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Benign radiation change (BRC) in cervical-vaginal smears may be difficult to distinguish from postirradiation dysplasia (PRD) or recurrent cervical carcinoma. The utility of DNA analysis in postirradiation smears was evaluated retrospectively in 71 patients. Representative Papanicolaou smears were restained with a Feulgen method and 100 to 250 cells were analyzed for DNA content using the CAS 200 image analysis system. Thirty-three control irradiated patients had negative smears with a minimum 3-year follow-up. Thirty controls (91%) had diploid histograms with a mean coefficient of variation of 8.2% and an average of 6.8% of cells in S and G2M phase. Three control patients had atypical nondiagnostic histograms. Twenty-three patients had abnormal smears and subsequent local recurrence; 21 (91%) had abnormal histograms, with seven showing polyploidy and 14 showing aneuploidy. The remaining 15 patients had abnormal smears diagnosed as PRD but no evidence of recurrent carcinoma. Five were polyploid, six were aneuploid, one was diploid, and three were atypical but nondiagnostic. Interactive DNA cytometry is useful in differentiating BRC from PRD and recurrent cancer. Aneuploidy is rarely, if ever, seen in negative smears with BRC. However, BRC may be associated with broad diploid peaks and increased proliferating cells. An abnormal histogram can be seen with PRD and does not always correlate with recurrent disease.

Second-look laparotomy is performed to evaluate response to chemotherapy and to determine the need for additional treatment. The relationship between absolute levels of serum CA 125 less than 35 u/ml and disease status at second-look operation was evaluated in 95 patients with advanced-stage epithelial ovarian cancer. Eighty-six patients had Stage III disease and nine patients had Stage IV cancer. Residual tumor was documented at second-look laparotomy in 52 (55%) of the patients studied. Forty-nine percent of the 82 patients with serum CA 125 values less than 20 u/ml had residual disease. In contrast, 12 of 13 (92%) patients with serum CA 125 values of 20-35 u/ml had residual tumor at second-look laparotomy. All patients with serous cystadenocarcinomas and serum CA 125 values of 20-35 u/ml had residual tumor, and two-thirds of these cases had grossly visible disease. The positive predictive value of a serum CA 125 level of 20-35 u/ml was 0.92. These data suggest that second-look laparotomy should be deferred in patients with advanced-stage ovarian cancer until serum CA 125 values are less than 20 u/ml.

One hundred thirty-four patients with bulky and barrel-shaped cervix cancers were treated with preoperative radiation to 40-45 Gy, intracavitary therapy using Cs-137 or Cf-252 and extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) 4-6 weeks after radiotherapy. Outcome of therapy was traced for patients with residual tumor (positive) in the hysterectomy specimen and those who had no residual tumor (negative) in the specimens. All specimens were studied by a set protocol to carefully evaluate the TAHBSO specimen for gross or residual tumor. Ninety-two percent of the patients with negative specimens survived 5 years, but this dropped to 71% if the specimen was positive. These findings were observed in both the Cs-137- and Cf-252-treated patients. Patients with negative specimens failed mainly in distant sites, whereas those with positive specimens failed locally and distantly. Patient survival was less in patients with positive specimens. There was no difference in outcomes for adenocarcinoma and squamous cell carcinomas. The specimen histological findings have predictive value in patients treated with preoperative radiation and surgery.

Objective. The purpose of this study was to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. Methods. Annual TVS screening was performed on 14,469 asymptomatic women from 1987 to 1999. Eligibility criteria included (1) all women ≥ 50 years of age and (2) women ≥ 25 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid (length × height × width × 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm 3 in postmenopausal women or >20 cm 3 in premenopausal women or (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with abnormal TVS had a repeat sonogram in 4–6 weeks. Patients with a persistently abnormal second screen had a serum CA-125 determination, tumor morphology indexing, and Doppler flow sonography, and were advised to have surgical tumor removal. Results. One hundred eighty patients with persisting TVS abnormalities underwent exploratory laparoscopy or laparotomy. Seventeen ovarian cancers were detected: 11 Stage I, 3 Stage II, and 3 Stage III. Only three patients with Stage I cancers had a palpable ovarian mass on clinical examination. All patients with Stage I and II ovarian cancer are alive without recurrence 1.8–9.8 years (median, 4.5 years) after diagnosis. Two of the three Stage III patients have died of disease: one at 4.3 years and one at 7.7 years after detection. Four patients developed ovarian cancer within 12 months of a negative scan (FN): 2 Stage II, 2 Stage III. Three of these patients are alive with no evidence of disease 0.4, 1.9, and 5.5 years after diagnosis, and 1 patient has died of disease 0.7 years after diagnosis. Four patients developed ovarian cancer more than 12 months following a normal screen. All 4 presented clinically with Stage III disease. Two of these patients have died of disease and two patients are alive 1.5 and 2.1 years after diagnosis. TVS screening was associated with the following statistical variables: sensitivity, 81%; specificity, 98.9%; positive predictive value (PPV), 9.4%; and negative predictive value (NPV), 99.97%. After 46,113 screening years, there have been 3 ovarian cancer deaths in the annually screened population and 2 ovarian cancer deaths in women receiving less than annual screening. The survival of ovarian cancer patients in the annually screened population was 95.0 ± 4.9% at 2 years and 88.2 ± 8.0% at 5 years. Excluding all cases of nonepithelial or borderline epithelial malignancies, the survival of patients with ovarian cancer in the annually screened population was 92.9 ± 6.9% at 2 years and 83.6 ± 10.8% at 5 years. Conclusions. (1) TVS screening, when performed annually, is associated with a decrease in stage at detection and a decrease in case-specific ovarian cancer mortality. (2) TVS screening does not appear to be effective in detecting ovarian cancer in which ovarian volume is normal.

The goal of this study was to determine the relationship of ovarian volume to age, height, and weight in women undergoing transvaginal sonography.Thirteen thousand nine hundred sixty-three women 25-91 years of age undergoing annual transvaginal sonography as part of the University of Kentucky Ovarian Cancer Screening Program were the subjects for this investigation. Each ovary was measured in three dimensions, and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). Mean ovarian volume according to age was calculated for each decade of life.Data were obtained from 58,673 observations of ovarian volume. Mean ovarian volume was 6.6 +/- 0.19 cm(3) in women less than 30 years of age; 6.1 +/- 0.06 cm(3) in women 30-39; 4.8 +/- 0.03 cm(3) in women 40-49; 2.6 +/- 0.01 cm(3) in women 50-59; 2. 1 +/- 0.01 cm(3) in women 60-69; and 1.8 +/- 0.08 cm(3) in women/=70. Mean ovarian volume was 4.9 +/- 0.03 cm(3) in premenopausal women and 2.2 +/- 0.01 cm(3) in postmenopausal women (P0.001). The use of exogenous estrogens was associated with a significant reduction in ovarian volume in women 40-59 years of age, but not in women/= 60. Ovarian volume was unrelated to patient weight but was greater in tall women (68 in.) than in short women (58 in.).There is a statistically significant decrease in ovarian volume with each decade of life from age 30 to age 70. Mean ovarian volume in premenopausal women is significantly greater than that in postmenopausal women. The upper limit of normal for ovarian volume is 20 cm(3) in premenopausal women and 10 cm(3) in postmenopausal women.

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).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.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-16 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 TFI3 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.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.

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 ≥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.

Twenty-seven patients with operable Stage II cervical cancer with a mean diameter tumor of 8.0 cm were studied in a feasibility study using preoperative 252Cf implants plus whole-pelvis radiation to 45 Gy followed by extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy 4 to 6 weeks later. Hysterectomy specimens were studied by a set protocol. With the protocol used, 13/27 (51%) specimens and abdominal stagings were negative for residual tumor. The survival rate for the patients with negative findings was 93% at 5 years. In 14/27 (49%) patients the specimens were positive for residual tumor. In contrast, the 5-year survival rate for this group was 46% (P less than 0.001). In these patients several interrelated factors were determined to be of importance, i.e., (1) tumor size greater than 8 cm in maximum diameter, (2) positive or negative residual tumor status, and (3) total dose of radiation given. Survival was lower for larger tumors and specimens were more likely to show residual tumor. A lower treatment dose led to more positive specimens, as well as to poorer survival. While the patients with Stage II disease fared very well when negative specimens were found, further prospective studies of the appropriate treatment for those with positive tumor specimens are needed.

Seventy-four patients with Stage II endometrial cancer were treated by a combination of preoperative radiation therapy followed by extrafascial hysterectomy, bilateral salpingo-oophorectomy, and paraaortic lymph node sampling at the University of Kentucky Medical Center from 1967 to 1988. All patients had histologically confirmed endometrial cancer with involvement of the endocervix. The cell types and numbers of the tumors treated were as follows: adenocarcinoma, 58; adenoacanthoma, six; adenosquamous carcinoma, nine; and clear cell carcinoma, one. Preoperative radiation consisted of 4500 cGy external therapy followed by one intracavitary implant providing an additional 2000 cGy to point A. Surgery was done 4 to 6 weeks after completion of radiation therapy. Five patients (7.1%) had paraaortic lymph node metastases. Four were treated with extended-field radiation therapy and one with platinum-based combination chemotherapy. After treatment, the patients were followed at regular intervals from 2 to 22 years (mean, 5.4 years). Eleven patients (15%) had recurrent cancer, with the vagina and upper abdomen being the most common sites of spread. The estimated 5-year and 10-year disease-free survival rates of these patients are 88% and 76%, respectively. Cell type, depth of myometrial invasion, and lymph node status were the most important prognostic variables in the patients evaluated. These data confirm that the combination of preoperative radiation therapy and surgery produces excellent long-term survival in patients with Stage II endometrial cancer.

Since 1976 a clinical trial has been conducted to test the feasibility, the potential, and to develop methods for using the neutron-emitting radioactive isotope, californium-252 (Cf-252), for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced (Stages III and IV) cervical cancer patients using different doses and schedules; they were extended to include unfavorable presentations of Stages I and II because of favorable results in the initial trials. The authors began to treat patients with Stage IB bulky or barrel-shaped tumors and the majority were treated with both radiation and hysterectomy. Actuarial survival was determined for Stage IB disease and was 87% at 5 years and 82% at 10 years. For those tested with preoperative radiation it was 92% at 5 and 87% at 10 years. For Stage II, it was 62% 5 years and 61% at 10. Survival 5 years after combined radiation and surgical therapy for Stage II disease was 68%. For Stage III, it was 33% at 5 years and 25% at 10. However, 5-year survival using the early neutron implant was 46% versus approximately 19% for delayed Cf-252 or cesium 137. Different schedules and sequences of neutrons and photons greatly altered outcome. Neutron treatment before external photon therapy was better for all stages of disease. Only about 5% of all patients developed complications after neutron therapy. No hematologic or mesenchymal second tumors were observed. Neutron brachytherapy was found to be very effective for producing rapid response and greatly improved local control of bulky, barrel, or advanced cervical cancers. The clinical trial identified and evolved schedules, doses, doses per session, and developed methods different from standard photon therapy but highly effective for local control and cure of cervical cancers of all stages. Clinical and radiobiologic understanding for the use of neutron therapy was greatly advanced by this trial. Future trials will focus on patients with advanced disease and will require evaluation of adjuvant chemotherapy studies and neutron-enhancing chemicals.

From November 1987 to January 1991, 1300 postmenopausal women underwent screening with transvaginal sonography (TVS). Women eligible for screening were all asymptomatic with no known ovarian tumors. Ovarian volume was calculated using the prolate ellipsoid formula, and a value in excess of 8.0 cm3 was considered abnormal. Ovarian abnormalities were detected in 33 women (2.5%), and 27 underwent exploratory laparotomy. Ovarian tumors were noted in all 27 patients, including 2 primary carcinomas and 14 serous cystadenomas. The two women with ovarian carcinomas had normal results of pelvic examinations and normal serum CA-125 levels. Both women had Stage I disease, and are alive and well after conventional therapy. TVS was time efficient, easy to perform, and well-accepted by patients. Currently, there are more than 3000 patient years of follow-up in the screened population, and there have been no deaths due to ovarian cancer. A multi-institutional trial to determine the efficacy of TVS as a screening method for ovarian cancer is indicated.

PurposeWe hypothesized that common polymorphisms in excision repair cross-complementation group 1 (ERCC1), involved in nucleotide excision repair of platinum-induced damage, would be associated with progression-free survival (PFS) and overall survival (OS) in women with optimally resected, stage III epithelial ovarian cancer (EOC) treated with cisplatin and paclitaxel (C+P).Patients and MethodsSingle nucleotide polymorphism analysis was carried out by direct pyrosequencing at two sites (codon 118 and C8092A) in ERCC1 in leukocyte DNA from women who participated in the Gynecologic Oncology Group (GOG) phase III protocol-172 and were randomly assigned to intraperitoneal or intravenous C+P.ResultsERCC1 genotyping was performed in 233 of the 429 women who participated in GOG-172. The genotype distribution at codon 118 was 17% with C/C, 43% with C/T, and 40% with T/T, and the genotype distribution at C8092A was 56% with C/C, 37% with C/A, and 7% with A/A. Adjusted Cox regression analysis revealed that the codon 118 polymorphism in ERCC1 was not significantly associated with disease progression or death. Women with the C8092A C/A or A/A genotypes compared with the C/C genotype had an increased risk of disease progression (hazard ratio [HR] = 1.44; 95% CI, 1.06 to 1.94; P = .018) and death (HR = 1.50; 95% CI, 1.07 to 2.09; P = .018). Median PFS and OS were 6 and 17 months shorter for women with the C8092A C/A or A/A genotypes versus the C/C genotype, respectively.ConclusionAlthough the ERCC1 codon 118 polymorphism does not seem to be associated with clinical outcome, the C8092A polymorphism was an independent predictor of PFS and OS in women with optimally resected EOC.

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.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.Tumor cells were successfully isolated from 83.9% of patients. Chemoresponse profiles were robust and reproducible with coefficient of variance of3%. In a limited initial patient outcome correlation, assay score of docetaxel/capecitabine significantly predicted pCR; the cross-validated model was 75% accurate.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.

From November 1987 to April 1989, 1000 women 40 years or older underwent screening vaginal sonography at the University of Kentucky Medical Center (Lexington, KY). Patients included in this investigation were all asymptomatic and had no known pelvic abnormalities. Each ovary was measured in three planes and ovarian volume was calculated using the prolate ellipsoid formula. The upper limit of normal for ovarian volume was 18 cm3 in premenopausal women and 8 cm3 in postmenopausal women. In patients with normal scans, mean ovarian volumes decreased from 6.8 cm3 to 3.0 cm3 with menopause. Thirty-one patients (3.1%) had abnormal vaginal sonograms and 24 underwent exploratory laparotomy. All patients undergoing surgery had ovarian or fallopian tube tumors with dimensions identical to those predicted by ultrasound. Histologic diagnoses of these tumors included the following: adenocarcinoma, one, serous cystadenoma, eight; endometrioma, six; and cystic teratomas, two. Vaginal sonography was performed easily and without complications, and was well accepted by patients. All patients with normal sonograms have been rescreened annually and none have subsequently developed ovarian cancer. Further clinical trials to determine the efficacy of vaginal sonography as a screening method for ovarian cancer are indicated.

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.

To determine if percent surface area involvement (SAI) of tumor in endometrial cancer is predictive of lymph node metastasis.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%, and80%. 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.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 with35% SAI had lymph node metastasis, 17 of 165 (10%) patients with 35-80% SAI had lymph node metastasis, and 23 of 75 (31%) patients with80% SAI had lymph node metastasis. The percent SAI was significantly associated with lymph node metastasis (p0.001). Multivariate logistic regression indicated that for patients with80% 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, but35% SAI (p=0.03). A subset analysis of patients with superficial myometrial invasion was performed and 16% of patients with50% myometrial invasion and80% SAI had positive lymph nodes, while only 1.4% of patients with50% myometrial invasion and35% SAI had positive lymph nodes (p=0.02).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.

To evaluate the association between body mass index (BMI) and outcomes in women with advanced or recurrent endometrial cancer treated with doxorubicin/cisplatin.Data from patients treated on five Gynecologic Oncology Group trials were retrospectively reviewed. BMI was categorized as normal (25), overweight (or = 25 to30), obese (or = 30 to40), and morbidly obese (or = 40). BMI was analyzed for associations with demographics, clinical characteristics, toxicity, progression-free survival (PFS), and overall survival (OS).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 (p0.001), 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 BMIor = 40 vs. BMI25) but not recurrent patients. Higher BMI patients had less Grade 3/4 toxicities than normal patients (p0.001) but this difference disappeared for obese patients receivingor = 95% of the calculated dose.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.

From December 1987 to December 1993, 6470 women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Two groups of women were eligible to participate in this investigation: (i) asymptomatic postmenopausal patients or patients >50 years of age, and (ii) asymptomatic women >30 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm3 in postmenopausal women or >20 cm3 in premenopausal women, and (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with persistently abnormal scans had a serum CA-125 determination, tumor morphology indexing, and color Doppler sonography. Ninety patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy or laparoscopy for tumor removal. Thirty-seven patients had serous cystadenomas and six had primary ovarian cancers. Five patients had Stage IA ovarian cancer and one patient had Stage IIIB disease. Only one of the ovarian cancer patients had a palpable abnormality on pelvic examination, and none had an elevated (>35 u/ml) serum CA-125. All these patients are presently alive and well 1-5 years after conventional therapy. There was one false negative in this study, a 38-year-old white female who was noted to have a small ovarian cancer at the time of laparoscopic prophylactic oophorectomy 11 months after a normal scan. Over 17,000 screening years have been accrued and there have been no deaths from primary ovarian cancer in the screened population. A cost analysis of TVS screening is presented.

The objective of this study was to evaluate the effectiveness and degree of toxicity of paclitaxel and carboplatin (PC) combination chemotherapy in patients with recurrent or persistent cervical carcinoma.Fifteen patients who received PC chemotherapy for recurrent or persistent carcinoma of the cervix at the Magee-Womens Hospital from 1994-1998 were studied retrospectively. Demographic data, pathology, radiation treatment response, site of recurrence, chemotherapy response, survival rates, and toxicities were reviewed. Months of survival were calculated by the method of Kaplan-Meier from the date after initiation of chemotherapy to death or the last date of follow-up.Fifteen patients received PC for recurrence or persistence of disease with a median of six courses of PC (range, four to 26). Fourteen patients (93.3%) had received prior radiation, and one patient had received surgery as the primary therapy. Four (26.7%) of 15 patients had complete response and five (33.3%) had partial response for an overall clinical response rate of 60%. The median survival of all 15 patients treated with PC was 17 months (range, four to 39). Four patients demonstrated progression of disease while two patients had stable disease. Grade 3 or 4 neutropenia occurred in four patients (26.7%) while one patient (6.7%) suffered from sepsis. Three patients (20%) suffered from Grade 2 anemia and four patients (26.7%) patients developed Grade 2 or Grade 3 neuropathy. There was no incidence of nephrotoxicity.Paclitaxel/carboplatin chemotherapy appears to have promising activity in recurrent or persistent carcinoma of the cervix with an acceptable toxicity profile. Due to patient convenience and tolerance, consideration should be given to carboplatin as an alternative regimen to cisplatin in combination with paclitaxel.

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.

Objectives A deletion variant in the CHEK2 gene (del1100C) has been implicated as a low-penetrance risk factor for breast cancer. We sought to determine contribution of CHEK2 mutations to the etiology of ovarian cancer (OvCa). Methods We used cases ascertained from the United States through Gynecologic Oncology Group (GOG) protocols 172, 182, and 144, the University of Hawaii Cancer Research Center, and Creighton University. Control women were recruited from Pittsburgh and Hawaii. Denaturing high-performance liquid chromatography, sequence analysis, and single nucleotide polymorphism genotyping by Pyrosequencing were employed to analyze the CHEK2 gene. Results Mutation screening of the CHEK2 gene in 48 cases who had a first-degree relative with OvCa uncovered only del1100C and A252G variants. Altogether, the del1100C variant was detected in none of 751 unselected cases, in 1 of 52 (1.9%) cases who had a first-degree relative with OvCa, and in 3 of 521 (0.6%) unselected controls. The frequencies of del1100C and A252G variants did not show statistically significant differences between the cases and the controls. Conclusions These results suggest that variations in CHEK2 do not make a significant contribution to the pathogenesis of OvCa in the U.S. population.

Purpose: To determine if circadian timed (CT) chemotherapy results in improved response, progression-free survival (PFS), overall survival (OS), and lower toxicity, when compared with standard timed (ST) chemotherapy. Materials and Methods: Eligibility criteria were stage III, IV, or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery; measurable disease; and no prior chemotherapy. Therapy was randomized to schedules of ST doxorubicin 60 mg/m2 plus cisplatin 60 mg/m2, or CT doxorubicin 60 mg/m2 at 6:00 am plus cisplatin 60 mg/m2 at 6:00 pm. Cycles were repeated every 3 weeks to a maximum of eight cycles. Results: The ST arm included 169 patients, and the CT arm included 173 patients. The objective response rate (complete responses plus partial responses) was 46% in the ST group compared with 49% in the CT group (P = .26, one tail). Median PFS and OS were 6.5 and 11.2 months, respectively, in the ST group; and 5.9 and 13.2 months, respectively, in the CT group (PFS: P = .31; OS: P = .21, one tail). Median total doses were 209 mg/m2 doxorubicin and 349 mg/m2 cisplatin in the ST group, versus 246 mg/m2 doxorubicin and 354 mg/m2 cisplatin in the CT group. Grade 3 or 4 leukopenia occurred in 73% of patients in the ST arm and in 63% of patients in the CT arm. There were eight treatment-related deaths. Conclusion: In this trial, no significant benefit in terms of response rate, PFS or OS, or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma.

Objectives The goals of this study were to evaluate the feasibility of pelvic intensity-modulated radiotherapy (IMRT) in the adjuvant treatment of gynecologic malignancies and to compare the dose–volume histograms (DVHs) and determine the potential impact on acute and long-term toxicity based on the dose to target and nontarget tissues for both planning techniques. Methods Ten consecutive patients referred for adjuvant radiotherapy for gynecologic malignancies at the University of Pittsburgh School of Medicine and Magee–Womens Hospital were selected for CT-based treatment planning using the ADAC 3D version 4.2g and the NOMOS Corvus IMRT version 4.0. Normal tissues and critical structures were contoured on axial CT slices by both systems in conjunction with a gynecologic radiologist. These regions included internal, external, and common iliac nodal groups, rectum, upper 4 cm of vagina, bladder, and small bowel. Conventional treatment planning included 3D four-field box using 18-MV photons designed to treat a volume from the L 5 /S 1 border superiorly to the bottom of the ischial tuberosity on the AP/PA field and shaped blocks on the lateral fields to minimize the dose to the rectum and small bowel. A seven-field technique using 6-MV photons was used for IMRT. Restraints on small bowel for IMRT were set at 23.0 Gy ± 5% and 35.0 Gy± 5% for the rectum and 37.5 Gy ± 5% for the bladder while simultaneously delivering full dose (45.0 Gy) to the intrapelvic nodal groups in 1.8-Gy daily fractions. The dose–volume histograms where then compared for both treatment delivery systems. Results The volume of each organ of interest (small bowel, bladder, and rectum) receiving doses in excess of 30 Gy was compared in the 3D and IMRT treatment plans. The mean volume of small bowel receiving doses in excess of 30 Gy was reduced by 52% with IMRT compared with 3D. A similar advantage was noted for the rectum (66% reduction) and the bladder (36% reduction). The nodal regions at risk and the upper vagina all received the prescribed dose of 45.0 Gy. Conclusions Intensity-modulated radiotherapy appears to offer several advantages over conventional 3D radiotherapy (3D CRT) planning for adjuvant radiotherapy for gynecologic malignancies. These include a significant reduction in treatment volume for bladder, rectum, and small bowel. It is anticipated that this reduction in volume of normal tissue irradiated would translate into overall reduction in acute and potentially late treatment-related toxicity. Prospective trials are necessary to better evaluate the advantages in a larger group of patients.

Objective. The purpose of this investigation was to test the hypothesis that mutation of TP53 is a requirement for BRCA-associated cancer development. Methods. A cell line experimentally deficient in BRCA1 protein was constructed using a regulatable antisense expression vector expressing 4000 bp from the BRCA1 cDNA. Changes in BRCA1, p53, and p21 protein levels were assayed by immunoblotting. Ovarian tumors with germline mutations in BRCA1 or BRCA2 were screened for mutations in TP53 by single-strand conformation polymorphism analysis. Results. Antisense inhibition of BRCA1 protein caused p53 and p21 protein levels to rise, indicating that partial loss of BRCA1 function activates the p53 DNA damage response pathway. Somatic mutation of TP53 was observed in 7 of 14 BRCA-associated ovarian tumors. Conclusions. Our findings provide novel evidence that loss of BRCA1 function in human cells activates the p53 DNA damage response pathway and that loss of this pathway, by somatic mutation of TP53, is a likely requirement for BRCA-associated tumor development.

Objective. The aim of this study was to present a family with both BRCA1-related and sporadic ovarian cancer and address current difficulties in genetic testing. Methods. BRCA1 mutation detection was performed on a family having four confirmed cases of ovarian cancer, two cases of breast cancer, and one case each of colon, stomach, and prostate cancer. The incidence and types of cancer were consistent with a BRCA1 mutation although previous linkage analysis had excluded this family as being due to BRCA1. Results. A protein-truncating mutation in BRCA1, denoted 2799delAA, was identified in the germline DNA of each of the women affected with breast and ovarian cancer in this family except the proband, who was diagnosed with ovarian cancer at age 65. Conclusions. In an earlier study, which sought to determine the proportion of site-specific ovarian cancer due to BRCA1, the family described in this report was wrongly identified as not being due to BRCA1 when, in fact, all but one of the breast and ovarian cancer cases carry a deleterious BRCA1 mutation. Our analysis suggests that the proband, who was the first of the women in this family to seek genetic counseling, developed ovarian cancer by chance and not as the result of an inherited mutation. We describe the results of our analysis in light of current issues that face clinicians who may be involved in genetic testing for breast and ovarian cancer predisposition.

The efficacy of carbon dioxide laser therapy in the treatment of cervical intraepithelial neoplasia (CIN) was evaluated in 253 patients treated at the University of Kentucky Medical Center from 1984 to 1987. All patients had histologically confirmed CIN and were treated in an outpatient setting. Parameters examined included severity of neoplasia, presence of koilocytosis on biopsy, depth of laser ablation, and the number of cervical quadrants involved by CIN. Following therapy, patients were examined at 3-month intervals from 12 to 48 months (mean 18 months). Eighty-nine per cent of patients were successfully treated with one laser ablation and all patients were cured of disease with two treatments. Over 70% of patients initially failing therapy had CIN III or greater than or equal to 3 quadrant disease. The most significant predictor of failure was lesion size. Only 74% of women with 3 or 4 quadrant disease were successfully treated with one treatment. No patient experienced postoperative infection or bleeding requiring treatment. These data confirm that carbon dioxide laser therapy is a safe and highly effective treatment method for all forms of CIN.

The aim of this study was to determine the risk of malignancy in cystic ovarian tumors10 cm in diameter in asymptomatic postmenopausal women or womenor =50 years of age.All cystic ovarian tumors detected by transvaginal sonography screening in asymptomatic postmenopausal women or womenor =50 years of age were evaluated with respect to size and morphology. Histology was recorded on all tumors removed surgically. Follow-up data were available both on patients undergoing surgery and on those who elected to be followed without operative intervention.Unilocular cystic tumors were detected in 256 of 7705 patients (3.3%). All tumors were10 cm in diameter and 90% were5 cm in diameter. One hundred twenty-five of these cysts (49%) resolved spontaneously within 60 days and 131 (51%) persisted. Forty-five patients with persisting ovarian cysts underwent operative removal of these tumors. Thirty-two patients had ovarian serous cystadenomas, and the remainder had a variety of benign lesions. There were no cases of ovarian carcinoma in this group. Eighty-six patients with unilocular cystic ovarian tumors were followed at 3- to 6-month intervals without surgery, and none have developed ovarian cancer. Complex cystic ovarian tumors were detected in 250 patients (3.2%). All tumors were10 cm in diameter and 89% were5 cm in diameter. One hundred thirty-five (55%) resolved spontaneously within 60 days, and 115 (45%) persisted. One hundred fourteen of these patients underwent operative tumor removal. Seven patients had ovarian carcinoma, 1 had primary peritoneal cancer, and 1 had metastatic breast cancer to the ovary.Unilocular ovarian cysts10 cm in diameter in asymptomatic postmenopausal women or womenor =50 years of age are associated with minimal risk for ovarian cancer. In contrast, complex ovarian cysts with wall abnormalities or solid areas are associated with a significant risk for malignancy. These data are important in determining optimal strategies for operative intervention in these patients.

Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.

PURPOSE To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Seventy-four sporadic ovarian tumors were studied for loss of heterozygosity (LOH) and microsatellite instability (MI) with 20 polymorphic markers on chromosome 17 and at least I marker on every other chromosome. Additionally, activation of the K-ras oncogene was examined through mutation analysis of codon 12. A majority of the tumors analyzed were low grade and/or of the mucinous histologic type. A negative correlation between LOH on chromosome 17 and K-ras activation was observed, with the former alteration present in the majority of high grade serous and endometrioid tumors and the latter most commonly found in the mucinous and low malignant potential (LMP) tumors. In 60% of cases where LOH on chromosome 17 was present, it was observed at all informative markers, indicating chromosome loss. In these cases, frequent events of LOH were observed on the other chromosomes. When confined events of LOH were observed on chromosome 17, fewer events of LOH were observed on the other chromosomes. In the absence of LOH on chromosome 17, LOH on other chromosomes was rare. K-ras activation was most commonly observed in tumors with no LOH events. Two endometrioid tumors and 2 mucinous tumors demonstrated MI. Our data support the involvement of different molecular pathways in the development of different types of ovarian tumors.

Purpose: To evaluate the feasibility and toxicity of 252Cf neutron brachytherapy combined with hyperaccelerated chemoradiotherapy for Stage III and IV cervical cancers. Methods and Materials: Eleven patients with advanced Stage IIIB-IVA cervical cancers were treated with 252 Cf neutron brachytherapy in an up-front schedule followed by cisplatin (CDDP; 50 mg/m 2 ) chemotherapy and hyperfractionated accelerated (1.2 Gy bid) radiotherapy given concurrently with intravenous infusion of 5-Fluorouracil (5-FU) (1000 mg/m 2 /day × 4 days) in weeks 1 and 4 with conventional radiation (weeks 2, 3, 5, and 6). Total dose at a paracervical point A isodose surface was 80–85 Gy-eq by external and intracavitary therapy and 60 Gy at the pelvic sidewalls. Results: Patients tolerated the protocol well. There was 91 % compliance with the chemotherapy and full compliance with the 252 Cf brachytherapy and the external beam radiotherapy. There were no problems with acute chemo or radiation toxicity. One patient developed a rectovaginal fistula (Grade 3–4 RTOG criteria) but no other patients developed significant late cystitis, proctitis or enteritis. There was complete response (CR) observed in all cases. With mean follow-up to 26 months, local control has been achieved with 90% actuarial 3-year survival with no evidence of disease (NED). Conclusion: 252 Cf neutrons can be combined with cisplatin and 5-FU infusion chemotherapy plus hyperaccelerated chemoradiotherapy without unusual side effects or toxicity and with a high local response and tumor control rate. Further study of 252 Cf neutron-chemoradiotherapy for advanced and bulky cervical cancer are indicated. We found chemotherapy was more effective with the improved local tumor control.

From 1987 to 1992, 3220 asymptomatic postmenopausal women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume > 10cm3 or (2) a papillary projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. If the repeat sonogram was abnormal, a morphology index score was assigned to each tumor, and a serum CA-125 was obtained. The patient then had a pelvic examination and an exploratory laparotomy. Forty-four patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy. Twenty-one patients had serous cystadenomas and 3 had primary ovarian cancers. Two patients with primary ovarian cancer had Stage IA disease and one had Stage IIIB disease. All patients with ovarian cancer had normal pelvic examinations and normal serum CA-125 levels, and are presently alive and well 32, 31, and 8 months after conventional therapy. Over 5000 screening years have been accumulated at this institution, and there have been no ovarian cancer deaths in the screened population. TVS screening has produced a decrease in stage at detection and case-specific mortality from ovarian cancer. A multi-institutional trial to test the efficacy of TVS as a screening method for ovarian cancer is indicated.

A morphology index based on morphologic characteristics of ovarian tumors was developed. Specific categories included tumor volume, wall structure, and septal structure. A point scale (0-4) was developed within each category with the total points per evaluation varying from 0-12. Sonograms on 121 patients undergoing exploratory laparotomy for ovarian masses were evaluated using this index. Eighty ovarian tumors had a morphology index score5, and all were benign (negative predictive value, 1.000). In postmenopausal patients, a morphology index scoreor = 5 had a positive predictive value for malignancy of 0.45. All ovarian malignancies had significant abnormalities in wall structure and all had a total volume in excess of 10 cm3. The findings of the present investigation indicate that the morphology index is a cost effective adjuvant method which significantly increases the specificity and positive predictive value of transvaginal sonography. The routine application of a morphology index to screening sonography should decrease the amount of diagnostic surgery performed in order to detect each case of ovarian cancer.

The ability of 111 In-CYT-103 immunoscintigraphy to aid in the diagnosis of patients with primary or recurrent/residual ovarian cancer was evaluated in a multicenter trial. The 111 In-labeled immunoconjugate of the monoclonal antibody B72.3 was prepared using a site-specific conjugation method. A total of 103 patients received a 1 mg infusion of 111 In-CYT-103 and subsequently underwent surgery or biopsy. The infusion of 111 In-CYT-103 was well tolerated; only 1 patient experienced a modest elevation in blood pressure that was likely related to the infusion. 111 In-CYT 103 immunoscintigraphy correctly identified surgically confirmed tumor in 68% of patients with ovarian adenocarcinoma. The sensitivity of 111 In-CYT-103 immunoscintigraphy was positively influenced both by the size of the tumor lesion and the tumor TAG-72 antigen expression. The overall sensitivity of 111 In-CYT- 103 immunoscintigraphy was greater than that of CT imaging (44%). Antibody imaging detected occult disease in 20 of 71 patients with surgically documented ovarian adenocarcinoma; 6 patients being evaluated after initial surgery and chemotherapy had an otherwise negative presurgical workup and a normal CA 125 serum level. The results of this trial also indicate that 111 In-CYT-103 immunoscintigraphy can contribute to the medical and surgical management of some patients with ovarian cancer. The results of this trial indicate that 111 In-CYT-103 immunoscintigraphy should be a valuable addition to the presurgical evaluation of patients with suspected persistent or recurrent ovarian cancer.

Twenty-three patients with metastatic or recurrent Stage III or IV epithelial ovarian cancer who were refractory to or relapsed following previous chemotherapy with cisplatin or a cisplatin analog were entered into a phase II study of amonafide. The starting dose of amonafide was 300 mg/m2 delivered daily over 1 hr by intravenous infusion. In the absence of myelosuppression, the dose of amonafide was escalated by increments of 75 mg/m2 to a maximum of 450 mg/m2. There were 19 eligible and 17 fully evaluable patients. Grade 3 or 4 leukopenia occurred in 14 (74%) patients and grade 3 or 4 thrombocytopenia in 6 (32%) patients. No objective complete or partial responses were observed. Four patients had stable disease for 3, 4, 4.5, and 6 months, respectively. Therefore, amonafide in the doses used in the present trial does not have significant activity in previously treated patients with ovarian cancer.

16522 Background: A test to identify the most effective therapy for an individual patient (pt) has the potential to improve outcome and minimize toxicity from ineffective treatment. We evaluated th...

5540 Background: We hypothesized that polymorphisms in excision repair cross-complementation group 1 (ERCC1), involved in nucleotide excision repair (NER) of platinum-induced damage, would be assoc...

Karyotypic analysis of tumor specimens from 29 patients with untreated epithelial ovarian carcinoma was performed at the University of Kentucky Medical Center. Twenty-three of the twenty-nine tumors had adequate cells for analysis. Seventeen of these tumors exhibited chromosome abnormalities. Chromosome alterations were complex, with an average of seven different abnormal chromosomal patterns per tumor (range 2–14). Chromosomes 1 and 11 were the most commonly involved, being abnormal in 89 and 83% of tumors, respectively. Chromosomes 3 and 7 were also frequently abnormal. In contrast to invasive tumors, alterations in chromosomes 1 and 11 were not seen in the two tumors of borderline malignant potential. Evidence for DNA amplification of IGF2, Ha- ras -1, and c- ets was not observed. Amplification of the c- erb B-2 oncogene was present in two tumors. These findings indicate that multiple karyotypic abnormalities occur in untreated epithelial ovarian malignancies, with chromosomes 1 and 11 being the most frequently abnormal. These data also suggest that alterations of these chromosomes may be associated with the biologically aggressive behavior of frankly invasive ovarian tumors.

21050 Background: The association between polymorphisms in the excision nuclease ERCC1 and progression-free survival (PFS) or overall survival (OS) was examined in women with epithelial ovarian cancer (EOC) treated with cisplatin and paclitaxel. Methods: Women who were evaluable for the phase III trial, GOG-172, with sufficient leukocyte DNA for testing were eligible for this study. Participants were randomized to intraperitoneal (IP) or intravenous (IV) cisplatin and paclitaxel. Single nucleotide polymorphism (SNP) analysis was carried out by direct pyrosequencing. Results: Among the 233 eligible cases, the genotype distribution at codon 118 was 17% with C/C, 43% with C/T and 40% with T/T and at C8092A was 56% with C/C, 37% with C/A and 7% with A/A. Adjusted Cox regression analysis revealed that the codon 118 polymorphism was not significantly associated with disease progression or death, but women with the C/A or A/A genotype compared with the C/C genotype at C8092A had an increased risk of disease progression (hazard ratio [HR]=1.48, 95% confidence interval [CI]=1.09–2.00, p=0.011) and death (HR=1.46, 95% CI=1.04–2.04, p=0.029). Subset analysis stratified by treatment suggested that the C8092A polymorphism was significantly associated with increased risk of PFS and OS in the IP but not the IV arm. Conclusions: Although the ERCC1 codon 118 polymorphism does not appear to be associated with clinical outcome, the C8092A polymorphism in ERCC1 was an independent predictor of PFS and OS in optimally-resected EOC treated with cisplatin- paclitaxel chemotherapy. The preferential clinical utility of the C8092A polymorphism in the IP but not the IV arm requires validation. No significant financial relationships to disclose.

20073 Background: Multiple chemotherapy options exist for the treatment of primary breast cancer. While response rates are good, many patients are treated with unnecessary or ineffective chemotherapy. Inadequate treatments are partly due to the lack of accurate predictors of response in individual patients. To predict an individual’s response to therapy, ex vivo chemosensitivity and resistance assays (CSRAs) have long been evaluated, but have been limited by technical difficulties, including the need for large (1–2 gm) amounts of fresh tissue. However, these problems have largely been overcome with new technology. Novel methods used in Precision Therapeutics’ ChemoFx assay allow for testing smaller amounts of tissue (35 mg). The reduced tissue requirement is crucial in the breast cancer setting, as the diagnosis is often made by percutaneous biopsy. The goals of the study were to determine the growth success rate of culturing epithelial cells from breast tissue core needle biopsies and the feasibility of testing the cells in the assay. Methods: A prospective feasibility study involving women with invasive primary breast cancer. One to four core needle biopsy specimens were collected using a 14 gauge needle (est. per patient yield [Table: see text]

5134 Background: Carboplatin is the mainstay of primary ovarian cancer and is often used in recurrent ovarian cancer. The ability to identify tumors that will respond to this drug prior to selectio...

5059 Background: Only a subset of patients responds to a given chemotherapeutic regimen. The purpose of this analysis was to determine whether tumors are generally sensitive or resistant regardless...

5074 Background: Advanced ovarian cancer remains without chemotherapeutic cure. Numerous regimens can achieve clinical responses, but each only in a subset of women. The challenge is to predict whi...