, pp. 4324–4332, 2006.
- J. I. Weberpals, K. V. Clark-Knowles, and B. C. Vanderhyden, “Sporadic epithelial ovarian cancer: clinical relevance of BRCA1 inhibition in the DNA damage and repair pathway,” Journal of Clinical Oncology, vol. 26, no. 19, pp. 3259–3267, 2008.
- A. Ashworth, “A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair,” Journal of Clinical Oncology, vol. 26, no. 22, pp. 3785–3790, 2008.
- R. Saffhill and C. H. Ockey, “Strand breaks arising from the repair of the 5-bromodeoxyuridine-substituted template and methyl methanesulphonate-induced lesions can explain the formation of sister chromatid exchanges,” Chromosoma, vol. 92, no. 3, pp. 218–224, 1985.
- W. G. Kaelin Jr., “The concept of synthetic lethality in the context of anticancer therapy,” Nature Reviews Cancer, vol. 5, no. 9, pp. 689–698, 2005.
- H. E. Bryant, N. Schultz, H. D. Thomas, et al., “Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase,” Nature, vol. 434, no. 7035, pp. 913–917, 2005.
- H. Farmer, N. McCabe, C. J. Lord, et al., “Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy,” Nature, vol. 434, no. 7035, pp. 917–921, 2005.
- C. J. Lord and A. Ashworth, “Targeted therapy for cancer using PARP inhibitors,” Current Opinion in Pharmacology, vol. 8, no. 4, pp. 363–369, 2008.
- P. C. Fong, D. S. Boss, T. A. Yap, et al., “Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers,” The New England Journal of Medicine, vol. 361, no. 2, pp. 123–134, 2009.
- M. W. Audeh, R. T. Penson, M. Friedlander, et al., “Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer,” Journal of Clinical Oncology, vol. 27, no. 15S, 2009, (ASCO Meeting Abstracts), abstract 5500.
- T. Hay, H. Jenkins, O. J. Sansom, N. M. B. Martin, G. C. M. Smith, and A. R. Clarke, “Efficient deletion of normal BRCA2-deficient intestinal epithelium by poly(ADP-ribose) polymerase inhibition models potential prophylactic therapy,” Cancer Research, vol. 65, no. 22, pp. 10145–10148, 2005.
- S. L. Edwards, R. Brough, C. J. Lord, et al., “Resistance to therapy caused by intragenic deletion in BRCA2,” Nature, vol. 451, no. 7182, pp. 1111–1115, 2008.
- K. K. Zorn, T. Bonome, L. Gangi, et al., “Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer,” Clinical Cancer Research, vol. 11, no. 18, pp. 6422–6430, 2005.