Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer death in the United States, with an estimated 22,240 new cases and 14,030 deaths estimated for 2013 (ACS 2013). The vast majority of women are diagnosed with advanced stage EOC. Current practice consists of aggressive surgical removal of tumors, followed by platinum–taxane based chemotherapy (Muggia 2009). Despite initial aggressive treatment, most tumors recur, and the overall 5-year survival rate is 44% (Siegel, Naishadham, and Jemal 2012).
Emerging knowledge about underlying molecular alterations in ovarian cancer could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies. Approximately 10–20% of high grade ovarian cancers are associated with germline mutations in BRCA1/2 (Pal et al. 2005). Somatic alterations in BRCA1/2 and other genes associated with DNA repair are seen in approximately 50% of high grade ovarian cancers (TCGA 2011) and tumors with a ‘BRCAness’ molecular profile are relatively sensitive to treatment with DNA damaging agents cisplatin and PARP inhibitors (Konstantinopoulos et al. 2010).
More recently, EOC tumors have been broadly classified into two distinct groups with unique histological, clinical and molecular profiles (Table 1). Type I tumors have low grade serous, clear cell, endometrioid, and mucinous histological features. Typically, these tumors are slow growing and confined to the ovary, and are less sensitive to standard chemotherapy. BRAF and KRAS somatic mutations are relatively common in these tumors, which may have important therapeutic implications.
Type II tumors are high grade serous cancers of the ovary, peritoneum, and fallopian tube. Other high grade endometrioid and poorly differentiated ovarian cancers as well as carcinosarcomas are included in the type II group. These tumors are clinically aggressive and are often widely metastatic at the time of presentation. High grade serous EOC tumors display high levels of genomic instability with few common mutations, other than TP53, which is altered in over 90% of the cases (Kurman and Shih 2011; Landen, Birrer, and Sood 2008; TCGA 2011). PIK3CA and RAS signaling pathways are altered in 45% of the cases, but somatic mutations are rare and gene amplifications are far more common (TCGA 2011).
Currently, the most common ‘actionable’ alterations with potential for small molecule targeted therapy in EOC tumors are in the PIK3CA/PTEN and KRAS/BRAF signaling pathways.
Table 1. Frequency of Somatic Gene Mutations in Epithelial Ovarian Cancer (EOC)
|Gene Mutation||EOC Overall||High Grade Serous (Type II)||Low Grade Serous (Type I)||Clear Cell (Type I)||Endometrioid (Type I)||Mucinous (Type I)|
|BRAF||11% (Kurman and Shih 2011)||<1% (TCGA 2011)||24–33% (Nakayama et al. 2006; Singer et al. 2003)
||1% (Kuo et al. 2009)||24% (Singer et al. 2003)||50–75% (Gemignani et al. 2003)|
|KRAS||11% (Kurman and Shih 2011)||<1% (TCGA 2011)||33% (Nakayama et al. 2006; Singer et al. 2003)
||<1–7% (Kuo et al. 2009; Singer et al. 2003)||<1% (Singer et al. 2003)||50–75% (Gemignani et al. 2003)|
|PIK3CA||6.7% (Campbell, Russell, and Phillips 2005; Levine et al. 2005; Wang et al. 2005)||<1% (TCGA 2011)||5% (Nakayama et al. 2006)||20–33% (Campbell et al. 2004; Kuo et al. 2009)||20% (Campbell et al. 2004)||Rare|
|PTEN||20% (Kurman and Shih 2011)||<1% mutation (TCGA 2011)||20% (Landen, Birrer, and Sood 2008)||<1–5% (Kuo et al. 2009; Willner et al. 2007)||20–31% (Kurman and Shih 2011; Willner et al. 2007)||Rare|
Last Updated: February 19, 2013
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