Adjuvant therapy in women with early stage uterine serous carcinoma: A multi-institutional study.

OBJECTIVE: Uterine serous carcinoma is a rare but aggressive subtype of endometrial adenocarcinoma. Our objective was to compare adjuvant treatment strategies for patients with early stage uterine serous carcinoma. METHODS: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or any mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher's exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free and overall survival. RESULTS: There were 737 patients included. Most patients had Stage IA disease (75%), 49% of which had no myometrial invasion. Only 164 (24%) tumors had lymphatic/vascular space invasion. Adjuvant treatment varied: 22% received no adjuvant therapy, 17% had chemotherapy alone, 19% had cuff brachytherapy, 35% had cuff brachytherapy with chemotherapy, and 6% underwent pelvic radiation. Adjuvant treatment was significantly associated with a decreased risk of recurrence (p = 0.04). Compared with no adjuvant therapy, patients who received brachytherapy or brachytherapy/chemotherapy had improved recurrence-free survival (HR 0.59, 95% CI 0.40-0.86; HR 0.65, 95% CI 0.49-0.88, respectively) and overall survival (HR 0.53, 95% CI 0.35-0.79; HR 0.49, 95% CI 0.35-0.69, respectively). Improved survival with brachytherapy and brachytherapy/chemotherapy persisted on multivariable analyses. Chemotherapy alone was also associated with improved overall survival compared with no adjuvant treatment (HR 0.55, 95% CI 0.37-0.81). CONCLUSIONS: Adjuvant therapy was associated with a decreased risk of recurrence relative to observation alone. Adjuvant cuff brachytherapy with and without chemotherapy was associated with improved survival outcomes in patients with early stage uterine serous carcinoma.

Endometrial Cancer Characteristics and Risk of Recurrence.

OBJECTIVES: To describe clinicopathologic characteristics and survival outcomes of endometrial adenocarcinomas stratified by mismatch repair (MMR) status. METHODS: Single-institution, retrospective study of all women with endometrioid adenocarcinomas treated from January 2012 through December 2017. Patients were categorized into one of three groups based on MMR testing: intact MMR expression (MMR+), probable MMR mutation (MMR-), or MLH1 hypermethylation (hMLH1+). Demographics, pathologic characteristics, recurrence rates, and survival differences were analyzed. RESULTS: In total, 316 women were included in the analysis: 235 (74.4%) patients in the MMR+ group, 10 (3.1%) in the MMR- group, and 71 (22.5%) in the hMLH1+ group. Patients with hMLH1+ were significantly older, exhibited higher-grade histology and presence of lymphovascular space invasion, and were more likely to have received adjuvant treatment. The early stage hMLH1+ patients were more likely to recur (15.3% hMLH1+ vs 2.3% MMR+ vs 12.5% MMR-, P < .001). Hypermethylation remained a significant predictor of recurrence in multivariable analysis (odds ratio, 5.09; 95% confidence interval [CI], 1.54-16.86; P = .008). Recurrence-free survival was significantly reduced in early stage hMLH1+ (hazard ratio, 7.40; 95% CI, 2.80-21.62; P < .001). CONCLUSIONS: Women with hMLH1+ endometrial cancer have worse prognostic features and recur more frequently, even in patients traditionally considered low risk for recurrence.

Venous Thromboembolism Treatment and Prevention in Cancer Patients: Can We Use Pills Yet?

OPINION STATEMENT: Cancer increases a patient's risk for developing a venous thromboembolism (VTE) and is a relatively common finding in this population. Traditionally, anticoagulants used to treat VTE have included low molecular weight heparin (LMWH) or vitamin K antagonists (VKA). However, within the last several years, a newer class of anticoagulant, the direct oral anticoagulants (DOACs), has emerged as a potential option for pharmacologic thromboprophylaxis and for treatment of VTE in patients with cancer. While data is still limited and evolving, DOACs offer several benefits that are worth considering, including ease of administration and similar efficacy compared to LMWH in preventing recurrent VTE. However, some studies have reported a notable risk of increased bleeding associated with the use of DOACs. Additional studies are underway to evaluate the role of DOACs compared to LMWH in the setting of cancer. In our practice, based on existing data, we have been using DOACs for the chronic treatment of acute VTE and prevention of recurrent VTE in patients who do not have contraindications to anticoagulation and do not have severe renal insufficiency (creatinine clearance < 30 mL/min). For cancer patients admitted to the hospital with an acute medical illness, we use LMWH for primary prevention of VTE. In the perioperative setting, for patients undergoing major surgery with an active cancer, we prefer pharmacologic thromboprophylaxis with LMWH, although there is some emerging evidence that DOACs may be safe in this setting.

Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study.

PURPOSE: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. PATIENTS AND METHODS: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. RESULTS: Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). CONCLUSIONS: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523.

Factors prognostic of survival in advanced-stage uterine serous carcinoma.

OBJECTIVES: The study objective was to analyze the impact of prognostic factors, including treatment modality, on outcome in patients with advanced-stage uterine serous carcinoma (USC). METHODS: A retrospective review of patients diagnosed with stage III or IV USC between 1993 and 2012 was performed. Summary statistics were used to describe demographic and clinical characteristics. Overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier analysis. Cox proportional hazards regression was used to model the association of potential prognostic factors with OS and RFS. RESULTS: The study included 260 patients with median follow-up of 26.6months (range 1-172.8). Median age was 63years (range 30-88) and 52.3% had stage III disease. In all, 60% were treated with surgery followed by chemotherapy, 18.1% received surgery, chemotherapy, and radiotherapy, 11.5% had surgery and radiotherapy, and 10.4% had neoadjuvant chemotherapy. The overall complete response rate was 68.9%, and the cumulative incidence of recurrence was 82.7%. Treatment that included surgery, chemotherapy, and radiation and stage III disease were associated with improved RFS on multivariate analysis. For OS, therapy with surgery, chemotherapy, and radiation, mixed histology, and stage III disease were associated with better OS on multivariate analysis. CONCLUSIONS: Patients with advanced-stage USC have a poor prognosis, regardless of clinical factors or treatment received. However, combination therapy that includes chemotherapy and radiation appears to be associated with improved survival in these women.

Lean Body Weight and Metformin Are Insufficient to Prevent Endometrial Hyperplasia in Mice Harboring Inactivating Mutations in PTEN.

OBJECTIVES: Obesity is a major risk factor for endometrial cancer. We evaluated whether obesity exacerbates progression of endometrial hyperplasia (EH) using the PRCre/+ PTENflox/+ mouse model and examined if the type 2 diabetes drug, metformin, could prevent EH. METHODS: Twenty obese (PRCre/+ PTENflox/+) mice were maintained on a high-fat diet, while 20 lean mice ate a matching low-fat diet. Ten mice from each group received metformin (1,000 mg/day) in drinking water. Mice were euthanized at 26 weeks. Uterine tissue was scored for degree of EH. Immunohistochemical staining for Ki67 was used to evaluate cellular proliferation. Markers of PI3K/AKT/mTOR activity were evaluated by immunohistochemistry using activation-specific antibodies. Serum adiponectin was quantified by ELISA. RESULTS: Obesity had no effect on the extent of EH in (PRCre/+ PTENflox/+) mice. While metformin significantly altered circulating adiponectin levels in obese and lean animals, it had no effect on EH. There were no differences in endometrial proliferation as measured by Ki67 staining. Neither obesity nor metformin altered PI3K/AKT/mTOR activity in these animals. CONCLUSIONS: Weight and metformin did not affect the severity of EH resulting from PTEN inactivation. Alternative mouse models of early endometrial cancer are required for preclinical cancer prevention studies.

The search continues: looking for predictive biomarkers for response to mammalian target of rapamycin inhibition in endometrial cancer.

OBJECTIVE: PI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor. METHODS: Specimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed. RESULTS: Six of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%-100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%-100%). CONCLUSIONS: S6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.

Pelvic exenteration: impact of age on surgical and oncologic outcomes.

OBJECTIVE: To evaluate whether preoperative age impacts surgical outcomes, complication rates, and/or recurrence in women undergoing pelvic exenteration. METHODS: All women who underwent a pelvic exenteration for any gynecologic indication at our institution from 1993 to 2010 were included. Women were stratified into groups based on age in years (young: ≤ 50, middle: 51-64, and senior: ≥ 65). Baseline characteristics, surgical outcomes, early (<60 days) and late (≥ 60 days) postoperative complications, and recurrence/survival outcomes were ascertained. Fisher's exact test or Kruskal-Wallis test was performed. Kaplan-Meier survival curves were compared. RESULTS: 161 patients were included (58 young, 62 in the middle, and 41 senior). Women in the young group predominately had a diagnosis of cervical cancer (82.8%) while women in the senior group primarily had a diagnosis of vulvar or vaginal cancer (70.7%). Senior women were also more likely to have hypertension (p < 0.0001) and pulmonary disease (p = 0.040). Operative time was significantly shorter for women in the senior group (8.5h) compared with the middle (9.5h) and young group (10.1h) (p = 0.0089). There were no significant differences in early or late complications when stratified by age. The overall survival did not differ between age groups (p = 0.3760). CONCLUSION: Although hypertension and pulmonary disease were more frequent in the senior age group, duration of surgery, blood loss, length of hospital stay and complication rates did not increase with age. Advanced chronological age should not be considered a contraindication to a potentially curative surgical procedure.

Extensive cutaneous metastases of ovarian cancer after prolonged response to liposomal doxorubicin.

•Cutaneous metastases are rare and clinically challenging to manage. When present, they often represent end-stage disease.•Treatments for cutaneous metastases are limited, and primarily palliative in nature.

Another surprise from Metformin: novel mechanism of action via K-Ras influences endometrial cancer response to therapy.

Metformin is an oral biguanide commonly used for the treatment of type II diabetes and has recently been demonstrated to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Using both in vitro and in vivo models, we examined the effects of metformin on endometrial tumors with defined aberrations in the PI3K/PTEN/mTOR and MAPK signaling pathways to understand metformin mechanism of action and identify clinically useful predictors of response to this agent. In vitro assays of proliferation, cytotoxicity, and apoptosis were used to quantify the effects of metformin on endometrial cancer cell lines with mutations in the PI3K/PTEN/mTOR and MAPK signaling pathways. The in vivo effects of oral metformin on tumor progression were further examined using xenograft mouse models of endometrial cancer. K-Ras localization was analyzed by confocal microscopy using GFP-labeled oncogenic K-Ras and by immunoblot following subcellular fractionation. Metformin inhibited cell proliferation, induced apoptosis, and decreased tumor growth in preclinical endometrial cancer models, with the greatest response observed in cells harboring activating mutations in K-Ras. Furthermore, metformin displaces constitutively active K-Ras from the cell membrane, causing uncoupling of the MAPK signaling pathway. These studies provide a rationale for clinical trials using metformin in combination with PI3K-targeted agents for tumors harboring activating K-Ras mutations, and reveal a novel mechanism of action for metformin.

Personalized care in uterine cancer.

Endometrial cancer typically presents at an early stage when surgery alone, with or without radiotherapy, is often curative. However, in women who present with advanced disease or who develop disease recurrence, long-term prognosis is poor. While surgical cytoreduction remains the mainstay of initial therapy, over the last several decades, the roles of cytotoxic chemotherapy, radiotherapy, and hormonal therapy have been evaluated in both the adjuvant and recurrent setting in an attempt to improve long-term survival while also minimizing associated toxicities. Unfortunately, response rates remain poor and survival is limited in these settings. More recently, with the introduction of personalized cancer treatment, several biologic agents have been developed that target specific pathways critical to tumor initiation and growth. Molecular studies have found that many endometrial cancers are driven by some of these tumorigenic pathways, which has led to early clinical studies evaluating the role of these targeted agents in patients with advanced or recurrent endometrial cancer. This review describes existing treatment options for patients with early and advanced endometrioid endometrial cancer, as well as for patients with uterine serous cancers. Furthermore, this review examines the growing body of literature involving targeted biologic agents as treatment for patients with advanced or recurrent endometrial cancer.

The effect of body mass index on surgical outcomes and survival following pelvic exenteration.

OBJECTIVE: We sought to evaluate whether preoperative body mass index (BMI) impacts surgical outcomes, complication rates, and/or recurrence rates in women undergoing pelvic exenteration. METHODS: All women who underwent pelvic exenteration for gynecologic indications at our institution from 1993 through 2010 were included. Women were stratified into 3 groups based on BMI. Baseline characteristics, surgical outcomes, early (<60 days) and late (≥ 60 days) postoperative complications, and recurrence/survival outcomes were collected. Multivariate logistic regression analyses were performed. Kaplan-Meier survival curves were compared using log-rank test. RESULTS: 161 patients were included (59 normal weight, 44 overweight, 58 obese). Median follow-up times were 22, 29, and 25 months. Most patients underwent total pelvic exenteration (68%); 64.6% had a vaginal reconstruction. On multivariate analysis, both overweight and obese patients had a higher risk of early superficial wound separation compared to normal weight patients - OR 10.74 (3.33-34.62, p<0.001) and OR 4.35 (1.40-13.52, p=0.011), respectively. Length of surgery was significantly longer for overweight (9.6h, OR 1.26, 1.02-1.55, p=0.032) and obese (10.1h, OR 1.24, 1.04-1.47, p=0.014) patients than for normal weight patients (8.7h). Late postoperative complications for patients in the normal weight, overweight, and obese groups were 47.5%, 45.5%, and 43.1% (p=0.144). There were no differences in time to recurrence (p=0.752) or overall survival (p=0.103) between groups. CONCLUSION: Although operative times were longer and risk for superficial wound separation was significantly higher, pelvic exenteration appears to be feasible and safe in overweight and obese women with overall complication rates and survival outcomes comparable to normal weight women.

Understanding obesity and endometrial cancer risk: opportunities for prevention.

Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.

Role of minimally invasive surgery in staging of ovarian cancer.

OPINION STATEMENT: Since the introduction of laparoscopy and robotic surgery in gynecologic practice in the last several decades, use of these minimally invasive surgical techniques has increased dramatically. The role of minimally invasive surgical techniques continues to expand because they offer reduced intraoperative and postoperative complications, less intraoperative blood loss, and a shorter postoperative recovery. Despite initial concerns about the use of minimally invasive surgery in gynecologic oncology, this approach has been shown to be safe and effective in the management of uterine and cervical cancer, and minimally invasive surgical management of these malignancies is now commonplace. Concerns remain regarding the use of minimally invasive surgery for the staging and management of ovarian cancer, including concerns regarding the adequacy of abdominal exploration and staging with minimally invasive approaches compared to traditional laparotomy and the risks and implications of intra-operative tumor cyst rupture and port-site metastases. However, several case series, retrospective reviews, and case-control studies have demonstrated that minimally invasive surgery is both safe and effective for the staging of borderline ovarian tumors and early-stage epithelial ovarian cancer when performed by a trained gynecologic oncologist. Data to support the role of minimally invasive surgery for advanced epithelial ovarian cancer are scant and use of minimally invasive surgery in this setting is not recommended.

The effectiveness of endometrial ablation with the Hydro ThermAblator (HTA) for abnormal uterine bleeding.

OBJECTIVE: We sought to determine the overall effectiveness and risk factors for failure of hydrothermal ablation in the management of abnormal uterine bleeding. STUDY DESIGN: We performed a retrospective cohort analysis of patients who underwent hydrothermal ablation for abnormal uterine bleeding at our institution from July 2005 through February 2008. Variables analyzed included patient demographics, insurance status, body mass index, bleeding pattern, obstetric history, prior medical therapy and duration, uterine characteristics, and tobacco use history. RESULTS: In all, 159 patients were identified and 142 charts were eligible for evaluation. A total of 45 patients (31.6%) had return of preablation vaginal bleeding. Menometrorrhagia was a significant predictor for failure (P = .027) and subsequent hysterectomy (P = .0025). Younger age (P = .044), tobacco use (P = .042), and Medicaid/Medicare insurance status (P = .039) were also associated with a higher risk of failure. CONCLUSION: Women who are younger, use tobacco products, and have menometrorrhagia are more likely to fail hydrothermal ablation.