Novadaq.

No abstract

Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein.Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function. (Mol Cancer Res 2009;7(2):210 -20)

Background Our purpose was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen. Methods Women with advanced or recurrent ovarian cancer participated in a survey inclusive of three methods to measure patient preferences (ratings, rankings and a discrete-choice experiment [DCE]) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort and PFS. Participants were asked to choose between two unlabeled treatment scenarios characterized using the 7 attributes. Each participant completed 12 choice questions wherein attribute levels were assigned according to an experimental design and a fixed choice question representing two chemotherapy regimens for ovarian cancer. Results 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (p<0.0001 for all). DCE revealed that the relative odds that a participant would choose a scenario with 18, 21 and 24 months of PFS versus 15 months of PFS were 1.5 (p=0.01), 3.4 (p<0.001) and 7.5 (p<0.001), respectively. However, participants' choices indicated that they were willing to accept lower PFS to avoid severe side effects: 6.7 months to reduce severe nausea and vomiting to mild, 5.0 months to reduce severe neuropathy to mild, and 3.7 months to reduce severe abdominal symptoms to moderate. Conclusion PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in this study were willing to trade significant PFS time for reductions in treatment-related toxicity.

SummaryBackground Activating FGFR2 mutations are found in 10-16% of primary endometrial cancers and provide an opportunity for targeted therapy. We assessed the safety and activity of dovitinib, a potent tyrosine-kinase inhibitor of fi broblast growth factor receptors, VEGF receptors, PDGFR-β, and c-KIT, as second-line therapy both in patients with FGFR2-mutated (FGFR2

BackgroundMutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.MethodsThe TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage.ResultsMissense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers.ConclusionsThis represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.

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Purpose Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). Patients and Methods Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. Results Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1–24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6–31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9–43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and Angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. Conclusion Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.