BRCA: the breast, ovarian, and other cancer genes.
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BRCA2 Protein↗
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A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan.
BACKGROUND: DX-8951f is a water-soluble camptothecin derivative with greater in vivo and in vitro activity than topotecan or irinotecan. The objectives of this phase II study were to determine the antitumor activity, safety and pharmacokinetic profile of DX-8951f administered intravenously for five consecutive days, every 3 weeks in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. METHODS: Enrolled in the study at The University of Texas M. D. Anderson Cancer Center were 16 patients with measurable cancer resistant to platinum, taxane and topotecan. All 16 patients were assessable for safety and 15 for efficacy analyses. Treatment consisted of a daily infusion of DX-8951f at 0.3 mg/m(2) per day (except for one minimally pretreated patient who started at 0.5 mg/m(2) per day) over 30 min for five consecutive days every 3 weeks. The pharmacokinetic and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Disease was stable in 7 of 16 patients (44%) (4 minor response and 3 stable disease). The median time to tumor progression was 43 days (95% CI 37-92 days). The median overall survival was 117 days (95% CI 90-279 days). The main toxic effect was neutropenia and leukopenia with 50% of patients experiencing grade 3 or 4 neutropenia and leukopenia. One episode of neutropenic fever was observed. Grade 3 or more anemia and thrombocytopenia were seen in 25% and 13% of patients, respectively. Grade 3 nonhematologic side effects included nausea (25% of patients) and fatigue (19%). Other side effects were not more than grade 2, and included gastrointestinal dysfunction, stomatitis, dermatitis, alopecia, liver dysfunction and drug fever. DX-8951 displayed linear pharmacokinetic characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were 2.1 l/h per m(2), 20 l/m(2) and 9.5 h, respectively. CONCLUSIONS: DX-8951f administered parenterally as a single agent daily at a dose of either 0.5 or 0.3 mg/m(2) per day for 5 days is feasible in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Although no responses were observed, a significant number of patients had stable disease with a decrease in CA-125 levels. In this heavily pretreated population, DX-8951f has clinically relevant hematologic and gastrointestinal toxicities in about 25% of patients. DX-8951 appeared to have linear pharmacokinetic characteristics on the basis of multiple administrations.
Adult↗
Society of Gynecologic Oncologists Clinical Practice Committee Statement on Prophylactic Salpingo-oophorectomy.
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Breast Neoplasms↗
Phase II trial of imatinib mesylate in patients with recurrent platinum- and taxane-resistant epithelial ovarian and primary peritoneal cancers.
OBJECTIVES: To evaluate the efficacy and tolerability of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) in patients with recurrent ovarian and primary peritoneal cancer. METHODS: This was an open-label, single-institution phase II trial. Patients were eligible if they had measurable platinum/taxane-resistant disease, received 2-4 prior treatment regimens, and over-expressed at least one imatinib target (c-Kit, PDGFR-beta, or c-Abl) by immunohistochemistry. Imatinib was administered orally at 600 mg daily for 6 weeks (one course) and was repeated in the absence of measurable progression. RESULTS: Sixteen enrolled patients were evaluable for toxicity and 12 for response. The median number of prior treatments was 4. A total of 29 courses were initiated. No complete or partial responses were documented during a median follow-up of 6.6 months. However, 4 (33%) of the 12 evaluable patients had stable disease lasting 3.8, 6.4, 7.5, and 8+ months. Expression of PDGFR-beta and c-Abl was seen in 15 (94%) and c-Kit in 8 (50%) patients' tumors. There was no relationship between best response (stable disease) and target expression. Adverse events were uncommon, with fatigue and nausea/vomiting being reported in 34% and 31% of cycles, respectively. Two patients underwent dose reduction for rash and edema (n = 1) and grade 3 neutropenia (n = 1). No grade 4 toxicity was observed. CONCLUSION: Imatinib mesylate was well tolerated but did not produce clinical responses in patients with previously treated metastatic ovarian and primary peritoneal carcinoma.
Aged↗
Detection of non-maternal components of gestational choriocarcinoma by PCR-based microsatellite DNA assay.
OBJECTIVE: Gestational and non-gestational choriocarcinomas have distinctly different tissues of origin, parental genotypes, natural histories, and responses to therapy. Our objective was to develop a convenient, fast, and reliable assay that would, using only patient tissue, allow separation of gestational from non-gestational choriocarcinomas. METHOD: Benign and malignant tissues, preserved in paraffin blocks and separated by microdissection, were examined using a commercial PCR-based tissue identity assay (ABI AmpFlSTR Profiler Plus Kit and ABI 377 DNA sequencer) to detect genetic profiles of 9 microsatellite markers, along with X and Y chromosome markers. Cases included 6 choriocarcinomas. Controls included eight non-germ cell reproductive tract tumors and two hydatidiform moles. RESULTS: The microsatellite markers identified the five choriocarcinomas diagnosed on clinical and histological grounds as gestational, to be of genetically non-maternal (androgenic) origin. The neoplasm previously classified as a non-gestational choriocarcinoma was demonstrated to be of maternal origin, as were the non-germ cell reproductive tract tumors. Samples from hydatidiform moles contained either androgenic markers only or a mix of maternal and androgenic markers, as previously seen in complete and partial moles, respectively. CONCLUSION: A commercially available microsatellite DNA diagnostic assay is a quick and convenient way to discriminate between gestational and non-gestational choriocarcinoma.
Alleles↗
The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer.
OBJECTIVE: The clinical significance and optimal management of patients with stage IIIA endometrial cancer are controversial. We sought to determine whether recurrence and survival of patients with stage IIIA endometrial cancer differ with surgical pathologic findings (positive peritoneal cytology versus positive adnexae or serosa) and adjuvant treatment. METHODS: Retrospective single institution analysis of patients surgically staged for IIIA endometrial cancer at Duke University Medical Center from 1973 to 2002. Stage IIIA patients were stratified into positive cytology alone (group IIIA1, n=37) and positive adnexae or uterine serosa (group IIIA2, n=20). Comparison was made with previously reported group of 467 patients with surgical stage I/II disease. Recurrence and survival were analyzed using Kaplan-Meier estimations and Cox proportional hazards model. RESULTS: Mean age of 57 patients with stage IIIA endometrial cancer was 63. Adjuvant therapies were administered to 89% patients (74% radiotherapy, 4% chemotherapy, 19% progestins). Five-year overall (OS) and recurrence-free disease-specific survival (RFDSS) were 64% and 76%, respectively. Survival was similar comparing IIIA1 (62%) and IIIA2 (68%, p=0.999). RFDSS by adjuvant therapy was: external beam radiotherapy 89% (n=10), intraperitoneal P32 84% (n=21), progestins 78% (n=9), none 75% (n=6). 61% recurrences included extrapelvic component. In multivariable analysis of stage I-IIIA patients (n=517), positive cytology but not adnexal/serosal metastasis was predictive of death (HR 1.70, 95% CI 1.06-2.73) and disease recurrence (HR 1.70, 95% CI 1.07-2.71). CONCLUSION: Among patients with stage IIIA endometrial cancer, metastasis to adnexae or serosa does not appear to confer worse prognosis than positive cytology alone. Positive cytology is an independent predictor of prognosis among patients with stage I-IIIA endometrial cancer. While optimal adjuvant therapy for these groups remains unclear, recurrence patterns suggest that systemic therapies are appropriate.
Adnexa Uteri↗
Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer.
OBJECTIVE: Docetaxel and carboplatin are active in relapsed ovarian, peritoneal and tubal cancer. Recently, two prospective-randomized trials showed an advantage of carboplatin combination regimen with paclitaxel or gemcitabine over carboplatinum alone in platinum-sensitive cases. The question on the most effective combination with the best tolerable side effects still needs to be answered. METHODS: Eligible patients had recurrent ovarian, peritoneal or tubal cancer (platinum-free interval >6 months), performance status 0-2 and normal bone marrow, renal and hepatic function. 25 patients (age 18-75 years) were enrolled into this phase II trial. Patients with debulking operation of recurrence were excluded from this study. Docetaxel 75 mg/m(2) via 30-min infusion was given on day 1 followed by carboplatin (area under curve [AUC] 5) on day 1. The administration was repeated every 3 weeks over 6 courses. Primary endpoint of this trial was the response rate; secondary endpoints were progression-free survival, overall survival and toxicity. RESULTS: In the intent-to-treat population, there were 16 (64.0%) complete and 2 (8.0%) partial responses resulting in an overall response rate of 72.0%. Three patients (12.0%) showed a stable disease and other 2 patients (8.0%) a progression of cancer. Two patients (8.0%) were not evaluable for response. Neutropenia was the most frequent G3/G4 hematologic toxicity in 15/25 patients (60.0%); but no neutropenic fever occurred in this trial. Diarrhea G3 was the most frequent G3/G4 non-hematologic toxicity in only 3/25 patients (12.0%). Dose-limiting toxicities were hypersensitivity reaction in one and depressive mood alteration requiring therapy in another case. CONCLUSION: Carboplatin in combination with docetaxel is highly active and well tolerated in patients with recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Prospective-randomized trials comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer are a possible option for the future to answer the question on the best combination regimen.
Adult↗
Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas.
The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods.
Adenocarcinoma↗
Gemcitabine and cisplatin chemotherapy is an active combination in the treatment of platinum-resistant ovarian and peritoneal carcinoma.
The treatment of recurrent ovarian cancer with the combination of gemcitabine and cisplatin chemotherapy has recently been shown to be an active regimen. But the majority of positive responses have been observed in patients considered either platinum-sensitive or who have had extended platinum-free intervals. The purpose of our study was to review our experience with this regimen in women with platinum-resistant ovarian and peritoneal carcinoma with more recent exposure to platinum. We studied twenty-two patients who had relapsed within six months of their most recent platinum-based regimen and were treated with gemcitabine (450-600 mg/m(2)) and cisplatin (30 mg/m(2)) on days 1 and 8 of a 21-day cycle. The overall response rate was 64% (95% C.I. 42-85%) with seven (32%) complete and seven (32%) partial responses. The median progression-free interval was 6.7 months for responding patients and 3.9 months for the entire study group. Median survival for responders was 15.8 months compared to 8.8 months for non-responders. Overall survival was 11.4 months. Grade 3 or 4 toxicity was encountered in 59% of treatments. We conclude from this limited review that the combination of gemcitabine and cisplatin chemotherapy is an active regimen in platinum-resistant ovarian and peritoneal carcinoma and warrants consideration in the management of patients with recurrent disease.
Adult↗
Follicle center lymphoma involving the female genital tract: a morphologic and molecular genetic study of three cases.
Primary female reproductive system lymphomas are distinctly uncommon, and are defined as lymphomas that present primarily as gynecologic tumors. We describe 3 cases which presented in this location, 1 primary ovarian disease and 2 others presenting the initial manifestations of disseminated lymphoma. Clinical history, follow-up information, and paraffin embedded archival tissue were available for all 3 cases. A panel of immunoperoxidase studies and molecular genetic studies were performed for each case. The primary ovarian follicle center lymphoma was a grade III/III (large cell) while the cases representing secondary involvement were grade I/III (small cell). Immunohistochemistry demonstrated reactivity of the malignant cells in each case with CD20 and bcl-2. In the grade I/III cases the cells were immunoreactive for CD45RA and CD10. Molecular genetic analysis demonstrated the t(14;18) translocation in the case of primary ovarian follicle center lymphoma. Follicle center lymphoma uncommonly presents in the female genital system, and may rarely be primary to this site. Immunoperoxidase and molecular studies in concert with the morphology are invaluable in rendering a correct diagnosis and ensuring correct treatment of the patient.
Aged↗
[Multiple cancers in gynecologic oncology].
An analysis of 97 patients with multiple primary gynaecological neoplasms (90 double-, 6 triple- and 1 quadruple carcinomas) was done at the Gynaecological Department of the University of Innsbruck. Two thirds of the tumour combinations were located in the female genital tract including the breast. Concerning the early detection of simultaneous or subsequent malignancies of the cervix or corpus uteri, one should pay attention to the mamma being involved in the treatment or aftercare of such cancers. In the same way the inner female genital tract has to be observed in breast cancer patients. Regular colposcopic and cytological examinations of the cervical portio as well as a systematic prevention of endometrial cancer (pistolet in local anaesthesia) is highly recommended. The prognosis of the "highly malignant" tumour does not worsen as a result of a second malignant cancer.
Breast Neoplasms↗
Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin.
Five cases of cervical squamous cell carcinoma with synchronous superficial squamous cell carcinoma in the upper genital tract were genetically analyzed to demonstrate the possibility of a clonal neoplastic process. In these cases, the cervical lesions were squamous cell carcinoma in situ (cases 1, 2, and 3) and invasive squamous cell carcinoma (cases 4 and 5). Loss of heterozygosity (LOH) analyses with a panel of microsatellite markers revealed a monoclonal process in four of the five cases. Homogeneous LOH throughout the microdissected lesions was most frequently detected on 6p and 6q (3 cases), followed by 11p and 11q (2 cases), loci known to be commonly lost in typical cervical squamous cell carcinoma. In two cases, genetic progression in terms of additional LOH was found in the upper genital tract but not in the cervix. Most of these squamous cell carcinomas were monoclonal neoplasms originating from the cervical mucosa with subsequent superficial migration of the tumor clone to the upper genital mucosa, and in some cases, genetic progression.
Aged↗
Women harboring BRCA1/2 germline mutations are at risk for breast and female adnexal carcinoma.
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Breast Neoplasms↗
Origin of adenocarcinoma cells observed on cervical cytology.
OBJECTIVE: To clarify the ratio of diseases suspected when malignant glandular cells are observed on cervical cytology. STUDY DESIGN: Seventy cases of cervical adenocarcinoma/adenosquamous carcinoma, 207 cases of endometrial adenocarcinoma, 7 cases of tubal adenocarcinoma and 83 cases of ovarian adenocarcinoma were reviewed. The positive rate in cervical cytology performed 3 months before surgery was calculated. Based on the positive rate for each entity and the number of cases treated in the previous 10 years, we estimated the incidence of disease responsible for malignant glandular cells on cytology. RESULTS: The positive rate was 93% in cervical adenocarcinoma/adenosquamous carcinoma, 45% in endometrial adenocarcinoma, 14% in tubal adenocarcinoma and 6% in ovarian adenocarcinoma. These positive rates and case numbers at our institute indicated the percentage of suspicious diseases to be 38% for cervical aaenocarcinoma/adenosquamous carcinoma, 53% for endometrial adenocarcinoma, 1% for tubal adenocarcinoma and 8% for ovarian adenocarcinoma. CONCLUSION: When a cytologic specimen suggested the existence of adenocarcinoma, the most probable disease was endometrial adenocarcinoma, and the second was cervical adenocarcinoma/adenosquamous carcinoma. Adnexal malignancies were responsible in 9% of cases. In the case of positive cervical cytology suggesting adenocarcinoma, the ratio of suspicious diseases is as valuable as the cytologic findings for the differential diagnosis.
Adenocarcinoma↗
Extrauterine malignancies. Role of Pap smears in diagnosis and management.
OBJECTIVE: To further elucidate the cytologic manifestations of extrauterine malignancies, to evaluate their possible distinction from primary cervical malignancies and to analyze their clinical significance and role in staging. STUDY DESIGN: Papanicolaou (Pap) smears in 33 cases with abnormal cells originating in histologically proven extrauterine carcinomas were evaluated. These cases came from the files of the Medical College of Pennsylvania and Lankenau Hospitals. RESULTS: Ovary, gastrointestinal tract and breast were the three most frequent primary sites, accounting for 28 of the 33 cases (85%). The histologic types encountered were adenocarcinoma, 29 cases (88%); mucoepidermoid carcinoma, 1 (3%); small cell carcinoma, 1 (3%); cloacogenic carcinoma and large cell lymphoma, 1 (3%). The following diagnoses were rendered at the time of initial evaluation: adenocarcinoma consistent with metastasis, 21 cases; carcinoma, primary versus metastatic, 2; adenocarcinoma, suspicious for endometrial primary, 2; suspicious for carcinoma, 1; and atypical glandular cells, 7. CONCLUSION: The yield for positive Pap smear diagnoses in extrauterine malignancies is best in patients with an established diagnosis of a primary neoplasm. The degree of tumor differentiation and extent of tumor involvement did not appear to correlate with diagnostic yield. There appeared to be no statistically significant association of tumor diathesis with primary versus metastatic carcinoma and presence or absence of documented local involvement of the endometrium, cervix or vagina. Therefore, while Pap smears can serve as a diagnostic tool in the evaluation of extrauterine malignancies, they are best utilized as an adjunct to tumor staging and patient management.
Adenocarcinoma↗
Nonovarian pelvic cancers in BRCA1/2 mutation carriers and the BRCAPRO statistical model.
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BRCA1 Protein↗
FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology.
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Ascites↗
CD34 immunohistochemistry in female genital tract carcinosarcoma (malignant mixed müllerian tumors) supports a dominant role of the carcinomatous component.
Female genital carcinosarcomas (FGTCSs) are aggressive biphasic malignant neoplasms with histologic features of both carcinomas and sarcomas. However, their behavior is dominated by the carcinomatous component. CD34 is useful in distinguishing carcinomas with sarcomatoid features from epithelioid sarcomas, as it is never expressed in carcinomas although often expressed in epithelioid sarcomas. This investigation hypothesizes that CD34 expression in FGTCSs will contribute useful histogenetic and clinical information. Paraffin sections from a surgical series of 43 FGTCSs were stained using anti-CD34 with an automated immunohistochemical stainer, antigen retrieval, and appropriate external/internal controls. Reactions were graded as follows: negative (N) or S1-3, strong reactivity in <10% = S1, 10-50% = S2, or >50% = S3 of cells, respectively. The series included 31 endometrial, 6 ovarian, 5 cervical, and 1 fallopian tubal FGTCSs, 70% exhibiting heterologous elements (22 rhabdomyosarcomas, 11 chondrosarcomas, 1 osteosarcoma, and 1 liposarcoma). The carcinomatous component included 19 endometrioid, 12 serous, 6 adenosquamous, 4 clear cell, and 2 poorly differentiated carcinomas: modified International Federation of Gynecologic Oncology grade I, 9%; II, 21%; and III, 70%. CD34 reactivity was 100% N in the carcinomatous components. CD 34 stained 21 % of sarcomatous components as follows: 2S1, 6S2, and 1S3 (three homologous and six heterologous). Of the heterologous components, only rhabdomyosarcoma stained with the following patterns: 1S1, 2S2, 1S3. Two of six heterologous FGTCSs exhibited staining of only the homologous sarcomatous component with the following pattern: 2S2, as the heterologous sarcomatous component (pure rhabdomyosarcoma in both cases) showed no staining. The staining pattern was unrelated to primary site of the FGTCSs. The pattern of CD34 expression (N in the carcinomatous component like carcinomas) supports the generally accepted opinion of dominance of FGTCS by the carcinomatous component. The staining of the sarcomatous component was rare (21%) and focal (only one of nine was S3). CD34 staining may help distinguish FGTCSs from epithelioid sarcomas, which strongly express CD34.
Aged↗