Objective

Cisplatin is a DNA-damaging antitumor agent that is highly effective in treating ovarian cancer. It activates the p53/p21 pathway for its cytotoxic mode of action, but it does not induce p21-dependent cell cycle arrest in G1. Therefore, we investigated this paradox, and used the model analog DAP as a positive control for p21-dependent G1-arrest.

Methods

Studies were conducted in p53-proficient ovarian A2780 tumor cells to examine Cdk activity, cell cycle distribution and DNA damage signaling after cisplatin or DAP in combination with the mitotic inhibitor nocodazole.

Results

Cisplatin consistently induced transient S-phase arrest by inhibiting Cdk2/cyclin A complex in S-phase at 12 h and then a durable G2/M-arrest by inhibiting Cdc2/cyclin B complex at 12–18 h. These inhibitions were associated with Chk1 and Chk2 activation and resultant increase in inhibitory tyrosine phosphorylation of Cdk2 and Cdc2. Cisplatin also potently inhibited G1-phase Cdk4/cyclin D1 and Cdk2/cyclin E activities at ~18 h. In agreement, exposure of cisplatin-treated A2780, HCT-116p53−/− and HCT-116p21−/− tumor cells to nocodazole revealed limited G1-arrest that was dependent on p53 and p21. In contrast, the durable G1-arrest by DAP, which failed to activate Chk1 and Chk2, was unaffected by nocodazole.

Conclusions

Cisplatin induced G1-arrest, but at an attenuated level. This was primarily due to orchestration of Cdk inhibition in S-phase first, then in G2, and finally in G1 that effectively blocked cells in G2 and prevented cells from progressing and arresting in G1. These studies demonstrate that cisplatin unequivocally activates G1-checkpoint response, but the fidelity of G1-arrest is compromised by Chk1/2 activation and checkpoint response in S- and G2/M-phase.

Objective

Tumor markers with increased sensitivity and specificity for endometrial cancer are needed to help monitor response to therapy and to detect recurrent disease. Currently, the tumor maker CA125 is utilized in this role with limited value. The objectives of this study were to examine the levels of several novel tumor markers HE4, SMRP, CA72.4 and CA125 as potential markers in patients diagnosed with endometrioid adenocarcinoma of the uterus.

Methods

Preoperative serum samples from surgically staged patients with endometrioid adenocarcinoma of the uterus were analyzed for levels of HE4, SMRP, CA72-4 and CA125. Control samples were obtained from healthy postmenopausal women. Logistic regression models and receiver operating characteristic (ROC) curves were constructed for each tumor marker and for all combinations, with cross-validation analyses to obtain average sensitivities at set specificities of 90%, 95%, and 98%.

Results

Serum samples from 156 healthy subjects and 171 patients with endometrial cancer (122 stage I, 17 stage II, 26 stage III, and 6 stage IV) were analyzed. At a 95% specificity, the sensitivities for differentiating between healthy subjects and all stages of cancer were 45.5% for HE4 and 24.6% for CA125. For stage I disease, HE4 yielded a 17.1% improvement in sensitivity compared with CA125.

Conclusion

HE4 is elevated in all stages of endometrial cancer and is more sensitive in early-stage endometrial cancer compared to CA125. Further investigation of HE4 as a marker for early detection of recurrent endometrial cancer and monitoring response to therapy is warranted.

Introduction

Patients diagnosed with epithelial ovarian cancer (EOC) have improved outcomes when cared for at centers experienced in the management of EOC. The objective of this trial was to validate a predictive model to assess the risk for EOC in women with a pelvic mass.

Methods

Women diagnosed with a pelvic mass and scheduled to have surgery were enrolled on a multicenter prospective study. Preoperative serum levels of HE4 and CA125 were measured. Separate logistic regression algorithms for premenopausal and postmenopausal women were utilized to categorize patients into low and high risk groups for EOC.

Results

Twelve sites enrolled 531 evaluable patients with 352 benign tumors, 129 EOC, 22 LMP tumors, 6 non EOC and 22 non ovarian cancers. The postmenopausal group contained 150 benign cases of which 112 were classified as low risk giving a specificity of 75.0% (95% CI 66.9-81.4), and 111 EOC and 6 LMP tumors of which 108 were classified as high risk giving a sensitivity of 92.3% (95% CI=85.9-96.4). The premenopausal group had 202 benign cases of which 151 were classified as low risk providing a specificity of 74.8% (95% CI=68.2--80.6), and 18 EOC and 16 LMP tumors of which 26 were classified as high risk, providing a sensitivity of 76.5% (95% CI=58.8--89.3).

Conclusion

An algorithm utilizing HE4 and CA125 successfully classified patients into high and low risk groups with 93.8% of EOC correctly classified as high risk. This model can be used to effectively triage patients to centers of excellence.

Purpose

Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy.

Methods

Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model.

Results

The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59–0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67–1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS.

Conclusion

The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.

Purpose

To explore the association between baseline quality of life (QOL) scores and overall survival (OS) in ovarian cancer patients receiving adjuvant chemotherapy.

Methods

Patients with stage III ovarian cancer on Gynecologic Oncology Group protocol #172 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and were then randomly assigned to either intravenous (IV) or intraperitoneal (IP) chemotherapy. The FACT scale includes physical, functional, social, and emotional well-being domains (PWB, FWB, SWB, EWB). The PWB item, lack of energy, was used to assess the presence of fatigue.

Results

After adjusting for patient age, treatment assignment, and the presence of gross disease, PWB was associated with OS. Patients who reported baseline PWB scores in the lowest 25% (PWB score < 15 points) relative to those who scored in the highest 25% (PWB score > 24 points) had decreased OS (HR: 1.81; 95% CI: 1.2~2.72; p=0.005). Patients experienced death rates 20% lower for every mean item point increase in PWB (Hazard Ratio [HR]: 0.80; 95% CI: 0.68 ~ 0.93; p=0.005). Patients complaining of fatigue did not have an increased risk of death compared with those not feeling fatigued (HR: 1.21; 95% CI: 0.91~1.61; p=0.19).

Conclusions

Poor physical well-being reported at baseline is associated with risk of death in patients undergoing adjuvant chemotherapy for advanced ovarian cancer. Identifying modifiable characteristics that are associated with survival offers the potential for providing support that may improve outcomes.

Purpose

To compare two methods of determining therapeutic response and disease progression - modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma.)

Patients and Methods

Patients were treated with bevacizumab 15 mg/kg every 21 days. Modified GCIG definitions of progression and response were retrospectively applied and compared to RECIST-defined progression and response. The prognostic significance of CA-125- and RECIST-defined responses and progressions were explored.

Results

Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125. Median progression-free survival (PFS) by RECIST and progression-free interval (PFI) by CA-125 were 4.7 and 5.2 months respectively. However, 12.9% of those with CA-125 defined progression remained progression-free according to RECIST for at least 8 months. Thirteen of 62 patients (21%) had response by RECIST and 14/45 (31%) by CA-125. Time dependent analyses indicated that progression by CA-125 was associated with a 5.2 fold increased risk of progression by RECIST, and response by CA-125 had a 5 fold decrease in risk of progression by RECIST. Landmark and time dependent analyses showed prognostic value of responses by CA-125 and RECIST.

Conclusions

In this study, disease assessment by RECIST and CA-125 appear to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125.

Goals

Economic burden is emerging as a crucial dimension in our understanding of adjustment to cancer during treatment. Yet, economic burden is rarely examined in cancer survivorship. The goal of this paper is to describe the effect of economic hardship and burden among women with breast cancer.

Methods

We examined baseline and follow-up (3 and 6 month) data reported by 132 stage I and II breast cancer survivors assigned to the Wait Control arm of the Breast Cancer Education Intervention (BCEI), a clinical trial of education and support interventions. Repeated measures models fitted with linear mixed models were used to examine relationships between aspects of economic burden and overall quality of life (QOL) scores. Structural equation models (SEM) were used to examine the relationship between overall economic burden and QOL.

Results

Nineteen economic events were reported. The proportion of survivors who reported increase in insurance premiums increased in the 6-month study period (p=.022). The proportion of survivors reporting change in motivation (p=.016), productivity (p=.002), quality of work (p=.01), days missed from work (p<.001) and sacrificing other things (p=.001) declined. An increase in economic events was significantly associated with poorer quality of life at each of the study time points.

Conclusion

Economic burden of breast cancer extends into post-treatment survivorship. Better understanding of economic impact and managing economic burden may help maintain QOL.

Background

Few studies have examined the dietary habits of ovarian cancer survivors. Therefore, we conducted a study to assess the feasibility and impact of two dietary interventions for ovarian cancer survivors.

Methods

In this randomized, parallel-group study, 51 women (mean age, 53 years) diagnosed with stage II–IV ovarian cancer were recruited and randomly assigned to a low fat, high fiber (LFHF) diet or a modified National Cancer Institute diet supplemented with a soy-based beverage and encapsulated fruit and vegetable juice concentrates (FVJCs). Changes in clinical measures, serum carotenoid and tocopherol levels, dietary intake, anthropometry, and health-related quality of life (HRQOL) were assessed with paired t-tests.

Results

The recruitment rate was 25%, and the retention rate was 75% at 6 months. At baseline, 28% and 45% of women met guidelines for intake of fiber and of fruits and vegetables, respectively. After 6 months, total serum carotenoid levels and α- and β-carotene concentrations were significantly increased in both groups (P < 0.01); however, β-carotene concentrations were increased more in the FVJC group. Serum β-cryptoxanthin levels, fiber intake (+5.2 g/day), and daily servings of juice (+0.9 servings/day) and vegetables (+1.3 servings/day) were all significantly increased in the LFHF group (all P < 0.05). Serum levels of albumin, lutein and zeaxanthin, retinol, and retinyl palmitate were significantly increased in the FVJC group (all P < 0.05). No changes in cancer antigen-125, anthropometry, or HRQOL were observed.

Conclusion

Overall, this study supports the feasibility of designing dietary interventions for stage II–IV ovarian cancer survivors and provides preliminary evidence that a low fat high fiber diet and a diet supplemented with encapsulated FVJC may increase phytonutrients in ovarian cancer survivors.

Objective

Withaferin A, a natural withanolide, has shown anti-cancer properties in various cancers including breast cancer, but its effects in ovarian cancer remain unexplored. Notch 1 and Notch3 are critically involved in ovarian cancer progression. We decided to examine the effects of Withaferin A in ovarian carcinoma cell lines and its molecular mechanism of action including its regulation of Notch.

Methods

The effects of Withaferin A were examined in CaOV3 and SKOV3 ovarian carcinoma cell lines using MTS assay, clonogenic assay, annexin V/propidium iodide flow cytometry, and cell cycle analysis. Western analysis was conducted to examine the molecular mechanisms of action.

Results

Withaferin A inhibited the growth and colony formation of CaOV3 and SKOV3 cells by inducing apoptosis and cell cycle arrest. These changes correlated with down-regulation of Notch1, Notch3, cdc25C, total and phosphorylated Akt, and bcl-2 proteins.

Conclusions

Withaferin A inhibits CaOV3 and SKOV3 ovarian carcinoma cell growth, at least in part by targeting Notch1 and Notch3.

Objective

The number of Chinese-American breast cancer survivors (BCS) is increasing as a result of increasing incidence rates. There has been little research on Chinese BCS’ follow-up cancer care. This qualitative study aims to understand how Chinese-American BCS experience and cope with physical distress relative to non-Hispanic White (NHW) survivors.

Methods

Seventy-one BCS (37 Chinese immigrant, 7 US-born Chinese, 27 NHW) were recruited from the Greater Bay Area Cancer Registry to participate in focus group discussions or one-on-one interviews about their survivorship experiences. All BCS were diagnosed with breast cancer at stage 0-IIA between 2006-2009, and had survived for 1-4 years without recurrence. Interviews were conducted in Cantonese, Mandarin, or English. Data analyses followed established qualitative methods of content analysis.

Results

BCS experienced pain and side effects from radiation, surgery, and hormonal therapy. Physical distress subsequently caused emotional concerns about recurrence or metastasis. Most BCS consulted physicians about their physical distress. Chinese immigrant BCS were less likely to have their issues resolved compared to NHW and US-born Chinese who were more likely to question physicians, ask for referrals, and make repeat attempts if their problems were not resolved. Some Chinese immigrant BCS turned to Traditional Chinese Medicine for relief or accepted the idea that physical distress was part of survivorship.

Conclusion

Chinese immigrant BCS may be at risk for greater distress compared with US-born Chinese and NHW BCS because of cultural norms that make them less inclined to express their needs to physicians or challenge physicians when their needs are not met. Furthermore, they may express symptoms in culturally unique ways (e.g., hot-cold imbalances). Further research is needed to determine how to best improve survivorship care experiences in this understudied population, with the goal of decreasing BCS’ physical distress and improving quality of life.

Objective

The aim was to evaluate antitumor activity of the combination of ixabepilone and sunitinib in preclinical models of chemotherapy naïve and refractory epithelial ovarian tumors, and to investigate the mechanism of synergy of such drug combination.

Research Design

HOVTAX2 cell line was derived from a metastatic serous papillary epithelial ovarian tumor (EOC) and a paclitaxel-resistant derivative was established. Dose response curves for ixabepilone and sunitinib were generated and synergy was determined using combination indexes. The molecular mechanism of antitumor synergy was examined using shRNA silencing.

Results

The combination of ixabepilone and sunitinib demonstrated robust antitumor synergy in naïve and paclitaxel-resistant HOVTAX2 cell lines due to increased apoptosis. The GTPase, RhoB, was synergistically upregulated in cells treated with ixabepilone and sunitinib. Using shRNA, RhoB was demonstrated to mediate antitumor synergy. These results were validated in two other EOC cell lines.

Conclusions

Ixabepilone plus sunitinib demonstrated antitumor synergy via RhoB in naïve and paclitaxel-resistant cells resulting in apoptosis. This study demonstrates a novel mechanism of action leading to antitumor synergy and provides ‘proof-of-principle’ for combining molecular targeted agents with cytotoxic chemotherapy to improve antitumor efficacy. RhoB could be envisioned as an early biomarker of response to therapy in a planned Phase II clinical trial to assess the efficacy of ixabepilone combined with a receptor tyrosine kinase inhibitor such as sunitinib. To the best of our knowledge, this is the first demonstration of antitumor synergy between these two classes of drugs in EOC and the pivotal role of RhoB in this synergy.

Background

Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety.

Methods

Ovarian and primary peritoneal cancer patients, pre-treated with at least one prior platinum-containing regimen, performance status (PS) 0–1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1–15; oxaliplatin was given days 1 and 15; cycles repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses 1) 0.2/65; 2) 0.2/75; 3) 0.2/85; 4) 0.3, 85; 5) 0.4/85.

Results

Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 yrs (range, 37–77); PS: 0 =12 and 1 = 11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles (1–9) were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels.

Conclusion

Topotecan continuous infusion, combined with oxaliplatin was associated with no grade 4 hematologic toxicity, and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1–15 with oxaliplatin 85 mg/m2 on days 1, 15. A phase II evaluation as 2nd-line treatment for both platinum-sensitive and resistant ovarian cancer recurrences is ongoing.

Objective

Current intraperitoneal (IP) regimens for the treatment of ovarian cancer rely on cisplatin (DDP) whereas intravenous regimens rely on carboplatin (CBDCA). A major question in the field is whether CBDCA can replace DDP for IP treatment. We compared the uptake of IP administered DDP and CBDCA into human ovarian carcinoma nodules of various sizes growing on the peritoneal surface of nu/nu mice.

Methods

Human 2008 cells expressing GFP were inoculated IP in nu/nu mice. When small tumor nodules became visible by external imaging, a maximum tolerated dose of DDP, or either an equimolar or equitoxic dose of CBDCA, was injected IP. Platinum (Pt) concentration in tumor nodules was measured by inductively coupled plasma mass spectrometry.

Results

A total of 749 tumors harvested from 33 mice were analyzed for Pt concentration. DDP produced a 3.4-fold higher level of Pt in tumor nodules when compared to an equimolar dose of CBDCA (p=0.02). However, when DDP and CBDCA were injected at doses that were equitoxic to the mice, tumor Pt levels were equivalent (p=0.63). Although Pt concentrations of equal-sized nodules were highly variable, tumor Pt content (ng Pt/mg tumor) decreased with increasing nodule size following IP DDP, an effect not seen with IP administration of equitoxic doses of CBDCA (p<0.001).

Conclusions

These results suggest that IP CBDCA has comparable or better drug penetration when compared to DDP given at equitoxic doses, and thus provide support for replacing DDP with CBDCA in the IP treatment of patients with ovarian cancer.

Purpose

Our goal was to determine if symptom-based ovarian cancer screening was feasible in a primary care clinic and acceptable to women and practitioners. In addition, we wanted to describe the outcomes for a pilot group of screened women.

Methods

A prospective study of 2262 women over age 40 with at least one ovary participated in symptom-based screening using a symptom index (SI). The first 1001 were in a non-intervention study arm and 1261 were screened for symptoms and referred on to testing with CA125 and transvaginal ultrasound (TVS) if the SI result was positive. Patients and practitioners were surveyed about acceptability of study procedures. All patients were linked to the Western Washington SEER Cancer Registry to determine if ovarian cancer was diagnosed in any women.

Results

Of the eligible women visiting the clinic, 72.5% were interested in participating, and the participation rate was 62.1%. Of the 1261 who participated in the screening arm 51(4%) were SI positive and 47 participated in CA125 (45/47 normal) and TVS (32/47 normal). Two endometrial biopsies and one hysteroscopy D&C were performed secondary to study enrollment (pathology negative). No laparotomies or laparoscopies were performed secondary to study involvement. A survey of patient acceptability, on a scale of 1–5, revealed a mean score of 4.8 for the acceptability of SI screening and 4.7 for TVS and CA125 testing among SI positive women. Providers also rated the SI procedures highly acceptable with a mean score of 4.8. Two participating patients were diagnosed with ovarian cancer; one had a true positive SI in the non-intervention arm and one had a false negative SI in the screened arm.

Conclusion

While our pilot study is not large enough to assess sensitivity or specificity of a symptom-based screening approach, we did find that this type of screening was feasible and acceptable at the time of a primary care visit and referred approximately 4% of women for additional diagnostic testing. Symptom-based screening also resulted in minimal additional procedures.

Objective

In the US, second non-ocular malignancies are the primary cause of death in retinoblastoma survivors with the germline RB1 mutation. Soft tissue sarcomas are one of the most likely malignancies to pose a risk to these patients, with leiomyosarcoma (LMS) being the most common subtype. As our cohort is followed for a longer period, we discover new second malignancy risks for these patients.

Methods

We estimated the risk for uterine leiomyosarcoma (ULMS) in a cohort of 1854 patients with retinoblastoma who were diagnosed at two US institutions from 1914 through 1996. The standardized incidence ratio and excess absolute risk were calculated by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The cumulative risk at 50 years of age was also calculated.

Results

Seven of 525 female hereditary retinoblastoma patients developed ULMS. Five of these patients were used in the risk analysis, resulting in an excess risk of 3.87 per 10,000 women. Among hereditary patients who developed ULMS the excess risk increases dramatically with age: to 20/10,000 for female hereditary retinoblastoma patients aged between 30–39 years, and to 27/10,000 for patients aged 40+ years.

Conclusion

There is a substantial excess risk of ULMS in female hereditary retinoblastoma patients. As more patients survive into their thirties, this number is likely to increase. These findings raise the question of early childbearing, screening and prophylactic measures in hereditary retinoblastoma patients: all issues that would benefit from confirmation from other retinoblastoma cohorts, to allow for better guided counsel of these patients.

Objective

To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates.

Methods

Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m2 on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m2 on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles.

Results

The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples.

Conclusions

Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.

Objective

The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols.

Method

Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I2 statistics.

Results

Ten suitable studies comprising 1,815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71–2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified.

Conclusions

Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies.

Purpose

To evaluate local control, survival and toxicity in patients with early-stage endometrioid adenocarcinoma of the uterus treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) alone using a novel low dose regimen

Methods

We reviewed records of 414 patients with stage IA to stage II endometrial adenocarcinoma treated with VB alone from 2005 to 2011. Of these, 157 patients with endometrioid histology received 24 Gy in 6 fractions of HDR vaginal cylinder brachytherapy and constitute the study population. Dose was prescribed at the cylinder surface and delivered twice weekly in the post-operative setting. Local control and survival rates were calculated by the Kaplan-Meier method.

Results

All 157 patients completed the prescribed course of VB. Median follow-up time was 22.8 months (range, 1.5–76.5). Two patients developed vaginal recurrence, one in the periurethral region below the field and one in the fornix after treatment with a 2.5-cm cylinder. Three patients developed regional recurrence in the para-aortic region. Two patients developed distant metastasis (lung and carcinomatosis). The 2-year rate of vaginal control was 98.6%, locoregional control was 97.9% and disease-free survival was 96.8%. The 2-year overall survival rate was 98.7%. No Grade 2 or higher vaginal, gastrointestinal, genitourinary or skin long-term toxicity was reported for any patient.

Conclusion

Vaginal brachytherapy alone in early-stage endometrial cancer provides excellent results in terms of locoregional control and disease-free survival. The fractionation scheme of 24 Gy in 6 fractions prescribed to the cylinder surface was well-tolerated with minimal late toxicity.

Objective

To test if estrogen promotes carcinogenesis in vitro and in a genetic mouse model of ovarian cancer and whether its effects can be inhibited by a novel selective estrogen receptor modulator (SERM), bazedoxifene.

Methods

Bazedoxifene was synthesized and it was confirmed that the drug abrogated the uterine stimulatory effect of 17β-estradiol in mice. To determine if hormones alter tumorigenesis in vivo LSL-K-rasG12D/+PtenloxP/loxP mice were treated with vehicle control, 17β-estradiol or bazedoxifene. Hormone receptor status of a cell line established from LSL-K-rasG12D/+PtenloxP/loxP mouse ovarian tumors was characterized using western blotting and immunohistochemistry. The cell line was treated with hormones and invasion assays were performed using Boyden chambers and proliferation was assessed using MTT assays.

Results

In vitro 17β-estradiol increased both the invasion and proliferation of ovarian cancer cells and bazedoxifene reversed these effects. However, in the genetic mouse model neither treatment with 17β-estradiol nor bazedoxifene changed mean tumor burden when compared to treatment with placebo. The mice in all treatment groups had similar tumor incidence, metastatic nodules and ascites.

Conclusion

While 17β-estradiol increases the invasion and proliferation of ovarian cancer cells, these effects do not translate into increased tumor burden in a genetic mouse model of endometrioid ovarian cancer. Likewise, while the SERM reversed the detrimental effects of estrogen in vitro, there was no change in tumor burden in mice treated with bazedoxifene. These findings demonstrate the complex interplay between hormones and ovarian carcinogenesis.

Objectives

An immune response sufficient to induce organ failure may provide protection and therapy against tumors derived from the targeted organ particularly when removal or ablation of the organ is part of the standard therapy and does not threaten survival. We have previously shown that a targeted immune response directed against the ovarian-specific protein, inhibin-α, causes ovarian failure. Here we determined whether inhibin-α autoimmunity is effective in both prevention and treatment of ovarian tumors.

Methods

A transgene consisting of the SV40 large tumor transformation antigen under the regulation of an anti-Mullerian hormone promoter (AMH-SV40Tag) was transferred by backcrossing for 12 generations to SJL/J mice producing SJL.AMH-SV40Tag (H-2s) females that develop a high incidence of autochthonous granulosa cell tumors. We determined whether immunization of SJL.AMH-SV40Tag female mice with the IAs-restricted p215-234 peptide of mouse inhibin-α was capable of preventing and treating these ovarian tumors.

Results

The growth of autochthonous ovarian granulosa cell tumors in SJL.AMH-SV40Tag transgenic mice was significantly inhibited in mice immunized with Inα 215-234. In addition, significant inhibition of tumor growth occurred when mice with established ovarian granulosa cell tumors were therapeutically vaccinated with Inα 215-234.

Conclusions

Our results indicate that induction of ovarian-specific autoimmunity may serve as an effective way to prevent the emergence of autochthonous ovarian tumors and control the growth of established ovarian malignancies.

Objective

Approximately 20% of patients receiving platinum-based chemotherapy for epithelial ovarian cancer (EOC) are refractory or develop early recurrence. Identifying these patients early could reduce treatment-associated morbidity and allow quicker transfer to more effective therapies. Much attention has focused on ERCC1 as a potential predictor of response to therapy because of its essential role in the repair of platinum-induced DNA damage. The purpose of this study was to accurately measure protein levels of ERCC1 and its essential binding partner XPF from patients with EOC treated with platinum-based therapy and determine if protein levels correlate with mRNA levels, patient genotypes or clinical outcomes.

Methods

ERCC1 and XPF mRNA and protein levels were measured in frozen EOC specimens from 41 patients receiving intraperitoneal platinum-based chemotherapy using reverse transcription polymerase chain reaction and western blots. Genotypes of common nucleotide polymorphisms were also analyzed. Patient outcomes included progression free (PFS) and overall survival (OS).

Results

Expression of ERCC1 and XPF were tightly correlated with one another at both the mRNA and protein level. However, the mRNA and protein levels of ERCC1 were not positively correlated. Likewise, none of the SNPs analyzed correlated with ERCC1 or XPF protein levels. There was an inverse correlation between mRNA levels and patient outcomes.

Conclusion

Neither genotype nor mRNA levels are predictive of protein expression. Despite this, low ERCC1 mRNA significantly correlated with improved PFS and OS.

Objective

We evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119).

Methods

Tissue microarrays of metastatic or recurrent (n=42) tumor were developed and immunohistochemistry performed. Average expression (percent staining × intensity) was assessed in tumor epithelium (E) and stroma (S) and categorized into tertiles (T1, T2, T3) for E-cadherinE, N-cadherinE, alpha-cateninE, beta-cateninE, gamma-cateninE, p120-cateninE and Ki-67E; as negative, below median or above median for p16E, p27E and CD44S; or as negative or positive for p53E, Ki-67S and APCS (adenomatous polyposis coli). End points included response and survival.

Results

E-cadherinE, p16E, and p53E varied by race (p=0.003, p=0.024, p=0.002,) and N-cadherinE, Ki-67E, p16E and p27E by tumor type (p=0.015, p=0.011, p=0.005, p=0.021). Correlations were observed among E-cadherinE with p120E (r=0.66), p53E (r=−0.32), alpha-cateninE (r=0.52), beta-cateninE (r=0.58), and gamma-cateninE (r=0.58). High E-cadherinE (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR]=0.14, 95% confidence interval [CI]=0.06–0.37 or HR=0.17, 95% CI=0.07–0.42) and adjusted models (HR=0.18, 95% CI=0.05–0.59 or HR=0.22, 95% CI=0.07–0.70). High p16E versus negative expression was associated with worse survival in unadjusted (HR=3.87, 95% CI=1.74–8.61) and adjusted (HR=4.18, 95% CI=1.28–13.6) models. Positive versus negative expression of p53E was associated with worse survival in unadjusted (HR=2.31, 95% CI=1.16–4.60) but not adjusted models.

Conclusions

E-cadherinE and p16E appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with T+M, and merit further study.

Purpose

Intraperitoneal (IP) chemotherapy prolongs survival in optimally reduced ovarian cancer patients. For patients in whom optimal debulking cannot be achieved, one could incorporate IP therapy post-operatively if the cancer was optimally debulked following neoadjuvant chemotherapy. We sought to evaluate overall survival (OS), progression-free survival (PFS), percent of patients optimally debulked and toxicity in patients treated with this strategy.

Methods

Women with adenocarcinoma by biopsy or cytology with stage III/IV (pleural effusions only) epithelial ovarian, fallopian tube or primary peritoneal carcinoma that presented with bulky disease were treated with neoadjuvant intravenous (IV) paclitaxel 175 mg/m2 and carboplatin AUC 6 q 21 days x 3 cycles followed by surgery (if ≥ 50% decrease in CA125). If optimally debulked they received IV paclitaxel 175 mg/m2 and IP carboplatin AUC 5 (day 1) and IP paclitaxel 60 mg/m2 (day 8) q 28 days x 6 cycles.

Results

Sixty-two patients were registered. Four were ineligible. Fifty-six were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia (3), anemia, leukopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia. Thirty-six patients had debulking surgery. Two had grade 4 hemorrhage. Twenty-six patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia. At a median follow-up of 21 months, median PFS is 21 months and median OS is 32 months for all 58 patients. PFS and OS for the 26 patients who received IV/IP chemotherapy is 29 and 34 months respectively.

Conclusions

These results compare favorably with other studies of sub-optimally debulked patients.

Objective

The value of neoadjuvant chemotherapy (NAC) for the treatment of advanced ovarian cancer has yet to be determined. While NAC may facilitate and simplify complete cytoreduction and reduce the risk of surgery, the delay of surgery related to NAC needs to be balanced against any potential benefit.

Methods

Surveillance, Epidemiology and End-Results (SEER) data linked to Medicare claims were used to identify 6844 women with treated stage III/IV epithelial ovarian cancer (1995–2005). Patients were classified by primary treatment (surgery (PDS) or chemotherapy), and the primary chemotherapy group was characterized as having NAC or palliative chemotherapy (PC) based on whether there was documentation that surgery was recommended. We compared surgical complications and survival between the groups.

Results

4827 (71%) of women were treated with PDS, 958 received NAC (14%) and 1059 (15%) had PC. Only 577 (60%) of women with NAC underwent surgery and they had fewer ostomies (8.5% vs. 19.2%, p<0.001) and fewer infections, gastrointestinal and pulmonary complications than PDS (all p<0.01). Comparing NAC to PDS there was a 16% increase in the risk of death at 2 years (RR 1.16, 95%CI 1.01–1.34) for women with stage III disease and a 15% reduction in the risk for women with stage IV disease (RR 0.85, 95%CI 0.73–0.99).

Conclusions

NAC followed by surgery was associated with fewer surgical complications than PDS. The direction and magnitude of the difference in survival between women receiving NAC and those receiving PDS differed according to the stage of disease and follow up time.

Objective

Ten percent of ovarian cancer is attributed to hereditary syndromes, most commonly to mutations in the BRCA1 or BRCA2 genes. These cancers are characterized by a prolonged sensitivity to platinum agents in spite of presentation at advanced stages. We hypothesized that women with BRCA-associated ovarian cancer would also show a high response rate to pegylated liposomal doxorubicin (Doxil).

Methods

A retrospective cohort study was conducted to compare the response rate, progression-free, and overall survival among women with BRCA-associated or sporadic ovarian cancer who were treated with Doxil.

Results

A response to Doxil was seen in 13 of 23 patients with BRCA mutations (56.5%; 3 by RECIST criteria and 10 by CA125 levels) compared with only 8 of 41 women with non-hereditary cancers (19.5%; 2 by RECIST criteria and 6 by CA125 levels; p=0.004). This was associated with an improved progression-free and overall survival as measured from the time of Doxil administration. Notably, platinum sensitivity did not directly correlate with a response to Doxil.

Conclusions

Women with BRCA-associated ovarian tumors demonstrate a greater sensitivity to cytotoxic therapy with Doxil than has previously been reported in unselected cases.