Development of a preclinical serous ovarian cancer mouse model

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ABSTRACTS / Gynecologic Oncology 120 (2011) S2–S133

The aim of this study was to compare the outcomes of RH with those of CCRT in these patients. From two tertiary centers, 191 patients with stage IB2 and IIA2 who underwent RH (n = 134) or CCRT (n = 57) were included in this retrospective analsysis. The primary endpoint was recurrencefree survival and the secondary endpoint was treatment-related complications. Results: There were no between-group differences in age, body mass index, performance status, FIGO stage and histologic type. However, mean tumor size on imaging study was significantly larger in the RH group (3.8 cm vs 5.4 cm, P < 0.001). The five-year, recurrence-free survival rates were 78 and 76% for the RH and CCRT groups, respectively (P = 0.928). About 32% of patients in the RH group did not require adjuvant radiotherapy and none of them had a recurrence. Treatment-related complications were significantly lower in these patients than in the CCRT group. Conclusions: Radical hysterectomy and concurrent chemoradiation therapy had similar efficacy in the treatment of patients with stage IB2 and IIA2 cervical cancer. However, significant proportions of the patients in these groups were successfully salvaged by surgery alone without significant treatment-related complications.

Conclusions: We have developed an inheritable GEM model of serous ovarian cancer (K18-gT121+/–; p53fl/fl; Brca1fl/fl mouse model). Most importantly, this model can be strategically altered to integrate other potential genomic attributes of this disease. Such a model system, which allows for the longitudinal study of serous ovarian cancer evolution, is paramount for understanding the sequence of malignant events required for this disease and is a critical tool needed in the search for better diagnostic and therapeutic interventions.

doi:10.1016/j.ygyno.2010.12.050

44 Development of a preclinical serous ovarian cancer mouse model V. Bae-Jump1, C. Yin1, X. Zong1, T. Van Dyke2 1 University of North Carolina, Chapel Hill, NC, 2National Cancer Institute, Frederick, MD Objective: Minimal improvements in overall survival for ovarian cancer have been made in the past several decades, and this can be partially attributed to the paucity of appropriate animal models of ovarian cancer, especially those recapitulating tumors of serous histology. Thus, our goal was to develop an inheritable genetically engineered mouse (GEM) model of serous ovarian cancer. Given the high frequency with which pRb function is impaired in most epithelial ovarian cancers, we generated TgK18-gT121 conditional transgenic (Tg) mice, in which inactivation of all three Rb proteins by T121 (a fragment of the SV40 large T antigen) is driven by the keratin 18 (K18) promoter. A floxed stop codon upstream of the T[121 transgene allows it to be silenced until being activated by Cre recombinase. We then crossed that mouse with conditional knockout mice floxed for the p53 and Brca1 tumor suppressor genes. This led to the creation of an ovarian cancer mouse model that specifically and somatically deletes the tumor suppressor genes of interest in adult ovarian surface epithelial cells (K18-gT121+/–; p53fl/fl;Brca1fl/fl mouse model). The inactivation of the tumor suppressor genes, as well as induction of the T121 transgene, is achieved via injection of an adenoviral vector expressing Cre (AdCre) into the ovarian bursa cavity of adult female mice. Results: Within three months of Cre-induced induction, ovarian carcinoma in situ was present within the injected ovary (4/4 mice). At six months postinduction, tumors developed in the injected ovary, while the contralateral un-injected ovary remained normal. At nine– 14 months, mice developed ovarian tumors, most accompanied by ascites and/or carcinomatosis (5/5 mice). Examination of tumor histology revealed papillary growth surrounding fibrovascular cores, solid features, massive necrosis, and a high mitotic rate. These tumors expressed markers of serous tumors, including keratin 18, survivin, and WT-1.

doi:10.1016/j.ygyno.2010.12.051

45 Impact of episodic transparent quality assessment on the staging of endometrial cancer K. Podratz, S. Dowdy, J. Bakkum-Gamez, A. Weaver, M. McGree, W. Cliby, B. Gostout, T. Wilson, G. Keeney, A. Mariani Mayo Clinic, Rochester, MN Objective: The purpose of this study was to determine whether transparent episodic assessment of surgical quality by gynecologic oncologists within a single institution translates into improved staging of endometrial cancer (EC) and to identify patient-specific and process of care risk factors that influence surgical quality. On January 1, 2004, a prospective treatment algorithm for EC including periodic analyses of the quality of pelvic and paraaortic lymphadenectomy (LND) was implemented. With the number of nodes harvested as a surrogate, staging quality during 2004–2008 (QA) was compared with that in the previous five-year interval (preQA). Since 2004, low-risk cases (e.g., grade 1/2, endometrioid, myometrial invasion (MI) < 50%, and primary tumor diameter <2 cm) based on frozen section have not undergone LND and were excluded from both cohorts. Patient and perioperative risk factors influencing the quality of LND during both intervals were identified and compared. Results: The inclusion of pelvic and paraaortic LND during the preQA era (n = 420) was 77.9 and 48.8%, respectively, compared with 89.3 and 83.6% after initiation of QA (n = 561) (P < 0.001). The median number of pelvic and paraaortic nodes harvested in cases having LND was 29 and 10, respectively, during the preQA era compared with 34 and 16 after QA. Defining stringent LND adequacy as the mean node count minus 1 SD during QA, adequate pelvic (>22 nodes) and paraaortic (>10 nodes) LND occurred in 57.4 and 25.7% preQA compared with 77.9 and 70.8% during QA, respectively (P < 0.001). Multivariable logistic regression analysis demonstrated the following