S.R. Pierce

Nonoperative management of atypical endometrial hyperplasia and grade 1 endometrial cancer with the levonorgestrel intrauterine device in medically ill post-menopausal women

OBJECTIVE To assess the endometrial response rates to treatment with the levonorgestrel intrauterine device in post-menopausal women with atypical hyperplasia/endometrial intraepithelial neoplasia and grade 1 endometrioid (AH/EC) endometrial carcinoma who are not surgical candidates. METHODS Chart review was undertaken of patients with AH/EC who underwent levonorgestrel intrauterine device insertion by a gynecologic oncologist within two academic health systems between 2002 and 2013. When available, tissue blocks were evaluated with immunohistochemical staining for progesterone receptor expression. RESULTS A total of 41 patients received treatment for AH/EC with the levonorgestrel intrauterine device. Follow up sufficient to assess response occurred in 36 women (88%). Complete response was documented in 18 of 36 women (50%), no response in 8 patients (22%), partial response in 3 women (8%) and progression of disease in 7 patients (19%). Four of 18 patients with complete response (22%) later experienced relapse of hyperplasia or cancer. Four patients (10%) died during the study period: none had evidence of metastatic disease and 1 of the 4 woman died of perioperative complications following hysterectomy for stage I disease. Patients responding to treatment had significantly lower progesterone receptor expression on post-treatment biopsies. CONCLUSIONS Intrauterine levonorgestrel is a viable treatment option for post-menopausal women with AH/EC who are poor candidates for standard surgical management. The response rate in this series is similar to published reports in premenopausal patients and includes cases of disease recurrence following conversion to benign endometrium.

A multi-institutional study of outcomes in stage I–III uterine carcinosarcoma

OBJECTIVE To evaluate the use of adjuvant therapy after primary surgery for stage I-III uterine carcinosarcoma (CS). METHODS A multi-institutional retrospective study of women with stage I-III CS was conducted. Analyses were stratified by stage (I/II and III). Patients were categorized according to adjuvant therapy: observation (OBS), radiation (RT), chemotherapy (CT) or multimodal therapy (CT+RT). Overall survival (OS) and progression-free survival (PFS) were analyzed using log-rank tests and Cox proportional hazards models. RESULTS 303 patients were identified across four institutions: 195 with stage I/II and 108 with stage III disease. In stage I/II disease, 75 (39.9%) received OBS, 33 (17.6%) CT, 37 (19.7%) RT, and 43 (22.9%) CT+RT. OBS was associated with a fourfold increased risk of death compared to CT (adjusted hazard ratio (aHR)=4.48, p=0.003). Patients receiving CT+RT had significantly improved PFS compared to those receiving CT alone (aHR=0.43, p=0.04), but no difference in OS. In the stage III cohort, 16 (15.0%) received OBS, 34 (31.8%) CT, 20 (18.7%) RT, and 37 (34.6%) CT+RT. OBS was associated with worse OS and PFS compared to CT (OS: aHR=2.46, p=0.04; PFS: aHR=2.39, p=0.03, respectively). A potential improvement in PFS was seen for those treated with CT+RT compared to CT alone, however it was not statistically significant (aHR=0.53, p=0.09). CONCLUSIONS Observation after surgery was associated with poor outcomes in uterine CS compared to CT and RT alone. Multimodality therapy for women with stage I/II disease was associated with improved PFS compared to chemotherapy alone. Novel treatment options are needed to improve outcomes in this aggressive disease.

A comprehensive review of diagnostic and treatment options for granulosa cell tumors of the ovary.

&NA; Granulosa cell tumors are rare and comprise approximately 2% to 8% of all ovarian malignancies. Research dedicated to these tumors is rare given the low incidence. These tumors are more difficult to diagnose than epithelial ovarian tumors, and understanding how they present may aid in appropriate referral to a gynecologic oncologist. The aim of this review was to summarize the epidemiology, risk factors, and clinical presentation of granulosa cell tumors to aid in provider recognition. We will also explore current diagnostic and treatment modalities with examination of newer, novel treatments. At the end of this review, the reader should understand how to appropriately diagnose and treat these rare malignancies. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After completing this CME activity, physicians should be better able to summarize the epidemiology, risk factors, and clinical presentation of granulosa cell tumors of the ovary, identify current diagnostic modalities to aid in provider recognition, and apply treatment options including examination of newer, novel treatments, to care for patients.

Prior breast cancer and tamoxifen exposure does not influence outcomes in women with uterine papillary serous carcinoma

OBJECTIVES To evaluate progression-free survival (PFS) and overall survival (OS) outcomes in women diagnosed with uterine papillary serous carcinoma (UPSC) who have had (UPSCBR+) or have not had (UPSCBR-) an antecedent history of breast cancer and to correlate their outcomes to prior tamoxifen exposure. METHODS Data were collected for women diagnosed with UPSC at two academic institutions between January 1997 and July 2012. Patient demographics, tumor histology, stage, and treatments were recorded. Patients were divided into two groups: those with and without a personal history of breast cancer. Within the UPSCBR+ cohort, we identified those with a history of tamoxifen use. Cox regression modeling was used to explore associations between selected covariates of interest and the time-to-event outcomes of PFS and OS. RESULTS Of 323 patients with UPSC, 46 (14%) were UPSCBR+. Of these, 15 (33%) had a history of tamoxifen use. UPSCBR+ patients were older than UPSCBR- (median years, 72 vs. 68, p=0.004). UPSCBR+ women showed no significant difference in PFS or OS compared to UPSCBR- (p=0.64 and p=0.73 respectively), even after controlling for age (p=0.15 and p=0.48 respectively). Within the UPSCBR+ cohort, there was no difference in PFS or OS with or without tamoxifen exposure (p=0.98 and p=0.94 respectively). CONCLUSIONS There was no difference in PFS or OS between the UPSCBR+ and UPSCBR- cohorts. We did not demonstrate significant OS or PFS differences in women who took tamoxifen prior to their endometrial cancer diagnosis. These findings have implications for counseling, and should be encouraging to women who are facing their second cancer diagnosis.

Abstract 1852: Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas

Objectives: Endometrial cancers (ECs) frequently harbor mutations in PI3K pathway genes. Our objective was to determine the mutation frequency of the PIK3 pathway in the tumors of EC patients prospectively enrolled on an IRB-approved institutional tumor sequencing initiative (UNCseq) and correlate these with clinical factors. Methods: Snap-frozen and FFPE tissue samples were collected from patients enrolled on UNCseq (NCT01457196). DNA was isolated using the Puregene DNA purification system, and Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets, were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Statistical analysis of clinical correlates was performed in R (v 3.1.1). Results: Data was collected from 109 EC patients. Thirty-six tumors (33.0%), 34 of which were endometrioid, had >2 mutations between PIK3CA and PIK3R1. 20 patients had multiple PIK3CA mutations (18.3%) and 11 had multiple PIK3R1 mutations (10.1%). In all but 5 cases, multiple mutations of PIK3R1 or PIK3CA were coincident with PTEN mutation (p = 0.018). There were strong correlations between PI3K pathway mutations and tumor grade and stage. High stage tumors (stage >2) were less likely (5/36) than stage 1 tumors (31/73) to have multiple PI3K mutations (p = 0.0056). Though not reaching significance, grade 3 tumors (8/37) were less likely than low-grade tumors (28/72) to demonstrate multiple PI3K mutations (p = 0.11). Of the 10 serous ECs, none exhibited multiple PI3K mutations. Conclusions: There is a strong relationship between mutated PIK3 pathway genes and clinically relevant tumor biology in ECs. Multiple mutations in the PIK3 pathway are common, suggesting that PI3K pathway inhibition in EC may need to be directed against PIK3CA and PIK3R1 simultaneously. These multiply mutated tumors are strongly linked to lower stage and grade tumors with concurrent PTEN mutations. We posit that initially PTEN mutant clones may give rise to subclonal populations with various PI3K mutations which may be relatively indolent until additional driver mutations are acquired such that one subpopulation predominates, resulting in higher grade and stage ECs. Citation Format: Dario R. Roque, Will R. Jeck, David N. Hayes, Arthur M. Dizon, Leslie Clark, Stuart Pierce, Weiya Z. Wysham, Tara Castellano, Paola A. Gehrig, Victoria Bae-Jump. Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1852.