Paula S. Lee

Relationship between tamoxifen use and high risk endometrial cancer histologic types

OBJECTIVES We wished to determine whether a pre-existing diagnosis of breast cancer or the use of tamoxifen among patients with pre-existing breast cancer influences the histologic type of subsequently diagnosed endometrial carcinoma, the interval between these diagnoses, or survival. METHODS A single institution retrospective review was performed of all patients who underwent primary surgery for endometrial carcinoma from 1995-2005. We compared the histologic type of endometrial carcinoma among patients with a prior history of breast cancer to those without. Patients with a previous diagnosis of breast cancer were further analyzed by comparing histologic type, progression-free and overall survival between tamoxifen users and non-users. RESULTS Among 732 women with endometrial carcinoma, 59 patients (8%) had a previous diagnosis of breast cancer, of whom 29 (49%) had used tamoxifen. Women with a history of breast cancer were more likely to have a high risk uterine histologic type (grade 3 endometrioid, papillary serous, or clear cell) (18/59; 31%) than those without this prior malignancy (120/670, 18%; p=0.024). Breast cancer survivors whose endometrial carcinoma was of a high risk histologic type had a longer median duration of prior tamoxifen use compared to those with lower risk histologic types (60 versus 46 months, p=0.034). CONCLUSIONS Among women with endometrial carcinoma, those with a history of breast cancer are more likely to harbor a high risk uterine histologic subtype. Tamoxifen use of at least 60 months is associated with high risk uterine histologic subtypes when compared to no tamoxifen use. This study adds to existing data suggesting a relationship between tamoxifen use and development of endometrial carcinoma of more aggressive histologic types.

A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group Study

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.

Yin Yang 1 modulates taxane response in epithelial ovarian cancer

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)

Medical and surgical treatment of placenta percreta to optimize bladder preservation.

BACKGROUND: Placenta percreta is associated with significant morbidity and mortality. Interventions are dictated by hemodynamic stability, desire to retain future fertility, and efforts to reduce surgical morbidity at time of delivery. CASES: Two cases of antenatally diagnosed placenta percreta with bladder invasion are presented. Conservative management was used, including endovascular interventions, leaving the placenta in situ, methotrexate, and delayed hysterectomy. Postoperative outcomes were acceptable, with no significant hemorrhagic complications or need for extensive bladder reconstruction. CONCLUSION: Antenatal diagnosis of placenta percreta with bladder invasion is essential in the multidisciplinary management of this potentially catastrophic condition. A comprehensive approach including delayed hysterectomy after medical management resulted in an excellent clinical outcome.

A Phase I Trial of Dasatinib, an Src-Family Kinase Inhibitor, in Combination with Paclitaxel and Carboplatin in Patients with Advanced or Recurrent Ovarian Cancer

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer. Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort. Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity. Clin Cancer Res; 18(19); 5489–98. ©2012 AACR.

Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer.

We previously found that the gene encoding the Myelin and Lymphocyte protein, MAL, was among the most highly expressed genes in serous ovarian cancers from short‐term survivors (<3 years) relative to those of long‐term survivors (>7 years). In the present study, we have found that this difference in expression is partially attributable to differences in DNA methylation at a specific region within the MAL promoter CpG island. While MAL was largely unmethylated at the transcription start site (Region 1; −48 to +73 bp) in primary serous ovarian cancers, methylation of an upstream region (Region 2; −452 to −266 bp) was inversely correlated with MAL transcription in the primary cancers (R = −0.463) and ovarian cancer cell lines (R = −0.444). Following treatment of the OVCA432 cell line with 5‐azacytidine, methylation of Region 2 decreased from 73.3% to 34.7% (p = 0.007) while Region 1 was unaffected. This was accompanied by a 10‐fold increase in MAL expression. Since MAL transcripts are elevated in tumors from short‐term survivors, all of whom were treated with platinum‐based therapy, MAL may have a role in cisplatin response. We therefore determined the 50% growth inhibitory dose of cisplatin in 30 ovarian cancer cell lines and compared this to MAL expression. MAL transcript levels were higher in the resistant ovarian cell lines (p = 0.04). MAL methylation status may therefore serve as a marker of platinum sensitivity while MAL protein may be a target for development of novel therapies aimed at enhancing sensitivity to platinum‐based drugs in ovarian cancer.

Expression signatures of TP53 mutations in serous ovarian cancers

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.

Inactivation of the MAL gene in breast cancer is a common event that predicts benefit from adjuvant chemotherapy

Dysregulation of MAL (myelin and lymphocyte protein) has been implicated in several malignancies including esophageal, ovarian, and cervical cancers. The MAL protein functions in apical transport in polarized epithelial cells; therefore, its disruption may lead to loss of organized polarity characteristic of most solid malignancies. Bisulfite sequencing of the MAL promoter CpG island revealed hypermethylation in breast cancer cell lines and 69% of primary tumors analyzed compared with normal breast epithelial cells. Differential methylation between normal and cancer DNA was confined to the proximal promoter region. In a subset of breast cancer cell lines including T47D and MCF7 cells, promoter methylation correlated with transcriptional silencing that was reversible with the methylation inhibitor 5-aza-2′-deoxycytidine. In addition, expression of MAL reduced motility and resulted in a redistribution of lipid raft components in MCF10A cells. MAL protein expression measured by immunohistochemistry revealed no significant correlation with clinicopathologic features. However, in patients who did not receive adjuvant chemotherapy, reduced MAL expression was a significant predictive factor for disease-free survival. These data implicate MAL as a commonly altered gene in breast cancer with implications for response to chemotherapy. (Mol Cancer Res 2009;7(2):199–209)

Cost-effectiveness of early palliative care intervention in recurrent platinum-resistant ovarian cancer.

OBJECTIVE To determine if early palliative care intervention in patients with recurrent, platinum-resistant ovarian cancer is potentially cost saving or cost-effective. METHODS A decision model with a 6 month time horizon evaluated routine care versus routine care plus early referral to a palliative medicine specialist (EPC) for recurrent platinum-resistant ovarian cancer. Model parameters included rates of inpatient admissions, emergency department (ED) visits, chemotherapy administration, and quality of life (QOL). From published ovarian cancer data, we assumed baseline rates over the final 6 months: hospitalization 70%, chemotherapy 60%, and ED visit 30%. Published data from a randomized trial evaluating EPC in metastatic lung cancer were used to model odds ratios (ORs) for potential reductions in hospitalization (OR 0.69), chemotherapy (OR 0.77), and emergency department care (OR 0.74) and improvement in QOL (OR 1.07). The costs of hospitalization, ED visit, chemotherapy, and EPC were based on published data. Ranges were used for sensitivity analysis. Effectiveness was quantified in quality adjusted life years (QALYs); survival was assumed equivalent between strategies. RESULTS EPC was associated with a cost savings of

Cyclin E Overexpression in Epithelial Ovarian Cancer Characterizes an Etiologic Subgroup

1285 per patient over routine care. In sensitivity analysis incorporating QOL, EPC was either dominant or cost-effective, with an incremental cost-effectiveness ratio (ICER) <