Robyn Sayer

An Integrated Genomic-Based Approach to Individualized Treatment of Patients With Advanced-Stage Ovarian Cancer

PURPOSE The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Retraction: Genomic signatures to guide the use of chemotherapeutics

The authors wish to retract this article because they have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan.

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

The authors wish to retract this article because they have been unable to reproduce certain crucial experiments showing validation of signatures for predicting response to chemotherapies, including docetaxel and topotecan.

Giant pelvic retroperitoneal leiomyoma arising from the rectal wall

BACKGROUND Pelvic retroperitoneal leiomyomas arising from the rectal wall are rare. We present a case of a giant retroperitoneal leiomyoma mimicking bilateral solid adnexal masses in a postmenopausal woman. CASE A 54-year-old postmenopausal woman presented with a large abdominopelvic mass. At surgery, the uterus was displaced anteriorly by a large retroperitoneal mass. The rectosigmoid colon was noted to course through the retroperitoneal mass. The patient underwent complete excision of the retroperitoneal mass along with a rectosigmoid resection of the involved colon with primary reanastomosis. Histopathology showed a leiomyoma arising from the muscularis propria of the rectum wall. CONCLUSION Retroperitoneal masses that extend into the pelvis may mimic adnexal masses and, therefore, represent a rare finding at gynecologic surgery.

The vascular portion of the cardinal ligament : surgical significance during radical hysterectomy for cervical cancer

OBJECTIVE The objective of the study was to analyze the histopathologic content of the vascular portion of the cardinal ligament in patients undergoing radical hysterectomy for cervical cancer. STUDY DESIGN The vascular portion of the cardinal ligament was completely removed during radical hysterectomy. The maximum cervical diameter and length of the vascular ligament were measured on the fresh specimen. After inking, the pathologist separated and embedded the entire vascular segment from each side. Microscopic examination followed. RESULTS Eighty-four patients were available for analysis. The mean cervical diameter was 3.9 cm (2-8), whereas the mean vascular segment length on the right and left sides were 4 cm (1-10) and 3.8 cm (1-7), respectively. Mean number of vascular segment lymph nodes were as follows: medial right = 0.7 (0-4), medial left = 0.6 (0-5), lateral right = 0.4 (0-3), and lateral left = 0.6 (0-6). Mean diameter of medial and lateral lymph nodes were 2 mm (0.25-8) and 3.3 mm (0.25-16), respectively. The length of the vascular segment correlated inversely with maximum cervical diameter. Thirty-one percent (26 of 84) had positive pelvic side wall lymph nodes. Fourteen patients had positive vascular segment lymph nodes (1 positive = 7, more than 1 positive = 7). Three of 7 patients had bilateral positive vascular segment lymph nodes; all 7 had microscopic disease in the paravaginal soft tissue, and all 7 had positive pelvic side wall lymph nodes (6 of 7 bilateral). Including the 14 patients, a total of 19 had nodal or nonnodal microscopic disease in the vascular segment. Of these, 7 had disease in the lateral half of the vascular ligament. Histologic sectioning revealed nerve twigs and/or scattered ganglia in the vascular segment but no large nerve trunks. CONCLUSION Among a population of women with high-risk, early-stage cervical cancer, the lateral vascular segment of the cardinal ligament contained metastatic disease in a substantial number of patients. This segment contains no major nerve trunks. When radical hysterectomy is chosen as primary treatment for such patients, the vascular segment of the cardinal ligament should be completely excised.

Corrigendum: Genomic signatures to guide the use of chemotherapeutics

Nat. Med. 12, 1294–1300 (2006); published online 22 October 2006; corrected after print 10 May and 10 October 2007 In the supplementary information initally published online to accompany this article, and in the revised supplementary information posted online on 10 May, the gene lists that make up the chemotherapy sensitivity signatures in Supplementary Table 1 contained errors.

Gene expression determinants of ovarian cancer platinum-response in older women

22059 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and more than half of new ovarian cancer cases arise in women over age 65. Although older women with EOC have poorer overall prognosis compared to younger women, the exact molecular basis to this difference remains unclear. The goal of this study is to improve our understanding of the molecular underpinnings of advanced stage EOC in older women and identify genes associated with chemo-response in older women such that therapy may be tailored to individual patients. Methods: We performed Affymetrix microarray gene expression analysis on 122 primary advanced stage epithelial ovarian cancers resected from 73 younger ( 65 years) women. For each age group, gene expression data was compared using Significance Analysis of Microarrays (SAM), between patients who demonstrated a complete-response (>65 years, n=38; 65 years, n=11; <65 years, n=25) to primary...

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Nat. Med. 12, 1294–1300 (2006); published online 22 October 2006; corrected after print 10 May and 10 October 2007 In the supplementary information initally published online to accompany this article, and in the revised supplementary information posted online on 10 May, the gene lists that make up the chemotherapy sensitivity signatures in Supplementary Table 1 contained errors.

Gene expression profiles that predict response to platinum and identify patterns of pathway deregulation in advanced ovarian cancer

5031 Background: Platinum drugs are the most active agents in epithelial ovarian cancer, however 30% of patients with advanced disease have an incomplete response. Current treatment strategies result in many patients receiving multiple cycles of platinum-based chemotherapy without complete response. We have developed gene expression profiles that predict response to platinum therapy, with the aim of individualizing therapy. In parallel, we identified patterns of oncogenic pathway deregulation within the non-responding patient group that provides a rational basis for directing targeted therapeutics. Methods: Affymetrix GeneChips were used to measure gene expression in 120 stage III/IV serous ovarian cancers from patients who underwent primary surgical cytoreduction followed by platinum therapy. Expression data was compared between cancers that demonstrated a complete and incomplete response to platinum therapy. Predictive models were developed to distinguish patients likely to respond to therapy. In additi...