E. Chapman-Davis

Role of Progesterone in Endometrial Cancer

Progesterone is a key hormone in the endometrium that opposes estrogen-driven growth. Insufficient progesterone will result in unopposed estrogen action that could lead to the development of endometrial hyperplasia and adenocarcinoma. Although these endometrial neoplasias can regress in response to progestin treatment, this does not occur in all instances. To understand this resistance to progesterone and to improve on existing hormonal therapies, it is imperative that the molecular mechanisms of progesterone action through its receptor be deciphered in endometrial cancer. This review highlights what is known thus far regarding the efficacy of progestin therapy in the clinic and the role of progesterone in endometrial cancer cell behavior and gene regulation.

Gynecologic cancer disparities: A report from the Health Disparities Taskforce of the Society of Gynecologic Oncology

OBJECTIVES To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities. METHODS We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non-Black women. RESULTS White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities. CONCLUSION Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities.

Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: Factors associated with resistance to single-agent methotrexate chemotherapy

OBJECTIVE To determine factors associated with resistance to methotrexate treatment of low-risk gestational trophoblastic neoplasia (GTN). METHODS We reviewed the records of 358 patients with low-risk GTN (FIGO stage I and stages II-III, score<7) treated initially with methotrexate 0.4 mg/kg (max 25mg) IV push daily × 5 days every 14 days between 1979 and 2009. Actinomycin D 0.5mg IV push daily × 5 days every 14 days was used in 64 patients who developed resistance or toxicity to initial methotrexate chemotherapy, and combination drug regimens were used in 20 patients who failed single-agent chemotherapy. Adjuvant surgery was used in 34 selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS The complete response rate to initial methotrexate chemotherapy was 81% (290/358) and the complete response rate to actinomycin D as secondary therapy was 75% (48/64), for an overall complete response rate to sequential single-agent chemotherapy of 94% (338/358). The remaining 20 patients (6%) were all placed into permanent remission with the use of multiagent chemotherapy with or without surgery. Resistance to initial methotrexate chemotherapy was associated with increasing FIGO score (p<.0001), clinicopathologic diagnosis of choriocarcinoma (p=.028), higher pretreatment hCG (p=0.001) and presence of metastatic, disease (p=.018). CONCLUSIONS Sequential single-agent chemotherapy with methotrexate (0.4 mg/kg-max 25mg) followed by actinomycin D (0.5mg) each given IV push for 5 consecutive days every other week for treatment of low-risk GTN resulted in only 6% of patients requiring multiagent chemotherapy and a 100% survival rate.

Synuclein-γ (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma

OBJECTIVES SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.

Prognostic significance of lymphadenectomy and prevalence of lymph node metastasis in clinically-apparent stage I endometrioid and mucinous ovarian carcinoma.

OBJECTIVE The aim of the present study was to investigate the prevalence of lymph node (LN) metastasis in women with apparent stage I ovarian carcinoma of endometrioid or mucinous histology and to examine the prognostic significance of LN sampling/dissection (LND) on patient survival. METHODS The National Cancer Institutes Surveillance, Epidemiology, and End Results database was accessed and a cohort of surgically-staged women, diagnosed between 1988 and 2013, with apparent stage I ovarian carcinoma of mucinous or endometrioid histology was selected. Information derived from the histopathology report was employed to determine whether LND was performed and the status of harvested LNs. Five-year cancer-specific survival (CSS) rate was calculated following generation of Kaplan-Meier curves. Comparisons were made using the log-rank test. Cox proportional hazard models were constructed to evaluate the effect of LND on survival. RESULTS A total of 3354 and 2855 women with endometrioid and mucinous tumors who met the inclusion criteria were identified. LND was performed in 2307 (68.8%) and 1602 (56.1%) of them (p<0.001), respectively. The rate of histopathologically confirmed LN metastasis was 2.1% and 1.7%, respectively. By multivariate analysis LND was associated with superior cancer-specific mortality only for women with endometrioid carcinoma. CONCLUSIONS Lymph node involvement in women with mucinous and endometrioid ovarian carcinoma grossly confined to the ovary is infrequent. LND is associated with a survival advantage for those with endometrioid carcinoma.

Should epithelial ovarian carcinoma metastatic to the inguinal lymph nodes be assigned stage IVB

OBJECTIVE According to the revised FIGO staging system women with ovarian carcinoma and inguinal lymph node (LN) metastases, formerly stage III, are now considered stage IVB. In this study we compare their survival to that of women with stage III and stage IV disease. METHODS Women diagnosed with epithelial ovarian carcinoma were drawn from the Surveillance, Epidemiology, and End Results database (2004-2013). Four groups were formed: group 1 (stage IV due to positive inguinal nodes), group 2 (stage III with positive para-aortic/pelvic nodes), group 3 (stage IV with positive distant nodes) and group 4 (stage IV with distant metastases). Overall (OS) and cancer-specific survival (CSS) rates were evaluated with the Kaplan-Meier method. The log-rank test and Cox-hazard models were employed for univariate and multivariate survival analysis. RESULTS A total of 11,152 women were identified. Five-year OS for women in group 1 (n=151) was 46.3% compared to 44.9% for those in group 2 (n=4,403) (p=0.4), 32.9% in group 3 (n=642) (p<0.001) and 25.3% in group 4 (n=5,956) (p<0.001). After controlling for age, race and histology, group 1 had improved overall and cancer-specific mortality compared to groups 3 and 4 but not group 2. CONCLUSIONS Ovarian cancer patients with stage IV ovarian cancer due solely to inguinal nodal metastases have similar survival as those with pelvic/para-aortic nodal involvement and improved survival compared to those harboring distant metastases. Our findings do not support the reclassification of these patients as stage IVB.

Fertility-preserving surgery for advanced stage ovarian germ cell tumors

OBJECTIVE To evaluate the prevalence and safety of uterine preservation among premenopausal women diagnosed with a malignant ovarian germ-cell tumor (MOGCT) of advanced stage (stage II-IV). MATERIALS AND METHODS The National Cancer Database was accessed and a cohort of women aged <40years, diagnosed with a MOGCT were identified. Those with stage II-IV disease who underwent cancer-directed surgery and received chemotherapy were selected for further analysis. Performance of hysterectomy was assessed from site-specific surgery codes. Overall survival (OS) was determined following generation of Kaplan-Meier curves and compared with the log-rank test. A Cox multivariate model was constructed to control for possible confounders. RESULTS A total of 526 eligible patients were identified; rate of hysterectomy was 20.2%. Women who had a hysterectomy were older (median age 30.5 vs 20years, p<0.001) and more likely to present with bilateral tumors (12.6% vs 3.8%, p<0.001). No differences were noted based on tumor histology (p=0.67). Rate of uterine preservation was 82.8%, 79.5% and 75% for those with stage II, III and IV disease respectively (p=0.46). There was no difference in OS between women who had hysterectomy and those who did not (p=0.051); five-year OS rates were 87.1% and 94.4% respectively. After controlling for disease stage, tumor histology and patient race, uterine preservation was not associated with a decreased survival (HR: 0.59, 95% CI: 0.28, 1.24, p=0.19). CONCLUSIONS Uterine preservation was not associated with decreased survival and should be considered in women with advanced stage GCTs interested in future fertility.

Safety of ovarian preservation in premenopausal women with stage I uterine sarcoma

Objective To evaluate the oncologic safety of ovarian preservation (OP) in premenopausal women diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) stage I uterine sarcoma. Methods The National Cancer Institutes Surveillance, Epidemiology, and End Results database was accessed and a cohort of women aged ≤50 diagnosed between 1988–2013 with a sarcoma limited to the uterus was drawn. Based on site-specific surgery codes, women who underwent hysterectomy with or without oophorectomy and did not receive radiation therapy were selected for further analysis. Overall (OS) and cancer-specific (CSS) survival were determined following generation of Kaplan-Meier curves; comparisons were made with the log-rank test. A Cox-proportional hazard model was constructed to control for possible confounders. Results A total of 1,482 women were included in the analysis; 800 (54.0%) were diagnosed with leiomyosarcoma (LMS), 520 (35.1%) with low-grade endometrial stromal sarcoma (LG-ESS), and 162 (10.9%) with adenosarcoma (AS). The OP group included 418 women (28.2%). Differences in the rate of OP were noted based on histology (p=0.014), year of diagnosis (p=0.001), patient age (p<0.001) and race (p=0.012). There was no difference in OS (p=0.220) or CSS (p=0.210) between women who had OP and those who did not. Multivariate analysis confirmed that OP was not associated with a worse mortality. Conclusion In this population-based cohort of women with sarcoma limited to the uterus, OP was not associated with worse oncologic outcomes. OP could be considered for women with LMS, sparing them from the morbidity associated with iatrogenic menopause. No conclusions could be made for those with LG-ESS or AS.

Could fertility-sparing surgery be considered for women with early stage ovarian clear cell carcinoma?

Objective The aim of the present retrospective population-based study was to investigate the oncologic impact of uterine and ovarian preservation (OP) in premenopausal women with stage IA or IC ovarian clear cell carcinoma (OCCC). Methods The National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) database was accessed and a cohort of surgically-staged premenopausal women (age <50 years) diagnosed with unilateral stage IA or IC OCCC was drawn. Based on site-specific surgery codes, women who did not undergo hysterectomy and/or bilateral salpingo-oophorectomy (BSO) were identified. Overall survival (OS) and cancer-specific survival (CSS) rates were calculated following generation of Kaplan-Meier curves; comparisons were made with the log-rank test. Multivariate Cox analysis was performed to control for possible confounders. Results A total of 741 premenopausal women who met the inclusion criteria were identified. Based on available information, rate of uterine preservation was 14.5% (96/663) while the rate of OP was 28.1% (71/253). Five-year CSS rates were 90.8% for women who did not undergo hysterectomy compared with 87.7% for those who did (p=0.290). Similarly, 5-year CSS rates in the OP and BSO groups were 92.6% and 85%, respectively (p=0.060). After controlling for disease sub-stage (IA vs. IC), uterine or OP was not associated with a worse overall or cancer-specific mortality. Conclusion In the present cohort, uterine and OP did not have a negative impact on oncologic outcomes. Selection criteria for fertility-sparing surgery (FSS) could be expanded to include women with stage IA OCCC.

Safety of Fertility-Sparing Surgery for Premenopausal Women With Sex Cord-Stromal Tumors Confined to the Ovary

Objective The aim of this retrospective population-based study was to investigate the oncologic safety of fertility-sparing surgery (FSS) for premenopausal women with malignant sex cord-stromal tumors (SCSTs) confined to the ovary. Methods A cohort of women aged 18 to 49 years and diagnosed with a stage I malignant SCST between 1984 and 2013 was drawn from the National Cancer Institutes Surveillance, Epidemiology, and End Results database. Based on site-specific surgery codes, women who had FSS, defined as unilateral oophorectomy/tumor resection without hysterectomy, and definite surgery were identified. Cancer-specific survival and overall survival were evaluated after generation of Kaplan-Meier curves, whereas comparisons between the 2 groups were made with the log-rank test. Results A total of 255 women who met the inclusion criteria were identified; 161 (63.1%) underwent FSS whereas 94 (36.9%) had definitive surgery (bilateral salpingo-oophorectomy and hysterectomy). Median follow-up was 104 months. Cancer-specific survival (P = 0.015) but not overall survival (P = 0.76) was superior for women who had definite surgery. Conclusions In this retrospective population-based cohort of premenopausal women with SCSTs confined to the ovary, FSS was associated only with a worse long-term cancer-specific survival compared with definitive surgery. Women undergoing FSS for early stage SCSTs should be extensively counseled and closely monitored.