Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer-An Opportunity for Targeted Therapy.

Ovarian cancer is the deadliest of all gynecologic malignancies claiming the lives of nearly 14,000 women in the United States annually. Despite therapeutic advances, the ovarian cancer mortality rate has remained stagnant since the 1980's. The molecular heterogeneity of ovarian cancers suggest they may be more effectively treated via precision medicine. Current guidelines recommend germline and somatic testing for all new epithelial ovarian cancer diagnoses to assist providers in identifying candidates for targeted therapies. Next generation sequencing (NGS) identifies targetable, driver, and novel mutations used to guide treatment decisions. Performing NGS is standard of care in many other malignancies, but for ovarian cancer the use of NGS in daily practice is still emerging. This review discusses the targetable genetic mutations and role of NGS and molecular biomarker testing in the treatment of ovarian cancer.

Significance of Pelvic Fluid Observed during Ovarian Cancer Screening with Transvaginal Sonogram.

The primary objective was to examine the role of pelvic fluid observed during transvaginal ultrasonography (TVS) in identifying ovarian malignancy. A single-institution, observational study was conducted within the University of Kentucky Ovarian Cancer Screening trial from January 1987 to September 2019. We analyzed true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) groups for the presence of pelvic fluid during screening encounters. Measured outcomes were the presence and duration of fluid over successive screening encounters. Of the 48,925 women surveyed, 2001 (4.1%) had pelvic fluid present during a TVS exam. The odds ratio (OR) of detecting fluid in the comparison group (TN screen; OR = 1) significantly differed from that of the FP cases (benign pathology; OR: 13.4; 95% confidence interval (CI): 9.1-19.8), the TP cases with a low malignant potential (LMP; OR: 28; 95% CI: 26.5-29.5), TP ovarian cancer cases (OR: 50.4; 95% CI: 27.2-93.2), and FN ovarian cancer cases (OR: 59.3; 95% CI: 19.7-178.1). The mean duration that pelvic fluid was present for women with TN screens was 2.2 ± 0.05 encounters, lasting 38.7 ± 1.3 months. In an asymptomatic screening population, free fluid identified in TVS exams was more associated with ovarian malignancy than in the control group or benign ovarian tumors. While pelvic free fluid may not solely discriminate malignancy from non-malignancy, it appears to be clinically relevant and warrants thoughtful consideration.

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance.

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K-Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

MUTYH as an Emerging Predictive Biomarker in Ovarian Cancer.

Approximately 18% of ovarian cancers have an underlying genetic predisposition and many of the genetic alterations have become intervention and therapy targets. Although mutations in MutY homolog (MUTYH) are best known for MUTYH associated polyposis and colorectal cancer, it plays a role in the development of ovarian cancer. In this review, we discuss the function of the MUTYH gene, mutation epidemiology, and its mechanism for carcinogenesis. We additionally examine its emerging role in the development of ovarian cancer and how it may be used as a predictive and targetable biomarker. MUTYH mutations may confer the risk of ovarian cancer by the failure of its well-known base excision repair mechanism or by failure to induce cell death. Biallelic germline MUTYH mutations confer a 14% risk of ovarian cancer by age 70. A monoallelic germline mutation in conjunction with a somatic MUTYH mutation may also contribute to the development of ovarian cancer. Resistance to platinum-based chemotherapeutic agents may be seen in tumors with monoallelic mutations, but platinum sensitivity in the biallelic setting. As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.

Disease-Specific Survival of Type I and Type II Epithelial Ovarian Cancers-Stage Challenges Categorical Assignments of Indolence & Aggressiveness.

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC.

Inherited alterations of TGF beta signaling components in Appalachian cervical cancers.

PURPOSE: This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women. METHODS: Appalachian women's survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n = 163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and χ2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics. RESULTS: Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18. CONCLUSIONS: This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.

Clinical Factors Associated with Longer Hospital Stay Following Ovarian Cancer Surgery.

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy and is treated with a combination of cytoreductive surgery and platinum-based chemotherapy. Extended length of stay (LOS) after surgery can affect patient morbidity, overall costs, and hospital resource utilization. The primary objective of this study was to identify factors contributing to prolonged LOS for women undergoing surgery for ovarian cancer. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify women from 2012-2016 who underwent hysterectomy for ovarian, fallopian tube and peritoneal cancer. The primary outcome was LOS >50th percentile. Preoperative and intraoperative variables were examined to determine which were associated with prolonged LOS. Results: From 2012-2016, 1771 women underwent elective abdominal surgery for OC and were entered in the ACS-NSQIP database. The mean and median LOS was 4.6 and 4.0 days (IQR 0-38), respectively. On multivariate analysis, factors associated with prolonged LOS included: American Society of Anesthesiologists (ASA) Classification III (aOR 1.71, 95% CI 1.38-2.13) or IV (aOR 1.88, 95% CI 1.44-2.46), presence of ascites (aOR 1.88, 95% CI 1.44-2.46), older age (aOR 1.23, 95% CI 1.13-1.35), platelet count >400,000/mm3 (aOR 1.74, 95% CI 1.29-2.35), preoperative blood transfusion (aOR 11.00, 95% CI 1.28-94.77), disseminated cancer (aOR 1.28, 95% CI 1.03-1.60), increased length of operation (121-180 min, aOR 1.47, 95% CI 1.13-1.91; >180 min, aOR 2.78, 95% CI 2.13-3.64), and postoperative blood transfusion within 72 h of incision (aOR 2.04, 95% CI 1.59-2.62) (p < 0.05 for all). Conclusions: Longer length of hospital stay following surgery for OC is associated with many patient, disease, and treatment-related factors. The extent of surgery, as evidenced by perioperative blood transfusion and length of surgical procedure, is a factor that can potentially be modified to shorten LOS, improve patient outcomes, and reduce hospital costs.

Consistency of in vitro chemoresponse assay results and population clinical response rates among women with endometrial carcinoma.

BACKGROUND: There are a number of equally efficacious chemotherapy options for the treatment of women with endometrial cancer, all of which work in only a subset of those women with this disease. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. Such an assay should yield response rates similar to those found in treated patient populations. The purpose of this investigation was to determine whether the patterns of in vitro tumor response rates as determined by ChemoFx are consistent with expected population response rates. METHODS: Nine hundred twenty-three tumor specimens from patients with high-risk early-stage, advanced stage, or recurrent endometrial cancer were sent for testing with the ChemoFx drug response marker from August 2, 2006, to August 31, 2009. Tumors were categorized as responsive (R), intermediately responsive (IR), or nonresponsive to each drug or combination tested. Response rates from clinical trials were identified and compared with the corresponding in vitro response rates. RESULTS: Of the 923 specimens received, 759 (82%) were successfully tested by ChemoFx. Of these, 755 were tested for at least 1 of 5 National Comprehensive Cancer Network-recommended endometrial cancer drugs. The response rates (R+IR) for these drugs were as follows: 66% carboplatin-paclitaxel, 48% carboplatin, 37% cisplatin, 23% doxorubicin, and 36% paclitaxel. Moreover, 20% of tumors were pan-sensitive (R or IR) to all 5 regimens tested, 27% were pan-resistant (nonresponsive), and 53% showed different degrees of response to different drugs. CONCLUSIONS: ChemoFx in vitro response rates were consistent with published population response rates, and the ChemoFx drug response marker may provide clinically useful information to better optimize individual chemotherapy for treatment of women with endometrial cancer.

Does the progression-free interval after primary chemotherapy predict survival after salvage chemotherapy in advanced and recurrent endometrial cancer?: a Gynecologic Oncology Group ancillary data analysis.

BACKGROUND: This study evaluated whether progression-free interval (PFI) following primary chemotherapy (PCT) was predictive of overall survival (OS) after second-line chemotherapy in advanced/recurrent endometrial cancer (EC). METHODS: This is a pooled analysis of patients who recurred after PCT and were treated with second-line chemotherapy on Gynecologic Oncology Group trials. PFI-1 measured from initiation of PCT to recurrence or treatment-free interval (TFI) measured from completion of PCT to initiation of second-line chemotherapy was evaluated in relation to clinical outcomes. RESULTS: A total of 586 patients treated on 5 phase 3 PCT protocols were included. Baseline factors in primary setting associated with clinical outcome after PCT were also predictive of OS after second-line chemotherapy, including race, Gynecologic Oncology Group performance status, grade, and prior radiation therapy (P<.01). PFI-1 was the most significant factor predictive of survival after second-line chemotherapy, with a 30% reduction in the risk of death for PFI-1>6 months compared with ≤6 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.59-0.84 [P<.0001]) and median OS after second-line chemotherapy of 10 versus 5 months. A total of 275 patients treated on 9 phase 2 second-line chemotherapy protocols were also evaluated, and TFI>3 months was associated with a 25% reduction in the risk of death (HR, 0.75; 95% CI, 0.57-0.97 [P=.030]) and median OS after second-line chemotherapy of 10 versus 7 months compared with TFI≤3 months. The tumor response to second-line chemotherapy was 9.6% versus 5.8%; the difference was not statistically significant. CONCLUSIONS: Time to recurrence after PCT is predictive of survival after recurrence in advanced/recurrent EC. However, there is no evidence that this variable can be used in selecting salvage chemotherapy.

Chemotherapy intensity and toxicity among black and white women with advanced and recurrent endometrial cancer: a Gynecologic Oncology Group Study.

BACKGROUND: The purpose of this study was to confirm whether black and white women with endometrial cancer are equally tolerant of chemotherapy and identify factors that impact survival. METHODS: A retrospective review of 169 black women and 982 white women with the International Federation of Gynecologists and Obstetricians stage III, stage IV, or recurrent endometrial carcinoma was performed. All patients received doxorubicin combined with cisplatin. Chemotherapy parameters that were reviewed included relative dose, relative time, and relative dose intensity. Treatment cycles > or =7 were defined as treatment completion. RESULTS: Although black patients were more likely to experience grades 3-4 anemia (20% vs 14%) and genitourinary (5% vs 1%) toxicity, and less likely to experience severe gastrointestinal toxicity (10% vs 17%), the overall incidence of grades 3-4 treatment-related chemotoxicity was the same between the 2 groups (82% vs 82%). There were no differences in the number of cycles received, relative dose (0.57 vs 0.58), relative time (0.77 vs 0.78), or relative dose intensity (0.76 vs 0.76) for black and white patients. CONCLUSIONS: Black patients with advanced stage or recurrent endometrial cancer, treated on 4 Gynecologic Oncology Group (GOG) protocols, had similar dose intensity and severe chemotherapy-related toxicity compared with white patients, suggesting that previously described racial disparities in survival among patients in GOG trials may have an novel etiology.

Fixed-dose rate gemcitabine plus carboplatin in relapsed, platinum-sensitive ovarian cancer patients: results of a three-arm Phase I study.

OBJECTIVES: Standard infusion of gemcitabine plus carboplatin showed improved efficacy compared to carboplatin alone in patients with platinum-sensitive (Pt-S) ovarian cancer (OC). Fixed-dose rate (FDR) administration of gemcitabine produces more efficient intracellular phosphorylation of gemcitabine to its active form. This study was designed to identify the maximum tolerated dose (MTD), toxicity profile, and response rate of FDR gemcitabine plus carboplatin in Pt-S OC. METHODS: Patients with measurable OC relapsing > or =6 months after exposure to platinum (N=60) were assigned to one of three treatment cohorts, each with a different delivery schedule and escalating doses of both FDR gemcitabine (10 mg/m(2)/min) and standard infusion carboplatin (60 min). MTDs were determined using dose-limiting toxicities (DLTs). Measurable disease was assessed using modified RECIST criteria. CA-125 levels were evaluated using Rustin criteria. Toxicities were assessed using NCI Common Toxicity Criteria, version 2.0. RESULTS: The MTD of Arm 1 was FDR gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin AUC 5 on day 1, every 21 days. The MTD of Arm 2 was FDR gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin AUC 2.5+AUC 2.5 on days 1 and 8, every 21 days. Patient accrual on Arm 3 consisting of bi-weekly FDR gemcitabine plus carboplatin was terminated because dose level 1 exceeded the MTD. Overall response rates were 38.1% (Arm 1), 58.8% (Arm 2), and 44.4% (Arm 3). CONCLUSIONS: FDR gemcitabine+carboplatin on a 21-day schedule was active and produced no unusual safety signals in patients with Pt-S OC.

Feasibility assessment of a chemoresponse assay to predict pathologic response in neoadjuvant chemotherapy for breast cancer patients.

BACKGROUND: For chemosensitivity and resistance assays to be clinically useful in predicting patient outcome, they should require small amounts of tissue and be highly reproducible and reliable. PATIENTS AND METHODS: Expanded tumor cells from transcutaneous biopsies of breast lesions (n=62) were tested for chemoresponse using the cell-based ChemoFx assay. Pathologic complete response (pCR) was determined on a subset of patients (n=34). Assay score and pCR were determined independently in a blinded manner. Logistic regression models were used to select predictors for response. RESULTS: Tumor cells were successfully isolated from 83.9% of patients. Chemoresponse profiles were robust and reproducible with coefficient of variance of <3%. In a limited initial patient outcome correlation, assay score of docetaxel/capecitabine significantly predicted pCR; the cross-validated model was 75% accurate. CONCLUSION: It is feasible to assess the chemoresponsiveness of small breast lesions using the ChemoFx assay to assist in choosing neoadjuvant chemotherapy for breast cancer patients.

Expression and activity of taxane-metabolizing enzymes in ovarian tumors.

OBJECTIVE: Current firstline chemotherapy for ovarian cancer consists of carboplatin combined with either paclitaxel or docetaxel. Disposition of carboplatin is determined by renal clearance, while the taxanes are metabolized by cytochrome P450 (CYP450) enzymes. Although the majority of taxane metabolism occurs in the liver, recent data have shown that some solid tumors express CYP450 enzymes in the tumors themselves. The objective of this study was to determine whether ovarian tumors express genes regulating cellular efflux and subsequent metabolism, and whether any clinico-pathologic features correlated with expression. METHODS: Gene expression of CYP2C8, CYP3A4/A5 and the ABC transporter ABCB1 was determined in 56 primary epithelial ovarian tumors. Cells were grown from seven different tumors and exposed ex vivo to paclitaxel (PAC) and docetaxel (DOC) for up to 24 h. PAC and DOC concentrations were measured in the media by an LC-MS assay. RESULTS: Results from this analysis demonstrate that ovarian cancer cells do express functional taxane-metabolizing enzymes. Such expression appeared to enhance the ability of cancer cells to metabolize DOC. Specifically, the PK of DOC was correlated with the ratio of CYP4A5 to ABCB1 gene expression, thus representing a novel mechanism of chemotherapy resistance. There was no relationship between PAC PK parameters and gene expression. CONCLUSIONS: Knowledge of inter-individual variation in CYP450 enzyme and ABC transporter tumor expression and activity may influence the individualization of chemotherapy, by avoiding agents that are rapidly metabolized and selecting agents that are not.

Percent surface area involvement is a predictor of lymph node metastasis in endometrial cancer.

OBJECTIVE: To determine if percent surface area involvement (SAI) of tumor in endometrial cancer is predictive of lymph node metastasis. METHODS: A retrospective study was performed of all patients diagnosed with endometrial cancer at Magee Women's Hospital between January 1990 and December of 1995. Papillary serous and clear cell histologic subtypes were excluded. Pathology reports were reviewed for percent SAI, myometrial invasion, grade, histologic subtype, lymphovascular space invasion, and lymph node metastasis. Percent SAI was categorized into three groups: <35%, 35-80%, and >80%. The primary outcome variables were pelvic or periaortic lymph node metastasis. Univariate and multivariate analysis logistic regression models were used to determine predictors of nodal metastasis. RESULTS: Of 558 patient records reviewed, 319 had lymph node dissections performed and 42 (13%) of those patients had positive lymph nodes. Two of 79 (3%) patients with <35% SAI had lymph node metastasis, 17 of 165 (10%) patients with 35-80% SAI had lymph node metastasis, and 23 of 75 (31%) patients with >80% SAI had lymph node metastasis. The percent SAI was significantly associated with lymph node metastasis (p<0.001). Multivariate logistic regression indicated that for patients with >80% SAI, the odds of having lymph node metastasis were 10.8 times (CI 1.3-90.4) that for patients with similar tumor histology, grade, and invasion, but <35% SAI (p=0.03). A subset analysis of patients with superficial myometrial invasion was performed and 16% of patients with <50% myometrial invasion and >80% SAI had positive lymph nodes, while only 1.4% of patients with <50% myometrial invasion and <35% SAI had positive lymph nodes (p=0.02). CONCLUSION: Our analysis indicates that percent SAI is an independent risk factor for lymph node metastasis. Furthermore, assessing SAI with myometrial invasion gives a more accurate prediction of lymph node metastasis than myometrial invasion alone. This becomes clinically relevant when assessing risk factors for lymph node metastasis intraoperatively.

The relationship between histology and outcome in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study.

OBJECTIVES: To explore associations between histology and outcome in advanced or recurrent endometrial cancer patients participating in Gynecologic Oncology Group chemotherapy trials. METHODS: Age, race, performance status, histologic type (serous=S; clear cell=CC; endometrioid=E), disease stage, and prior radiation were evaluated using various analytic methods to evaluate the probability of response and identify independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: Single agent or combination chemotherapy regimens including doxorubicin (A) (12%), doxorubicin/cisplatin (AP) (63%), doxorubicin/paclitaxel (AT) (13%), and paclitaxel/doxorubicin/cisplatin (TAP) (11%) were used among 1203 patients treated on 4 randomized clinical trials. Breakdown of disease stage was 7.8% stage III, 22.8% stage IV, and 69.4% recurrent disease. Histologic distribution was 18% S, 3.7% CC, 8.5% mixed, 51.7% E and 18.1% other. More S/CC patients enrolled on trials with advanced stage (III-IV) disease (as opposed to recurrent disease) compared to E patients (45% vs. 24%, p<0.05). Overall response rate was 42% (E=44%, S=44%, CC=32%). Histologic type was not an independent predictor of response. Independent predictors of PFS included race, performance status, disease stage, and CC histology. Histology was also an independent predictor of OS; the relative hazard ratio for S histology was 1.2 (1.02-1.4; p=0.03), and for CC was 1.51 (1.1-2.07; p=0.01). CONCLUSION: In patients with advanced/recurrent endometrial cancer treated with A, P and/or T, response was not associated with histology. This exploratory analysis does not support exclusion of S tumors in future trials. Poorer PFS and OS were observed in CC compared to other types, but a lack of benefit from chemotherapy was not shown, and as this histology represents such a small fraction, it does not seem feasible to have separate chemotherapy trials for CC.

Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate the association between body mass index (BMI) and outcomes in women with advanced or recurrent endometrial cancer treated with doxorubicin/cisplatin. METHODS: Data from patients treated on five Gynecologic Oncology Group trials were retrospectively reviewed. BMI was categorized as normal (< 25), overweight (> or = 25 to < 30), obese (> or = 30 to < 40), and morbidly obese (> or = 40). BMI was analyzed for associations with demographics, clinical characteristics, toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 949 patients, 533 (56%) had recurrent disease, 227 (23.9%) had Stage IV disease, and 189 (19.9%) had Stage III disease. Mean BMI was 29.8; 29.6%, 27.0%, 33.2% and 10.2% of patients, respectively, were categorized as normal, overweight, obese, and morbidly obese. The mean BMI was significantly different when compared by age group (p<0.001), stage (p=0.047), histologic type (p=0.024), and tumor grade (p=0.014). Older patients and those with clear cell, poorly differentiated tumors, or stage IV disease had a lower BMI. No significant associations between PFS and BMI were detected. Increasing BMI was significantly associated with an increased risk of death in Stage III/IV (HR=1.86, 95% CI 1.16-2.99 for BMI > or = 40 vs. BMI < 25) but not recurrent patients. Higher BMI patients had less Grade 3/4 toxicities than normal patients (p<0.001) but this difference disappeared for obese patients receiving > or = 95% of the calculated dose. CONCLUSIONS: BMI was not predictive of PFS in this endometrial cancer population although morbidly obese patients had decreased OS in primary Stage III/IV patients. Toxicities decreased with increasing BMI, perhaps secondary to capped dosing.

Racial disparity in survival among patients with advanced/recurrent endometrial adenocarcinoma: a Gynecologic Oncology Group study.

BACKGROUND: Previous studies have reported shorter survival of black women compared with white women who had advanced/recurrent endometrial cancer. It has been suggested that this may reflect racially based differences in treatment. METHODS: The authors retrospectively reviewed data from 169 black women and 982 white women with International Federation of Gynecologic Oncology (FIGO) Stage III, Stage IV, or recurrent endometrial carcinoma who were participants in 1 of 4 Gynecologic Oncology Group randomized treatment trials of doxorubicin alone or combined with paclitaxel and/or cisplatin. Demographic, histologic, treatment, and outcome data were analyzed to estimate survival, and between-group comparisons were performed. RESULTS: The pooled data revealed that black women were more likely to have papillary serous histology (P < .001), Stage IV disease (P < .001), and higher tumor grade (P < .001) compared with white women, and survival was worse among black women than among white women (median survival, 10.6 months vs. 12.2 months, respectively; P < .001). A Cox proportional hazards regression analysis that was adjusted for performance status, disease stage, tumor histology, tumor grade, and treatment demonstrated worse survival for black women (hazards ratio, 1.26, 95% confidence interval, 1.06-1.51; P = .010). CONCLUSIONS: The data from a large group of women with advanced/recurrent endometrial cancer suggested that a racial disparity in survival persists, despite the finding that black women and white women received similar treatment. Although the causes of racial disparity in endometrial cancer remain to be elucidated, socioeconomic, biologic, and cultural factors should be investigated to identify the etiologic origins of this multifactorial healthcare problem.

High-resolution methylation analysis of the BRCA1 promoter in ovarian tumors.

Both hereditary and sporadic ovarian tumors frequently have decreased BRCA1 expression. One mechanism of downregulating BRCA1 expression is hypermethylation of the BRCA1 promoter. Studies have shown that the BRCA1 promoter is aberrantly hypermethylated in a subset of ovarian tumors, although the proportion varies widely between reports. High-resolution analysis of the BRCA1 promoter in ovarian cancer may provide information regarding the extent and heterogeneity of methylation and guide future studies using methylation-specific polymerase chain reaction (MS-PCR). We screened 50 primary epithelial ovarian tumors for BRCA1 promoter hypermethylation using MS-PCR. The BRCA1 promoter was hypermethylated in 16% (8 of 50) of the tumors, including two stage IA tumors. Sequence analysis of the promoter revealed that methylation of the CpG island is both extensive and mosaic in the methylated samples. Two CpG dinucleotides in the BRCA1 promoter, within and adjacent to a Myb consensus binding site, were most frequently methylated in ovarian tumors. BRCA1 expression was significantly lower in methylated than in unmethylated samples. Our analysis of the BRCA1 promoter revealed preferential methylation of specific CpG sites in ovarian tumors. This finding could be exploited in the design of highly sensitive MS-PCR assays for direct assessment of tumor DNA and potentially for early detection of ovarian cancer in body fluids.

Centrosome abnormalities in ovarian cancer.

Centrosome abnormalities have been found in various cancer types and are thought to be involved in early development of cancer and/or progression. The contribution of centrosome abnormalities to ovarian tumorigenesis has not been previously evaluated. We sought to determine whether centrosome dysfunction occurs in ovarian tumorigenesis, and whether it could be used as an indicator of early neoplastic changes in ovarian surface epithelium (OSE). Primary cultures of normal OSE and ovarian tumors, as well as paraffin-embedded normal ovaries and ovarian tumors of different stages, were used for immunostaining with a gamma-tubulin antibody. Centrosomes were considered abnormal if there were more than 2 per cell, if their sizes were greater than 2-fold of a normal centrosome, and/or if they were abnormal in shape. Centrosomes in normal tissue were uniform in size, whereas centrosomes in ovarian tumors tended to be abnormal in size, number and shape. On average, 4.7% of cells in 5 primary normal OSE cultures had more than 2 centrosomes, whereas 14.1% of primary cells from 5 ovarian tumors displayed centrosome abnormalities (p = 0.008). Centrosome abnormalities were present in 60.9% of stage I (n = 23), 83.3% of stage II (n = 30) and all stage III (n = 10) paraffin-embedded ovarian tumor samples examined, but not in normal tissues. In addition, centrosome abnormalities occurred more frequently in ovarian tumors with higher grade and aggressive serous subtype. This is the first demonstration that centrosome abnormalities occur in ovarian tumors. Centrosome dysfunction may be an early event in ovarian carcinogenesis and involved in ovarian tumor progression.