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  • Review Article
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The biology of ovarian cancer: new opportunities for translation

Nature Reviews Cancer volume 9, pages 415–428 (2009)Cite this article

Key Points

  • Several factors make ovarian cancer a difficult disease to treat effectively. Although many patients experience symptoms, these often overlap with other ailments, and many patients are diagnosed after the cancer has metastasized. Ovarian cancer is also heterogeneous — multiple genetic and epigenetic changes are evident in patients with ovarian cancer; however, how such changes are selected for during tumorigenesis is not yet clear.

  • Mutation and loss of TP53 function is one of the most frequent genetic abnormalities in ovarian cancer and is observed in 60–80% of both sporadic and familial cases. Of the 16 candidate tumour suppressor genes identified to date in ovarian cancer, 3 are imprinted genes. Several growth inhibitory genes are also silenced by methylation or imprinting.

  • Inheritance of DNA repair defects contributes to as many as 10–15% of ovarian cancers. The lifetime risk of developing ovarian cancer in mutation carriers varies with the genetic defect (for BRCA1 30–60%, for BRCA2 15–30% and for hereditary non-polyposis colon cancer 7%).

  • At least 15 oncogenes have been implicated in ovarian cancers, and DNA copy number abnormalities have also been found in loci that are known to contain non-coding microRNAs. At least seven signalling pathways are activated in >50% of ovarian cancers, and mutations that affect cell proliferation, apoptosis and autophagy are also evident.

  • Ovarian cancer can be split into two groups on the basis of genetic changes: low-grade tumours with mutations in KRAS, BRAF and PIK3CA, loss of heterozygosity (LOH) on chromosome Xq, microsatellite instability and expression of amphiregulin; and high-grade tumours with aberrations in TP53 and potential aberrations in BRCA1 and BRCA2, as well as LOH on chromosomes 7q and 9p.

  • Changes in cell adhesion and motility also contribute to disease development and metastasis. Adhesion of ovarian cancer cells to the mesothelial cells and to the underlying stroma is mediated by CD44, CA125 and b1 intergrin on the surface of ovarian cancer cells that bind to mesothelin and hyaluronic acid on mesothelial cells, or to fibronectin, laminin and type IV collagen in the underlying matrix.

  • A crucial goal is to identify patients who would benefit from particular targeted therapies. Given the complexity of crosstalk between protein signalling pathways, predicting the impact and efficacy of any one signalling inhibitor is difficult. Inhibition of multiple pathways will almost certainly be required to substantially affect ovarian cancer growth.

  • Effective methods for early detection are needed. Given the prevalence of ovarian cancer, strategies for early detection must have a high sensitivity for early-stage disease (>75%), but an extremely high specificity (99.6%) to attain a positive predictive value of at least 10% (ten operations for each case of ovarian cancer). Using rising values of serum biomarkers such as CA125 to trigger transvaginal sonography is a promising approach.

Abstract

Over the past two decades, the 5-year survival for ovarian cancer patients has substantially improved owing to more effective surgery and treatment with empirically optimized combinations of cytotoxic drugs, but the overall cure rate remains approximately 30%. Many investigators think that further empirical trials using combinations of conventional agents are likely to produce only modest incremental improvements in outcome. Given the heterogeneity of this disease, increases in long-term survival might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.

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Acknowledgements

This work was supported by grants from the M. D. Anderson Ovarian SPORE National Cancer Institutes (P50CA83639), the National Foundation for Cancer Research, the Ovarian Cancer Research Fund, the Mossy Foundation and the Zarrow Foundation.

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  1. Departments of Experimental Therapeutics and Systems Biology, University of Texas M. D. Anderson Cancer Center, 1515 Holcolmbe Boulevard, Houston, 77030, Texas, USA

    Robert C. Bast Jr, Bryan Hennessy & Gordon B. Mills

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  1. Robert C. Bast Jr
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Correspondence to Robert C. Bast Jr.

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DATABASES

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azacytidine

belinostat

bevacizumab

carboplatin

cisplatin

cyclophosphamide

dasatinib

docetaxel

erlotinib

gefitinib

ONYX-015

paclitaxel

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Glossary

Intercurrent infection

An infection that occurs at the same time as a patient is suffering from a different disease.

Endometriosis

The growth of tissue that resembles the endometrium in areas within the pelvic cavity.

Loss of heterozygosity

(LOH). In cells that carry a mutated allele of a tumour suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome that carries the wild-type allele. Regions with a high frequency of LOH are thought to contain tumour suppressor genes.

Metronomic chemotherapy

The frequent, chronic administration of chemotherapy at low, non-toxic doses, with no prolonged drug-free breaks.

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Bast, R., Hennessy, B. & Mills, G. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 9, 415–428 (2009). https://doi.org/10.1038/nrc2644

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