David L. Tait

A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or persistent endometrial carcinoma: A gynecologic oncology group study

OBJECTIVE The study aims to evaluate the anti-tumor activity and toxicity of gemcitabine in patients with persistent or recurrent endometrial carcinoma. METHODS Patients with advanced or recurrent carcinoma of the endometrium previously treated with one chemotherapy regimen were treated on a phase II trial conducted by the Gynecologic Oncology Group (GOG). Gemcitabine was administered as an intravenous infusion at a dose of 800 mg/m² over 30 min on days 1 and 8 every 21 days. RESULTS Twenty-four patients were entered by 11 GOG member institutions. One patient was ineligible due to wrong primary tumor. A total of ninety 21-day cycles of therapy were administered with 35% of patients receiving four or more cycles. All patients had been previously treated with a platinum-based regimen. One patient had a partial response (4%), nine had stable disease (39%), and twelve had increasing disease (52%). The median progression-free survival was 1.7 months. Treatment was generally well tolerated with only 22% of patients experiencing grade 3 or grade 4 hematologic toxicity. There was one treated-related death due to pulmonary toxicity. CONCLUSION Gemcitabine has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested.

Correlation Analysis of HOX, ErbB and IGFBP Family Gene Expression in Ovarian Cancer

Utilizing microarray gene expression data in cancer research possesses the ability to identify deregulated cellular pathways involved in malignant development. This study investigated the relationships of three gene families, HOX, ErbB and IGFBP, with regard to the development of ovarian cancer. These families were of interest because of similar chromosomal locations and their deregulated expression in ovarian cancer. Higher level statistics were used to differentially analyze microarray data in 65 ovarian samples to assess correlation and relationships among the gene families of interest. Fifteen genes in the three families were found to be significantly deregulated. Thirty-eight significant correlations were found within and between the genes of interest. Our data indicates that the significantly modeled relationships between HOX, ErbB and IGFBP gene pairs could provide insight into the underlying biological mechanisms in ovarian cancer.

Oncofertility: an emerging discipline in obstetrics and gynecology.

&NA; Oncofertility is an exciting new interdisciplinary field that encompasses the obstetrician gynecologist, gynecologic oncologist, reproductive endocrinologist, and primary care physician in a common goal to provide fertility preservation options for cancer patients. Maintaining their fertility is of the upmost importance for many oncology patients diagnosed during their childbearing years. This review addresses the common types of cancers in reproductive-age patients and how the treatment of these cancers may impact reproductive potential. Fertility preservation treatments will also be discussed to assist health care providers in appropriately counseling patients about options after a diagnosis of cancer. The goal of oncofertility is to provide both physicians and patients with the knowledge and resources to make fertility an ongoing opportunity for all patients who desire a future with children. Target Audience Obstetricians and gynecologists, medical/surgical oncologists, family physicians Learning Objectives After completing this CME activity, physicians should be better able to manage patients with gynecological cancers, evaluate the impact of cancer treatment on fertility, and counsel patients regarding potential fertility-sparing treatment options.

Downregulation of HOXC6 in Serous Ovarian Cancer

Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiation. Although dysregulation of several HOX genes in ovarian cancer has been reported, little is known about HOXC6 expression in epithelial ovarian cancer. In this report, analysis of laser capture microdissected samples determined HOXC6 expression patterns in normal versus malignant serous ovarian carcinoma tissues. HOXC6 protein was quantified by ELISA in parallel serum samples and further validated in a larger cohort of serum samples collected from women with and without serous ovarian carcinoma. These data demonstrate significant downregulation of HOXC6 in serous ovarian cancer.

Endodermal sinus tumor of the ovary in an 86 year old woman

► Oldest reported patient with endodermal sinus tumor of the ovary. ► Chemotherapy for endodermal sinus tumor. ► BEP chemotherapy in an elderly patient.

Abstract 4188: Association of HOX gene expression with osteopontin in ovarian cancer: Implications for biomarker development

Ovarian cancer is characterized by poor early detection and serves as an excellent model system to develop potential markers for early diagnosis. Osteopontin is a glycophosphoprotein known to demonstrate multiple functions including mediation of cellular adhesion, suppression of macrophage interleukin production, prevention of angiogenesis, apoptosis, and inhibition of anchorage-dependent growth. Studies of Osteopontin in ovarian cancer have described increased expression and a role as a candidate biomarker. Secretion of Osteopontin into the extra cellular matrix is reported to facilitate metastasis and has been reported to be inhibited by the presence of cytoplasmic Homeobox proteins (HOX). The HOX family of genes encodes transcription factors involved in basic developmental processes and has been linked to oncogenesis. Dysregulation of HOX genes may be an early event in malignant transformation making the HOX gene family appealing for biomarker investigation. In this study we characterize HOX gene expression in malignant tumors of the ovary compared to Osteopontin, a known biomarker for ovarian cancer. Methods: Microarray analysis of mRNA from human ovarian tissues was performed on samples of normal, benign, and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human Genome Focus GeneChip (HG-Focus) microarray to distinguish the differential pattern of mRNA expression between the three types of samples. Immunohistochemistry staining of ovarian tissue samples was utilized to analyze confirmatory protein expression of the microarray findings. Results: Microarray analysis demonstrated up-regulation of HOXB2, HOXB7, and Osteopontin genes in malignant ovarian tumor samples compared to normal ovarian tissue controls. Conversely, HOXC6 was down-regulated in malignant tissue samples. Immunohistochemistry was performed for HOXB2, HOXC6 and Osteopontin on OCT embedded tissues samples. Similarly, increased protein expression was shown for HOXB2 and Osteopontin in malignant samples and increased HOXC6 in non-cancerous samples. Conclusion: Our results demonstrate multiple HOX genes to be up-regulated in ovarian cancer. Increased expression of HOXB2 and HOXB7, correlated with increased Osteopontin expression found in malignant ovarian tissue samples. HOXC6 demonstrated an inverse relationship with Osteopontin in non-cancerous ovarian tissue samples. The association of these HOX genes with Osteopontin expression warrants further investigation into the role of HOX genes as candidate biomarkers for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4188. doi:10.1158/1538-7445.AM2011-4188

Abstract 875: PAX8 protein detection in serum of patients with serous ovarian cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: The paired-box (PAX) genes encode a family of transcription factors (TFs) with critical roles in the formation of tissues and organs during embryogenesis. These TFs regulate expression of gene products that control cell proliferation and differentiation. Since these processes are also essential to the development of cancer, it shows that PAX genes may participate in the initiation and proliferation of cancer. PAX8 gene expression has been demonstrated in ovarian and other malignancies of Mullerian origin and identified as a marker specific to gynecologic malignancy. Determination of tissue PAX8 protein expression by IHC is used as a clinical diagnostic tool for gynecologic cancer. However, little is known about PAX8 protein expression in serum. Identification of PAX8 in the serum of patients with ovarian cancer would be important in developing an ovarian cancer-specific biomarker. We have previously reported up-regulation of PAX8 gene in ovarian cancer using Human Focus microarrays to characterize differences in gene expression between normal and malignant tissue types. In this study, microarray (MA) and qRT-PCR were performed on human ovarian tissue from patients with normal ovaries and serous ovarian carcinoma to determine PAX8 gene expression. To determine PAX8 protein expression in serum, ELISA was used to analyze serum samples collected from patients with and without serous ovarian cancer. Methods: MA analysis of mRNA from LCM captured cells from human ovarian tissues was performed on normal and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human EXON 1.0 ST microarray to distinguish the differential pattern of mRNA expression between malignant and normal samples. qRT-PCR was utilized to confirm up-regulation of PAX8 genes as determined by MA analysis. PAX8 protein on 17 normal and malignant serum samples were evaluated by indirect sandwich ELISA. RESULTS: MA analysis demonstrated up-regulation of PAX8 in serous ovarian cancer tissue in comparison with normal tissues (p=3.99E-6). This finding then was confirmed using qRT-PCR. Detection of PAX8 protein in serum was determined by ELISA and notably different between normal and malignant serum samples (p<0.03). CONCLUSIONS: This study comparing PAX8 expression in normal and serous ovarian cancer samples shows up-regulation of PAX8 in serous carcinoma of the ovary, in tissue and serum. In particular ELISA suggests that the expression patterns of PAX8 in ovarian tissues is translated to the protein component of these tissues. This resulting protein can be detectable in serum, with higher levels in malignant samples as compared to serum samples of normal human subjects. These findings warrant further study of PAX8 in additional ovarian cancers subtypes and corresponding serum, to better characterize the role of PAX8 up-regulation in ovarian cancer and validation of ELISA as diagnostic biomarker for detection of ovarian cancer. Citation Format: Zahra Bahrani-Mostafavi, Pourya Naderi Yeganeh, Megan E. Parrott, Christine Richardson, David L. Tait, M. Taghi Mostafavi. PAX8 protein detection in serum of patients with serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 875. doi:10.1158/1538-7445.AM2014-875

Abstract 3007: Down-regulation of HOXC6 in serous ovarian cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Objective: The Homeobox (HOX) family of genes consists of 39 genes encoding transcription factors important to morphogenesis and cell differentiation. Usually inactive in normal differentiated tissues, dysregulation of HOX genes has been reported in several malignancies. HOX genes have been linked to genes important in malignant transformation including vascular endothelial growth factor, Ras, interleukin-8, and fibroblast growth factor. We have previously reported up-regulation of HOXA2, HOXA7 and HOXB7 in ovarian cancer. Little is known about HOXC6 gene expression in ovarian cancer. In this study we evaluated HOXC6 expression in normal and malignant human ovarian tissue to characterize expression of HOXC6 in serous ovarian cancer. Methods: Microarray analysis of mRNA from LCM captured cells from human ovarian tissues was performed on 11 samples of normal, and malignant ovarian tissues. These samples were analyzed using the Affymetrix Human EXON 1.0 ST microarray to distinguish the differential pattern of mRNA expression between malignant and normal samples. Real-time reverse transcription PCR was utilized to confirm down-regulation of HOXC6 genes as determined by microarray analysis. HOXC6 protein in tissue was evaluated by immunohistochemistry. Results: Microarray analysis demonstrated significant down-regulation of the HOXC6 gene in malignant serous ovarian tumor samples compared to normal ovarian epithelial cells of control samples. RT-PCR and immunohistochemistry confirmed HOXC6 down-regulation in malignant samples. A 115-fold difference in malignant and normal primary tissue samples and cell lines was seen in the RT-PCR analysis. By immunohistochemistry nuclear staining of HOXC6 protein was seen in the nuclei of normal ovarian surface epithelial tissues but significantly reduced or absent in malignant ovarian samples. Conclusion: HOXC6 is significantly differentially expressed comparing normal ovarian tissue and serous malignant ovarian tissue based on both tissue mRNA and protein analysis. This finding of HOXC6 down-regulation in ovarian cancer is unique and opposite of the up-regulation of other HOX genes previously reported. Down-regulation of HOXC6 in serous ovarian cancer may be an important finding relative to oncogenic pathways and biomarker development. This suggests dysregulation of HOXC6 genes may be an early event in malignant transformation and additional studies to validate the role of the HOXC6 gene in ovarian cancer are warranted. Citation Format: David L. Tait, Zahra Bahrani-Mostafavi, Carol Vestal, Christine Richardson, M. Taghi Mostafavi. Down-regulation of HOXC6 in serous ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3007. doi:10.1158/1538-7445.AM2013-3007